366. Anesthetic loss to the plastic and rubber components of the anesthetic circuit hindering achievement of an adequate inspired concentration is a factor with which of the following anesthetics?

 A. Desflurane B. Nitrous oxide C. Sevoflurane D. Isoflurane E. All of the above

(D) Anesthetic agents are soluble in the rubber and plastic components found in the anesthesia machine. This fact

can impede the development of anesthetic concentrations of these drugs. The worst offender is the obsolete

volatile methoxyflurane. However, both isoflurane and halothane are soluble in rubber and plastic, but to a lesser

degree. Sevoflurane, desflurane, and nitrous oxide have little or no solubility in rubber or plastic. A different but

important issue should be borne in mind regarding loss of sevoflurane. This agent can be destroyed in appreciable

quantities by Baralyme and soda lime, but not calcium hydroxide lime (Amsorb). It is therefore recommended

that fresh-gas flow rates exceed 2 L/min when sevoflurane is administered

365. If the alveolar to venous partial pressure difference of a volatile anesthetic (Pa-Pv) is positive (i.e., Pa > Pv) and the arterial to venous partial pressure difference (Pa-Pv) is negative (i.e., Pv > Pa) which of the following scenarios is most likely to be true? A. The vaporizer has been shut off at the end of the case B. Induction has just started C. Steady state has been achieved D. The volatile anesthetic has been turned down from steady state, but not off E. The vaporizer was shut off during emergence, then suddenly turned up because the patient moved before closure of the incision The delivery of anesthetic gases to a patient is a complex series of events that starts with the anesthesia machineand culminates with achievement of an anesthetic partial pressure in the brain (PBr).The partial pressure measured in the blood for any volatile is either rising (at first rapidly, then more slowly) or falling (rapidly at first then more slowly). The vessel-rich group reaches steady state in about 12 minutes (for any dialed level of volatile). The rest of the body, however, approaches, but virtually never reaches, equilibrium (e.g. the equilibrium half time for the fat group is 30 hours for sevoflurane). Hence, a true zero gradient is never achieved in the steady state. When the anesthetic is discontinued or reduced, there is a fall in the arterial partial pressure such that it is less than the venous partial pressure. In fact, when the venous partial pressure exceeds the arterial partial pressure it means the volatile has been reduced (or shut off) because the lungs are “cleansing” the blood as the volatile filled blood passes through them. The newly “cleansed” blood then finds it way to the left ventricle with a very low Pa for the volatile in question. The present example can only be explained if the volatile had just been turned off or down (lungs cleansing) then suddenly turned back up. In this brief “window” the alveolar partial pressure gradient would exceed the venous partial pressure because there is a net transfer of anesthetic into the blood exiting the lungs (pulmonary vein). Since this just happened (turned up), the body has not had sufficient time to reverse the gradient in the left sided arterial and venous system. Moments later, the left sided arterial volatile partial pressure will exceed the venous partial pressure and the patient will become “deeper” 

Myocyte Contraction and Relaxation. 

At rest, crossbridge

cycling and generation of force do not occur

because either the myosin heads are blocked from physically

reacting with the thin filament or they are only

weakly bound to actin (Fig. 20-14).16 Cross-bridge cycling

is initiated on binding of Ca2+ to TnC, which increases

TnC-TnI interaction and decreases the inhibitory TnIactin

interaction. 

These events, which ensue from the

binding of Ca2+ to TnC, lead to conformational changes in

tropomyosin and permit attachment of the myosin head

to actin. Cross-bridging involves the detachment of the

myosin head from actin and a reattachment of myosin

to another actin on hydrolysis of ATP by myosin ATPase.

Binding of ATP to the nucleotide pocket of the myosin

head leads to the activation of myosin ATPase,31-33 ATP

hydrolysis, and changes in the configuration of the myosin

head, all of which facilitate binding of the myosin

head to actin and the generation of the power stroke of

the myosin head. Based on this model, the rate of crossbridge

cycling is dependent on the activity of myosin

ATPase.36 Turnoff of cross-bridge cycling is largely initiated

by the decrease in cytosolic Ca2+.

ACUTE RESPIRATORY FAILURE
ICUs were first developed to manage patients with acute
respiratory failure as a result of poliomyelitis. Since then,
management of patients with acute respiratory failure
has been revolutionized by the development of modern
mechanical ventilators. Ashbaugh and associates first
reported ARDS in 1967.76 They described 12 patients with
acute respiratory distress, cyanosis refractory to oxygen
therapy, decreased lung compliance, and diffuse bilateral
infiltrates on chest radiography. Because this initial
definition lacked specific criteria that could be used to
identify patients for research, the American-European
Consensus Conference Committee recommended new
definitions in 1994.77
Although critical for providing a framework for the
ARDS network (ARDSnet) and other studies, it was recognized
that the American-European consensus definitions
had significant limitations as a result of the variability in
the PaO2/FiO2 ratio with ventilator settings, poor reliability
of chest radiographic criteria, and difficulties distinguishing
hydrostatic edema. Therefore, a new consensus
conference was convened to update the definitions, and
the Berlin Definition of ARDS was formed.78 Table 101-2
compares the two lists of criteria used to define acute lung
injury (ALI) and ARDS.
Treatment of ALI or ARDS is primarily supportive and
consists of mechanical ventilation, which allows time for
treatment of the underlying cause of the lung injury and
for natural healing.79 Until recently, most studies of ALI
or ARDS reported a mortality rate of 40% to 60%, with
death attributed to sepsis or multiorgan failure rather
than the primary respiratory causes.80,81
Several clinical trials have addressed one of the hallmarks
of ALI or ARDS—decreased lung compliance. The
National Institutes of Health (NIH) ARDSnet reported the
definitive study on protective mechanical ventilation in
2000.38 In this prospective study of patients with ALI, the
mortality rate was reduced from 40% in patients receiving
tidal volume ventilation of 12 mL/kg to 31% in those
receiving 6 mL/kg. The low–tidal volume group also had
more ventilator-free and organ failure–free days than did
the higher–tidal volume group. Several reasons have been
postulated for the discrepancy between this study and
the previous inconclusive studies. First, the NIH study
may have been better able to show a difference because it
used lower tidal volumes than used in the other studies.
Second, the NIH study allowed treatment of respiratory
acidosis with high respiratory rates or with sodium bicarbonate.
Treatment of respiratory acidosis may have prevented
deleterious effects. Third, the NIH study enrolled
861 patients, which was by far the largest study and
increased the statistical power to find a positive effect of
low–tidal volume ventilation.82
In a second study using the same patient database, Eisner
and associates83 did not find any evidence that the
to the clinical cause of ARDS. Although the mortality rate
was highest (43%) in patients with sepsis, intermediate
(36%) in patients with pneumonia and aspiration pneumonitis,
and lowest (11%) in patients with trauma, no
evidence of differential efficacy of low–tidal volume ventilation
was found in different groups with ALI or ARDS.
The investigators concluded that the recommendations
for low–tidal volume ventilation should be applied to
all patients with ALI or ARDS, regardless of the inciting
cause.
Important advances in the ventilatory management
of patients with ALI or ARDS have led to improvements
in the care of patients in the ICU. With the impressive
9% absolute reduction in mortality demonstrated by the
ARDSnet trial, low–tidal volume mechanical ventilation
should be considered the standard of care for patients
with ALI or ARDS unless a more efficacious strategy is
demonstrated. Figure 101-2 shows the protocol used at
the University of California, San Francisco, for mechanical
ventilation of patients with ALI or ARDS. An unanswered
question remains regarding whether patients
without ARDS should be managed with a lung-protective
strategy. A recent meta-analysis showed that in patients
without lung injury, low tidal volume was associated with
less progression to lung injury and lower mortality.84
Nontraditional Ventilatory Interventions
In addition to low tidal volume, other therapies have
been used for the care of patients with ALI. Most have
tried to improve the ventilation-perfusion (V˙ /Q˙ ) mismatching
and hypoxemia that result from ALI. The following
sections discuss data associated with high PEEP,
recruitment maneuvers, prone positioning, inhaled nitric
oxide (iNO), neuromuscular blocking agents, and early
tracheostomy.
High Positive End-Expiratory Pressure. The use of
PEEP has been proposed as a mechanism to minimize
cyclical alveolar collapse and shear injury (atelectrauma).
Brower and coworkers (Assessment of Low–Tidal Volume

and increased End-Expiratory Volume to Obviate Lung

Glycemic Control in the Critically Ill
Critically ill patients admitted to the ICU with severe injury
or infection, such as burns, trauma, or sepsis, commonly
enter into a hypermetabolic state (see also Chapter 39).
This state is associated with enhanced peripheral glucose
uptake and use,47 hyperlactatemia,48 increased glucose
production,49 depressed glycogenesis,50 and insulin resistance.
49 Glucose intolerance develops after uptake of
glucose in skeletal muscle, adipose tissue, and liver, and
the heart becomes saturated,51 and hyperglycemia occurs
because of defective suppression of gluconeogenesis and
a resistance to the peripheral action of insulin. These
mechanisms all work to generate a hyperglycemic state to
satisfy an obligatory requirement for glucose as an energy
substrate. The intensity of the metabolic response peaks
several days after the initial insult and then diminishes as
the patient recovers.48 However, a prolonged hyperglycemic
response may occur in patients who continue to have
tissue hypoperfusion or persistent infection, which then
predisposes them to progressive metabolic derangements
and multisystem organ failure.
Traditionally, hyperglycemia, secondary to sepsis, was
viewed as a beneficial response because it promoted cellular
glucose uptake when cells were energy deprived.
A glucose concentration of 160 to 200 mg/dL was commonly
recommended and believed to maximize cellular
glucose uptake without causing hyperosmolarity.52 However,
neutrophil function is impaired in patients with
hyperglycemia because of decreased bacterial phagocytosis,
53 and many studies report the negative effects of
high blood sugar. Hyperglycemia in diabetic patients is
associated with an increased rate of postoperative infections,
54 and decreased long-term outcomes after myocardial
infarction.55 Hyperglycemia is also associated with
a poorer prognosis after stroke or head injury56 (see also
Chapter 70).
Van den Berghe and coworkers57 hypothesized that
even mild hyperglycemia (i.e., blood glucose levels
between 110 and 200 mg/dL) could be harmful by predisposing
critically ill patients to increased morbidity
and mortality. They performed a prospective, controlled
study involving 1548 patients in the surgical ICU who
were randomized to receive intensive insulin therapy (i.e.,
blood glucose maintained between 80 and 110 mg/dL) or
conventional treatment (i.e., blood glucose maintained
between 180 and 200 mg/dL). In patients who remained
in the ICU for longer than 5 days, intensive insulin therapy
reduced the mortality rate from 20.2% with conventional
therapy to 10% with intensive therapy (P = 0.005).
The group receiving intensive insulin therapy also had a
lower incidence of bloodstream infections (4.2% versus
7.8%, P = 0.003), renal failure requiring dialysis (4.8% versus
8.2%, P = 0.007) and critical illness polyneuropathy
(28.7% versus 51.9%, P = 0.001). Patients in the intensive
insulin group were also less likely to require prolonged
mechanical ventilation and intensive care. The results of
this trial made a persuasive argument for tighter glucose
control, at least in patients in the surgical ICU.
Opponents of the use of strict glycemic control in critically
ill patients argued that the risks of hypoglycemia
should be seriously considered and that the therapeutic
effect of insulin rather than glycemic control leads to the
beneficial outcomes. Insulin has multiple effects, including
the inhibition of tumor necrosis factor alpha (TNF-
α),58 which triggers procoagulant activity and fibrin
deposition and inhibits macrophage inhibitory factor,
thereby contributing to endotoxemia and toxic shock.59
To determine whether it was insulin effect or glycemic
control, van den Berghe and colleagues60 used multivariate
analysis to reanalyze their previous data. It appeared
that decreasing blood glucose levels rather than the
actual amount of insulin given was more closely correlated
with the beneficial reductions in mortality, polyneuropathy,
and bloodstream infections. Instead of the
glucose level, the dose of insulin correlates with the
incidence of renal failure. Investigators thought that
this difference might be the result of the direct effect
of insulin on the kidney or the need for less exogenous
insulin in patients with renal failure because insulin is
cleared through the kidney. Finney and associates61 in
a prospective, observational study provided additional
evidence that glycemic control, rather than insulin
administration, provided the benefit. They examined the
effects of glucose control in 523 patients admitted to a
single surgical ICU. In this trial the primary determinant
of a bad outcome was hyperglycemia rather than hypoinsulinemia,
and a lower mortality rate was associated
with glycemic control rather than a protective effect of
insulin administration. Increased insulin dosing resulted
in an increased mortality rate across all ranges of glycemia.
With regression analysis, their data also suggest
that keeping blood glucose below 145 mg/dL may provide
a survival benefit similar to that achieved with the
tighter range of 80 to 110 mg/dL.
A major criticism of the original van den Berghe study
was that it was performed on relatively homogeneous
surgical populations. The same group then published a
follow-up study examining tight glucose control in 1200
patients in medical ICUs.62 The results showed reduced
morbidity defined as a reduction in newly acquired renal
injury, earlier weaning from mechanical ventilation, and
earlier discharge from the ICU and the hospital but no difference
in mortality. With subgroup analysis, they were
able to determine a mortality benefit from tight glucose
control if the patient was admitted to the ICU for 3 days
or longer (43% versus 52.5%, P = 0.009). From the study
design, it is unclear whether intensive insulin therapy for
less than 3 days causes harm or perhaps the benefit from
intensive insulin therapy requires time to be realized.
Since then, several multicentered randomized controlled
studies have examined the risk-benefit ratio of tight glucose
control.63-65 Two studies (Volume Substitution and Insulin
Therapy in Severe Sepsis [VISEP] and Glucontrol) were
stopped early because of a high rate of hypoglycemia (17%
versus 4.1%, P < 0.001, and 8.7% versus 2.7%, P < 0.001,
respectively). The Normoglycemia in Intensive Care Evaluation
and Surviving Using Glucose Algorithm Regulation
(NICE-SUGAR) trial, the most recent and largest of the studies,
involved 42 ICUs and enrolled 6000 patients. The investigators
reported no difference between the two groups in
terms of days in the ICU, days on mechanical ventilation,
and days requiring renal replacement therapy. Disturbingly,
they found an increased incidence of hypoglycemia

Cortisol Replacement
With the recognition that severe sepsis represents a
state of overwhelming inflammation, corticosteroids
were among the first therapies tested in randomized trials
of patients with sepsis. At large doses and with short
courses, the studies showed a negative effect.40,41 Annane
and associates proposed a different hypothesis in 2002.42
Prompted by studies showing significantly improved
time to withdrawal of vasopressor therapy in patients
with sepsis who received small doses of hydrocortisone
over a longer period (>5 days),43,44 they administered lowdose
steroids for 7 days. Their results showed that among
patients who did not appropriately respond to the corticotropin
test, 63% in the placebo group versus 53% in the
corticosteroid group died (P = 0.02). Vasopressor therapy
was withdrawn in 40% of patients in the placebo group,
as opposed to 57% in the corticosteroid group (P = 0.001).
Despite this initial positive data, the administration of
steroids to patients with sepsis remained controversial. A
large randomized trial recapitulating the study of Annane
and coworkers has been completed and documents the
lack of efficacy of even low-dose steroids and the association
of increased infections with steroid administration.
The Corticosteroid Therapy of Septic Shock (CORTICUS)
study was carried out to assess whether low-dose corticosteroids
improve survival in patients with septic shock
and sepsis.45 A total of 499 patients were enrolled over
a period of 3 years from 52 European ICUs. Patients
received a tapering steroid regimen over an 11-day period
but no mineralocorticoids. The results refuted Annane’s
initial study. The 28-day mortality rate in patients receiving
low-dose steroids was not significantly improved from
that in the placebo group (34% versus 31%, P = 0.57). In
summary, although low-dose steroids with mineralocorticoids
initially appeared to be beneficial, the results have
not been reproducible in a large multicentered randomized
study. Large doses of corticosteroids should not be
used in patients with severe sepsis.
One issue raised by these investigations was the role of
etomidate in causing adrenal suppression. Patients who
received etomidate to facilitate endotracheal intubation
had worse outcomes, thus leading to suggestions that
etomidate not be used. Chan and associates conducted
a meta-analysis with five studies assessing mortality and
seven studies assessing adrenal insufficiency associated
with etomidate use in patients with severe sepsis and septic
shock.46 They found an increased pooled relative risk for
mortality of 1.20 (95% CI 1.02 to 1.42) and an increased
pooled relative risk (RR) for adrenal insufficiency of 1.33
(95% CI 1.22 to 1.46). Although the data are not conclusive,
the literature suggests that perhaps etomidate should
not be the first choice for use in patients with sepsis.

MANAGEMENT OF CRITICALLY
ILL PATIENTS
The following sections examine the care of patients with
some common diagnoses in critical care: sepsis, ARDS,
hepatic failure, and renal failure. Many management
plans have data supporting the use of protocol-based
therapy. Others are introductory management ideas that
may lead to integration into future protocols but are discussed
here because of their importance in critical care.
SEPSIS AND MULTISYSTEM ORGAN
FAILURE
Sepsis is the leading cause of death in critically ill patients
in the United States and develops in 750,000 people
annually.1 The economic costs of sepsis are large, with
annual expenditures totaling nearly $17 billion.1 The
high mortality rate and economic costs have led to considerable
interest in the development of effective therapies
for sepsis. As with other areas of medicine, adoption
plus integration of new treatment strategies into routine
clinical practice has been slow. After many years of unsuccessful
clinical trials, randomized controlled trials have
begun to show efficacy. The following therapies—cortisol
replacement, glucose control, and activated protein C—
have been intensively studied.

Indications for Tracheotomy
Tracheotomy is a common procedure in the ICU that is performed
in approximately 10% of critically ill patients who
require mechanical ventilation.104 Placement of a tracheotomy
is thought to allow a more secure and manageable
airway, earlier and safer enteral feeding, easier oral care,
and enhanced patient comfort while reducing sedation
needs and facilitating mobilization. Complications from
tracheotomy include stoma infection, pneumothorax, subcutaneous emphysema, tracheomalacia, and tracheostenosis.
105 Major questions concerning tracheotomy include
which patients with acute respiratory failure should have
the procedure and when it should be performed.
A review published in 1998 concluded that insufficient
evidence supports the view that timing of a tracheotomy
can alter the duration of mechanical ventilation
or prevent airway injury in critically ill patients.106 Since
then, individual studies have reported decreased days of
mechanical ventilation,107 decreased duration of ICU and
hospital LOS,108 and less damage to the upper airway107
with early tracheotomy. A meta-analysis attempted to
answer this question definitively. Unfortunately, only five
trials with 406 patients were found that met the inclusion
criteria.109 They reported that the timing of tracheotomy
did not alter mortality or increase the risk for hospitalacquired
pneumonia. Early tracheotomy did, however,
lower the duration of mechanical ventilation and the
overall LOS in the ICU (Table 101-3). The results were
far from conclusive. Heterogeneity was high in the metaanalysis
because of variability in inclusion and exclusion
criteria, definitions of early and late tracheotomy,

Intravenous Fluid Management
and Monitoring
The use of pulmonary artery catheters (PACs) in critically
ill patients has dramatically decreased. Most studies
have failed to show efficacy or have demonstrated harm.
The best known of these investigations is the Study to
Understand Prognoses and Preferences for Outcomes
and Risks of Treatments (SUPPORT), which was a retrospective,
observational study involving 5735 critically ill
patients.114 In those patients, the use of a PAC was associated
with increased mortality and cost. Richard and
coworkers completed a prospective, observational trial of
PACs versus central venous catheters (CVCs) in patients
with ARDS or shock.115 Clinical management was left
to the discretion of the treating physician. In 36 French
ICUs, no difference was observed in any of the outcome
variables measured in 676 patients.
The Fluids and Catheters Treatment Trial (FACTT),
conducted by the National Heart, Lung, and Blood Institute
(NHLBI) ARDSnet, compared hemodynamic management
guided by a PAC with hemodynamic management
guided by a CVC in 1000 patients with established ALI.116
Patients were treated at select academic ICUs by clinicians
who were trained in interpreting hemodynamic data and
who were following a specific management protocol.
Although serious catheter-related complications were
rare, the PAC group had a higher incidence of arrhythmias
and conduction blocks. The investigators were
unable to demonstrate prevention or reversal of organ
failure, reduced need for support (e.g., vasopressors,
assisted ventilation, renal replacement therapy), faster
discharge from the ICU, or decreased 60-day mortality in
the PAC group versus the CVC group. Possibly because of
this growing evidence, the use of the PAC has decreased
by 65% during the last decade in the United States.117
The interesting result from FACTT was that a conservative
fluid management plan appeared more effective
in patients with established ALI.118 Although the 60-day
mortality was similar in both groups, patients in the conservative
fluid management group had improved lung
function; improved central nervous system function;
and a decreased need for sedation, mechanical ventilation,
and intensive care. In addition, the patients in the
conservative fluid management group did not have an
increased incidence of complications, such as nonpulmonary
organ failure or shock.
For the past decade, the emphasis has been less on
the measurement of pulmonary capillary wedge pressure
or central venous pressure and more on the assessment
of fluid responsiveness. The belief is that this dynamic
measurement based on physiologic responses would be
better than a static indicator.119 The measurements can
be derived from an arterial pressure waveform (systolic
pressure variations [SPVs] and pulse pressure variations
[PPVs]), are minimally invasive, allow beat-to-beat monitoring,
and permit assessment of heart-lung interactions
in patients who are mechanically ventilated

Management of Fulminant Liver Failure
General Supportive Measures. 

Patients with ALF are
prone to rapid deterioration and should be closely monitored,
usually in an intensive care setting. The cause of
the ALF should be identified, and 
suitable candidates for
orthotopic liver transplantation should be moved early
to a transplantation center. Early tracheal intubation may
be necessary if neurologic status deteriorates and leads to
airway compromise. Volume expansion with crystalloids
and colloids is usually required to help maintain blood
pressure. Correction of acid-base disturbances, treatment
of hyperthermia, and close glucose monitoring are
important to prevent cerebral edema. Renal failure from
hepatorenal syndrome may develop and is reversible with
the return of hepatic function. Continuous renal replacement
therapy (CRRT) is often required in patients with
advanced ALF to treat renal insufficiency, volume status,
and cerebral edema. Early antibiotics and source control
are important because the incidence of bacteremia and
sepsis is higher in these patients than in the general population.
138 Although abnormalities exist in both the coagulation
and fibrinolytic pathways, the defects appear to
be balanced, and there is a relative preservation of hemostasis
unless the platelet count is very low.139 If a cause
is identified, then initiation of antidotes is needed (e.g.,
N-acetylcysteine for acetaminophen poisoning, penicillin
G for mushroom poisoning, early delivery for pregnancyrelated
ALF).134
Management of Increased Intracranial Pressure. 

The
development of cerebral edema and intracranial hypertension
is the most devastating complication associated
with ALF (see also Chapter 70). Osmotically active compounds,
normally cleared by the liver, accumulate in
blood and diffuse into the brain parenchyma. Movement
of water into neurons and glia results in swelling and can
cause herniation. The exact compounds responsible for
cerebral edema are unknown, but ammonia is probably a
major contributor.
Diagnosis of cerebral edema can be difficult. Serial
neurologic examination is essential, and frequent computed
tomography of the head can identify early signs
of edema. Many centers implement early invasive monitoring
of intracranial pressure, although this practice has
not been shown to improve outcome.140 Monitoring can
be achieved with either cranial or lumbar epidural monitors
because traditional intraventricular monitors carry
an unacceptable risk of bleeding.
Techniques to reduce intracranial pressure include
the removal of ammonia with CRRT, hypothermia, barbiturate
coma, and the administration of mannitol and
hypertonic saline.141 Although most available laboratory
evidence suggests that hypothermia should be helpful in
controlling the cerebral complications of ALF, randomized
clinical trials in patients to demonstrate its safety or
efficacy are currently lacking.142
Liver Support Devices
Bioartificial Livers. Bioartificial livers use hepatocytes to
mimic the synthetic, detoxifying, and excretory function
of the dying liver. Porcine hepatocytes are preferentially
used because human hepatocytes are difficult to grow
in culture.143 The device works by passing the patient’s
plasma through hollow-fiber capillaries while the hepatocytes
are placed in the extracapillary space. Molecules
are exchanged between hepatocytes and plasma across
a membrane that prevents passage of immunoglobulin,
complement, and cells. A prospective, multicenter, randomized
controlled trial using the HepatAssist liver support
system was published in 2004.144 The results did not
show any improvement in survival in the treated group.
Only during subgroup analysis were patients with fulminant
or subfulminant liver failure found to have improved
survival, but the results were marginal.
Artificial Extracorporeal Devices. Artificial extracorporeal
devices have received renewed interest because of
technology allowing the production of membranes that
can increase selectivity through small pores. The system
can be tailored for albumin-bound substances, which
include most of the toxins that accumulate with FHF.
Larger molecules such as immunoglobulins cannot cross.
This system is associated with significant biochemical
improvements,145 but these studies are small and uncontrolled,
and whether this will translate into improved
clinical outcomes still remains a matter of debate (see also
Chapter 107).
Overall, the liver support devices appear to be safe, but
adverse events can include bleeding, systemic infection,
disseminated intravascular coagulation, and anaphylaxis.
A meta-analysis of the use of artificial and bioartificial life
support systems in 8 randomized controlled trials involving
only 139 patients concluded that the evaluated support
systems have no significant effect on the mortality
in patients with ALF.146 Randomized clinical trials are
limited, considering the patient’s severity of illness. More
controlled trials addressing survival are warranted before
this therapy can be strongly recommended.

ACUTE LIVER FAILURE
Epidemiology
Acute liver failure (ALF) is an uncommon disorder that
leads to jaundice, coagulopathy, and multisystem organ
failure. The development of hepatic encephalopathy
within 8 weeks after the onset of jaundice in patients
with no known chronic liver disease defines ALF.127 ALF
affects approximately 2000 people per year in the United
States,128 with acetaminophen overdose the cause in a
majority of the cases.129 Mortality from fulminant hepatic
failure (FHF) can be high (60% to 80%) in the absence of
liver transplantation, depending on the cause.130 Causes
of death are mainly multisystem organ failure, sepsis, and
cerebral edema. Liver transplantation for ALF generally
has a worse outcome than transplantation for chronic
liver disease because of the high postoperative mortality
caused by sepsis and multiorgan failure.131
Prognostic Factors in Acute Liver Failure
The timing of transplantation and the selection of
patients are crucial because transplantation is the only
therapeutic intervention proved to be beneficial.132
Although scoring systems have been proposed, the myriad
causes of ALF limit their accuracy (Fig. 101-5). Most
case series are limited in number, and some span long
periods during which supportive therapies may have
changed. The King’s College criteria have been shown to
have good specificity (94.6%) for patients who will die
without transplantation but lower sensitivity (58.2%),
thus suggesting that a proportion of patients will die
and not fulfill the criteria.133 The criteria also have low
negative predictive value, which could lead to transplantation
in a patient who would have recovered without
surgery. Other predictors include the Model for End-
Stage Liver Disease (MELD),134 which has been shown
to be an excellent predictor of outcome in patients with
ALF of various causes, excluding acetaminophen.135
Blood lactate levels136 and hyperphosphatemia137 are
also promising.

FLUID SELECTION: COLLOID VERSUS
CRYSTALLOID
There is still no clear evidence as to what type of fluid
(colloid or crystalloid) should be used for fluid administration.
Finfer and associates randomized almost 7000
patients admitted to the ICU to receive either 4% albumin
or normal saline.124 Mortality from any cause during
the 28-day period was similar in both groups, leading the
authors to conclude that albumin and saline should be
considered equivalent for intravascular volume replacement
in a mixed population of ICU patients. Among colloids,
evidence against the use of hydroxyethyl starch
(HES), because it may increase kidney injury, seems to
exist. When comparing HES versus saline, more patients
in ICUs who were resuscitated with HES required renal
replacement therapy (7% versus 5.8%, P = 0.04) and developed
adverse effects (e.g., pruritus, skin rash) (5.3% versus
2.8%, P < 0.001).125 In patients with severe sepsis, the
use of HES compared with lactated Ringer solution led to
increased 90-day mortality (RR 1.17; 95% CI 1.01 to 1.36,
P = 0.03) and increased requirement for renal replacement
therapy (RR 1.35; 95% CI 1.01 to 1.80, P = 0.04).126
Presently, HES is increasingly becoming viewed as a solution
that should not be administered (see Chapter 61).

Management of Acute Renal Failure
General Supportive Measures. Patients with ARF should
be closely monitored. The cause of the ARF should be
identified by looking at prerenal, renal, and postrenal
causes. Laboratory evaluations should include serum and
urine electrolytes, urinalysis, and examination of urinary
sediment. Careful assessment of volume status is necessary
to determine hypovolemia, leading to prerenal azotemia
versus hypervolemia from oliguria. Correction of
acid-base disturbances may be necessary, as well as correction
of electrolyte abnormalities. Continuous renal
support is often required in patients with advanced renal
failure to help with volume overload and electrolyte disturbances.
Antibiotics and other medications should be
dosed according to creatinine clearance, and serum levels,
if available, should be closely monitored. Platelet dysfunction
may occur as a result of uremia and require desmopressin
(DDAVP) for support if bleeding is problematic.
Resuscitation fluids with high chloride concentration
(0.9% saline, 4% to 5% albumin) are associated with
decreased urine flow and electrolyte secretion, hyperchloremic
metabolic acidosis, and renal vasoconstriction.
A recent open-label, sequential study where high chloride-
containing solutions were restricted in critically ill
patients showed decreased progression to renal failure and
a reduction in the need for renal replacement therapy.151
Renal Support. ARF in the ICU often requires some
type of renal replacement therapy. Commonly, this is
accomplished by continuous venovenous hemofiltration
(CVVH), a form of CRRT. Although CRRT has several theoretic
advantages over intermittent hemodialysis (IHD),
such as enhanced hemodynamic stability, increased
solute removal, and greater ultrafiltration capacity,
individual randomized trials have not supported its superiority.
152,153 The timing and dosing of this therapy and
the patients most likely to benefit from it remain unclear.
Recently, it appears that the difference in efficacy lies
not in the type of dialysis (IHD versus CVVH) but in the
dialysis dose. Undertreatment appears to be harmful,154
whereas earlier application and higher filtration volumes
appear to be associated with decreased mortality in
patients with ARF.155 On the other hand, intensive-dose
CRRT has also not been shown to be beneficial in terms
.of mortality, renal function recovery, and ICU LOS.156-158
Even with IHD, which can cause more hemodynamic lability,
when studies are controlled for dialysis dose, polymer
membrane, and bicarbonate-based buffer, 60-day mortality
did not differ between the two groups (CRRT versus
IHD).159 Although a trend to use CRRT has developed,
favorable data with IHD are intriguing because using IHD
would allow more ICU resources to be allocated elsewhere.

ACUTE RENAL FAILURE
Epidemiologic Variables
The incidence and outcomes of acute kidney injury (AKI)
in the ICU are highly variable. Reported incidences can be
as high as 35%.147 Renal replacement therapy is the mainstay
of support for these patients, but mortality remains
high. Despite improvements in renal replacement technology
over the years, mortality caused by AKI in the ICU
has remained at higher than 50%.148
Diagnosis
The diagnosis of AKI has not been straightforward. A
recent survey revealed the use of at least 35 definitions
in the literature.149 This state of confusion has given rise
to the wide variation in reported incidence and clinical
significance of ARF. The Acute Dialysis Quality Initiative
(ADQI), which is made up of a group of experts consisting
of nephrologists and intensivists, has proposed new criteria
for describing renal dysfunction. They recognized the
clinical importance of milder forms of renal insufficiency
and that stratifying renal dysfunction (mild to severe)
would better describe the disease. They proposed the RIFLE
criteria (Table 101-4), which stand for risk, injury, failure,
and two outcome classes (loss and end-stage kidney disease).
For each increasing RIFLE class, a stepwise increase
in mortality independent of comorbidity occurs.150 These
data suggest that strategies to prevent even mild AKI may
improve survival, and recovery of renal function in the
ICU should be a specific therapeutic target.

Studies are also demonstrating improved clinical outcomes
with early mobility. An early mobility protocol that
provided rehabilitation therapy 7 days per week via a dedicated
mobility team—nurse, nurse assistant, and physical
therapist—showed a trend toward decreased hospital
mortality (12.1% versus 18.2%, P = 0.125). Early mobilization
was also associated with decreased LOS in the ICU
(5.5 days versus 6.9 days, P = 0.025) and decreased LOS in
the hospital (11.2 days versus 14.5 days, P = 0.006) after
adjusting for differences in body mass index, APACHE II
score, and vasopressor use.168
Despite the early data showing benefits, early mobilization
of critically ill patients in the ICU has unique challenges
and concerns. One barrier has been the culture regarding
the need for bed rest and activity restriction during critical
illness because of the presence of endotracheal tubes, vascular
access devices, or other medical equipment. However,
studies have demonstrated that mobilization of patients
who are mechanically ventilated can be safely performed.
Bailey and colleagues showed that in a study of 103 patients
in the ICU involving over 1400 activity events, only 14
minor events occurred in 9 patients, and no unanticipated
extubations or events occurred, requiring additional cost
or increased LOS in the hospital.169 Morris and colleagues
obtained similar results in their trial of early mobility on
145 patients who were intubated in the ICU. They reported
no incidents of accidental removal of devices.168
It is becoming more apparent that early mobility is
feasible in ICUs with a supportive culture, and early may
be significantly sooner than what has been customary.
Schweickert
and colleagues studied beginning therapy an
average of 1.5 days after intubation.170 The group of patients
who were mobilized early were more likely to be functionally
independent when they left the hospital (59% versus
35%, P = 0.02), and more patients were able to go directly
home (43% versus 24%, P = 0.06). Patients in the intervention
group had shorter duration of delirium (median 2.0
days versus 4.0 days, P = 0.02) and more ventilator-free days
(23.5 days versus 21.1 days, P = 0.05) during the 28-day
follow-up period than did study control participants.
Early mobilization in the ICU requires a multidisciplinary
team approach.171 Targets for culture change
include gaining support from institutional leaders and
bedside clinicians.172 Careful communication between
physicians, nurses, and therapists is paramount. More
research is necessary to identify whether specific groups
of patients will benefit from early mobilization more than
others, the appropriate amount of mobilization, and the
absolute and relative contraindications. The potential for
early mobilization to affect mortality seems promising.

INTENSIVE CARE UNIT–ACQUIRED
WEAKNESS
As survival after critical illness has improved over the
years, many patients now require on-going rehabilitation
after discharge from the ICU. Profound neuromuscular
weakness, or ICU-AW, is common and leads to severe
functional impairment in many ICU survivors. Risk factors
for ICU-AW are multifactorial and can include disease
severity, presence of systemic inflammatory response syndrome
(SIRS),161 number of days with two or more organ
dysfunctions, duration of mechanical ventilation,162 ICU
LOS, serum glucose levels,163 and use of corticosteroids
or NMBAs.164 Controversies exist over the risks and benefits
of tight glycemic control, and a causal relationship
between the use of corticosteroids or NMBAs has not
been clearly established. At present, few options are available
to prevent or treat ICU-AW specifically.165
A potential therapeutic option is the avoidance of
bed rest with early mobilization in the ICU. Exercise
can improve strength and increase the production of
antiinflammatory cytokines, which may play an important
role in muscle protection.166 Griffiths and coworkers
described the effects of continuous passive motion of one
leg in patients with respiratory failure receiving NMBAs.
The contralateral leg served as the control. Muscle DNAto-
protein ratio (an index of wasting) was significantly
less reduced in the leg receiving passive motion

Prevention of Catheter-Associated Urinary
Tract Infections
Unfortunately, no single CAUTI prevention strategy is
widely used. Saint and colleagues found that only 30% of
hospitals reported regularly using portable bladder ultrasound,
14% reported using condom catheters in men, and
9% reported using catheter reminders or stop orders.205
Processes that have been introduced include a checklist
of acceptable rationale for placement and a checklist to
guide the orders for removal and management.206 The
elements of performance listed by the Joint Commission
include the following:
1. Inserting indwelling urinary catheters according to
established evidence-based guidelines that address limiting
use and duration to appropriate situations and
using aseptic techniques for placement
2. Managing catheters so that urine flow is unobstructed
and the collection system remains sterile, and replacing
the system when required
3. Measuring CAUTI prevention processes by monitoring
compliance with guidelines or best practices, and
evaluating the effectiveness of prevention efforts.
Further research is needed to elucidate the relationship
between adherence to CAUTI prevention recommendations
and CAUTI incidence rates.

Catheter-Associated Urinary Tract Infection
Hospital-acquired urinary tract infections (HAUTIs) make
up 40% of HAIs with an estimated cost of $1200 to over
$2700 per episode.199 Approximately 80% of HAUTIs are
catheter-associated urinary tract infections (CAUTIs).200
In ICUs, where placement of Foley catheters is common,
the incidence rate ranges from 3.1 to 7.4 CAUTIs per 1000
urinary catheter days.201
Results from a survey of 441 hospitals suggest that little
attention had been focused on CAUTI prevention in
ICUs in the United States.202 To address this gap, multiple
public policy incentives and private sector quality initiatives
have been introduced to help reduce the rate of CAUTIs
and its resultant morbidity, mortality, and cost. For
instance, hospitals are held accountable by nonpayment
for CAUTIs from the Centers for Medicare and Medicaid
Services.202 In 2011, The Joint Commission included the
implementation of evidence-based practices to prevent
CAUTIs as one of its 2012 National Patient Safety Goals.203
This year, the Centers for Medicare and Medicaid enacted
public reporting of CAUTI rates through its Hospital Inpatient
Quality Reporting Program beginning in 2014

The need for a CVC should be reassessed daily, and unnecessary
catheters should be removed because the probability
of catheter-related infections increases with time. The risk
of infection with catheterization stays relatively low until
about the fifth to seventh days and then increases exponentially.
197 Several trials have studied scheduled replacement
of catheters over a guide wire or in a new site, but none of
these strategies were able to show an improved outcome.198
Optimal catheter insertion technique and maintenance can
minimize infectious risks, but the most efficacious maneuver
is to remove the CVC as soon as it is no longer required. The
need for central venous access should be reassessed again
before discharging the patient from the ICU because the discharge
procedure is often an opportune time to remove any
indwelling lines, including bladder catheters.

PREVENTION OF CENTRAL VENOUS
CATHETER INFECTIONS
Many recent studies have shown that the prevention of
CRBSIs is achievable through large-scale quality improvement
projects that involve a bundle of evidence-based
interventions.189,190 The Health Care Infection Control
Practices Advisory Committee recently released updated
multidisciplinary guidelines for the prevention of intravascular
catheter-related infections.191 Recommendations
include the use of ultrasound guidance for line
placement,192 skin preparation with chlorhexidine and
alcohol,193 chlorhexidine sponge for site dressing,194 antimicrobial-
impregnated CVCs,195 and 2% chlorhexidine
wash for daily skin cleansing,196 along with maximal sterile
barrier. The new guidelines also emphasize that only
trained personnel should be assigned these tasks and that
periodic assessment of these individuals should occur.

CATHETER-RELATED BLOODSTREAM
INFECTIONS
Central line–associated bloodstream infections are one of
the leading causes of health care–associated infections.
Fortunately, the rate of catheter-related bloodstream
infections (CRBSI) in the United States has decreased from
43,000 in 2001 down to 18,000 in 2009.186 This reduction
represents a 58% decrease during this 9-year period.
Along with a reduction in morbidity and mortality, this
decrease also resulted in substantial cost savings, since
each CRBSI is estimated to increase health care costs by
$16,550. The recognition that many CRBSIs are preventable
with the use of bundled clinical practice techniques
is growing. In fact, the Centers for Medicaid and Medicare
Services no longer reimburses hospitals for excess costs
associated with CRBSI,187 and many states now require
public reporting of hospital-specific CRBSI rates.188

Pooling of secretions above the endotracheal tube cuff
may increase the volume of bacteria that enter the airways.
Removal of these secretions by continuous aspiration
in the subglottic region requires the use of a specialized
endotracheal tube with a second lumen that permits a
suction catheter to exit proximal to the endotracheal tube
cuff. A meta-analysis identified 13 randomized controlled
trials that met the inclusion criteria. Of the 13 trials, 12
reported reduced VAP rates in the group that had subglottic
secretion drainage. The overall RR for VAP was 0.55
(95% CI 0.46 to 0.66, P < 0.00001). The use of subglottic
secretion drainage was associated with reduced ICU LOS
(−1.52 days; 95% CI −2.94 to −0.11, P = 0.03); decreased
duration of mechanical ventilation (−1.08 days; 95% CI
−2.04 to −0.12, P = 0.03), and increased time to first episode
of VAP (2.66 days; 95% CI 1.06 to 4.26, P = 0.001).
There were no beneficial effects on adverse events or on
hospital or ICU mortality.184 In the patients anticipated
to have a prolonged course of intubation with mechanical
ventilation, the use of endotracheal tubes with subglottic
secretion drainage appears effective for the prevention of
VAP. The reduction of the number of oral microorganisms
in the secretions with oral care and 2% chlorhexidine also
appears to be beneficial for VAP prevention in a recent
meta-analysis (RR 0.72; 95% CI 0.55 to 0.94, P = 0.02).185

Prevention of Ventilator-Associated

Pneumonia

As in all nosocomial infections, prevention is the most

efficacious approach. Excessive use of gastric pH–altering

medications for stress ulcer prophylaxis increases gastric

pH and the risk for VAP.182 The use of sucralfate, an

agent that does not increase gastric pH, may be preferable

to H2-receptor antagonists or proton pump inhibitors.

Positioning of the head of the bed at 30 degreesis the most cost-effective intervention to prevent VAP. With this intervention, Drakulovic and coworkers found

a decreased rate of VAP with no adverse effects.183 This

position results in decreased gastroesophageal reflux and

is easily implemented and monitored.

Fagon and colleagues180 used fiberoptic bronchoscopy
to obtain protected specimen brush samples or bronchoalveolar
lavage samples for quantitative culture. Patients were
considered to have VAP if at least 103 colony-forming units
(CFU)/mL of bacteria grew from the protected specimen
brush sample or at least 104 CFU/mL of bacteria grew from
the bronchoalveolar lavage fluid. The patients in the invasive
management group had reduced mortality at day 14 (16.2%
versus 25.8%, P = .022) and an increased number of antibiotic-
free days (5.0 ± 5.1 versus 2.2 ± 3.5 days, P < 0.001). This
study makes a compelling argument for a more definitive
diagnosis of VAP before initiating antibiotic therapy. Along
the same idea but with a less invasive approach, Bregeon
and associates181 showed that nonbronchoscopically guided
placement of protected brush catheters is just as sensitive as
directed bronchoscopy in detecting bacteria in the lungs.

The diagnosis of VAP is challenging. Frequently, a presumptive
diagnosis of pneumonia is made when fever,
leukocytosis, purulent secretions, and a new infiltrate on
chest radiography develop and when bacteria are isolated
by nonquantitative analysis of endotracheal aspirates.
These nonspecific diagnostic criteria may lead to unnecessary
antibiotic use, increased hospital cost, emergence
of resistant microorganisms, and a potential delay in
diagnosis of the true cause of the fever. These problems
led several investigators to propose an invasive management
strategy for the diagnosis of VAP.