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Resuscitation 46 (2000) 169±184
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Part 6: Advanced Cardiovascular Life Support
Section 7: Algorithm Approach to ACLS
7C: A Guide to the International ACLS Algorithms
Summary/Overview
The ILCOR algorithm presents the actions to take and
decisions to face for all people who appear to be in cardiac
arrest±unconscious, unresponsive, without signs of life. The
victim is not breathing normally, and no rescuer can feel a
carotid pulse within 10 to 15 seconds. Since 1992 the resuscitation community has examined and recon®rmed the
wisdom of most recommendations formulated by international groups through the 1990s. Sophisticated clinical trials
provided high-level evidence on which to base several new
drugs and interventions. Finally, we have learned that we
should continue to place a strong emphasis after 2000 on
building a base of critically appraised, international scienti®c evidence. Evidence-based review opened many eyes;
only a small proportion of resuscitation care rests on a base
of solid evidence.
Note: The numbers below, such as `1 (Fig. 1),' match
numbers in the algorithms.
Fig. 1: ILCOR Universal/International ACLS Algorithm
Fig. 1, the ILCOR Universal/International ACLS Algorithm, and Fig. 2, the Comprehensive ECC Algorithm, are
groundbreaking efforts to unify and simplify the essential
information of adult ACLS. They demonstrate the
integration of the steps of BLS, early de®brillation, and
ACLS.
The ILCOR algorithm (Fig. 1) shows how simply the
overall approach can be presented, with minimum elaboration of separate steps. The Comprehensive ECC Algorithm
(Fig. 2) provides more details, particularly to support the
AHA teaching approach based on the Primary and Secondary ABCD Surveys. Both algorithms depict many of the
concepts and interventions that are new since 1992.
Notes to the ILCOR Universal/International ACLS
Algorithm
1 (Fig. 1)
BLS algorithm. The simple instruction `BLS algorithm'
directs the rescuers to start the 6 basic steps of the international BLS algorithm:
1.
2.
3.
4.
5.
6.
Check responsiveness
Open the airway
Check breathing
Give 2 effective breaths
Assess circulation
Compress chest (no signs of circulation detected)
Note that step 6 does not use the term `pulse.' In their
1998 BLS guidelines, the European Resuscitation Council
and several ILCOR councils dropped a speci®c reference in
their algorithms to `check the carotid pulse.' They replaced
the pulse check with a direction to `check for signs of
circulation,' namely, `look for any movement, including
swallowing or breathing (more than an occasional gasp).'
Their guidelines instruct rescuers to `check for the carotid
pulse' as one of the `signs of circulation,' but the pulse
check does not receive the prominent emphasis that comes
from inclusion in the algorithm. By 2000 many locations
had con®rmed the success of this European approach.
Additional evidence had accumulated that the pulse
check was not a good diagnostic test for the presence or
absence of a beating heart. After international panels of
experts reviewed the evidence at the Guidelines 2000
Conference, they also endorsed the approach of omitting
the pulse check for lay responders from the International
Guidelines 2000.
2 (Fig. 1)
Attach de®brillator/monitor; assess rhythm. Once the
responders start the BLS algorithm, they are directed to
attach the de®brillator/monitor and assess the rhythm.
3 (Fig. 1)
VF/pulseless VT. If they are using a conventional de®brillator and the monitor displays VF, the rescuers attempt
de®brillation, up to 3 times as necessary. If using an AED,
the rescuers follow the signal and voice prompts of the
device, attempting de®brillation with up to 3 shocks. After
3 shocks they should immediately resume CPR for at least 1
minute. At the end of the minute, they should repeat rhythm
assessment and shock when appropriate.
4 (Fig. 1)
Non-VF rhythm. If the conventional de®brillator/monitor displays a non-VF tracing or the AED signals `no shock
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Part 6: Advanced Cardiovascular Life Support
Fig. 1. ILCOR Universal/International ACLS Algorithm
indicated,' the responders should immediately check the
pulse to determine whether the nonshockable rhythm is
producing a spontaneous circulation. If not, then start
CPR; continue CPR for approximately 3 minutes. With a
non-VF rhythm the rescuer needs to return and recheck the
rhythm for recurrent VF or for spontaneous return of an
organized rhythm in a beating heart. At this point the algorithm enters the central column of comments.
5 (Fig. 1)
During CPR: secure airway; IV access. In this period
the rescuers have many tasks to accomplish. The central
column includes the major interventions of ACLS: placing
and con®rming a secure airway, starting an IV, giving
appropriate medications for the rhythm, and searching for
and correcting reversible causes. Note that the ECC
Comprehensive Algorithm (Fig. 2) conveys this same
approach using the memory aid of the Secondary ABCD
Survey. In this survey A ˆ advanced airway (tracheal tube
placement); B ˆ con®rmation of airway location, oxygenation, and ventilation; and C ˆ circulation access via IV line
and circulation medications.
6 (Fig. 1)
VF/VT refractory to initial shocks: epinephrine or
vasopressin. The ILCOR Universal Algorithm indicates
Part 6: Advanced Cardiovascular Life Support
that response personnel give all cardiac arrest patients a
strong vasopressor, either epinephrine IV or vasopressin.
This recommendation for vasopressin is one of the more
interesting new guidelines. The discussions on adding amiodarone are detailed later in this section.
Consider buffers, antiarrhythmics, pacing, atropine;
search for and correct reversible causes. This short phrase
covers a multitude of interventions discussed and debated
during the Evidence Evaluation Conference and the international Guidelines 2000 Conference: multiple antiarrhythmics, neutralization of acidosis, and transcutaneous pacing.
The word `consider' has become an informal code in the
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resuscitation community interpreted to mean that we lack
the evidence that establishes one intervention as superior to
another. Whether this means that two interventions are
equally effective or equally ineffective is a debate being
waged constantly in resuscitation research.
7 (Fig. 1)
Consider causes that are potentially reversible. This
guideline applies primarily to non-VF/VT patients. For
this group there is often a speci®c cause of the loss of an
effective heartbeat. The International Guidelines 2000 take
the innovative step of listing the 10 most common reversible
causes of non-VF/VT arrest at the bottom of the algorithm.
Fig. 2. Comprehensive ECC Algorithm
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Primary ABCD Survey
(Begin BLS Algorithm)
Activate emergency response system
Call for de®brillator
A Airway: open airway; assess breathing (open airway,
look, listen, feel)
B Breathing: give 2 slow breaths
C CPR: check pulse; if no pulse !
C Start Chest Compressions
D De®brillator: attach AED or monitor/de®brillator
when available
Secondary ABCD Survey
A Secure airway as soon as possible
B Con®rm tube placement; use 2 methods to con®rm
² Primary physical examination criteria plus
² Secondary con®rmation device (qualitative and quantitativemeasures of end-tidal CO2)
B Secure tracheal tube
² Prevents dislodgment; purpose-made tracheal tube
holders recommended over tie-and-tape approaches
B Con®rm initial oxygenation and ventilation
² End-tidal CO2 monitor
² Oxygen saturation monitor
C Oxygen, IV, monitor, ¯uids ! rhythm appropriate
medications
C Vital signs: temperature, blood pressure, heart rate,
respirations
D Differential Diagnoses
Note: The primary and secondary ABCD action surveys
above are slightly different from the surveys in other algorithms. In subsequent algorithms the wording of the
Primary and Secondary ABCD Surveys is identical. The
difference in wording between the ®rst 2 algorithms and
the later algorithms allows the learners to see that the
overall concept is more important than `getting the algorithm exactly right.' Review these 2 surveys for Fig. 2.
Notice the way in which the vocabulary of the survey
changes but the overall content of the survey does not
change. People learn in different styles and remember by
different techniques. Under-standing is more important
than repetition.
This is discussed in detail in the section on pulseless electrical activity. End of Algorithm Notes
displays rescuers will need because they treat everyone in
cardiac arrest this way.
Fig. 2: Comprehensive ECC Algorithm
Notes to the Comprehensive ECC Algorithm1 (Fig. 2)
Both the ILCOR Universal Algorithm and the Comprehensive ECC Algorithm (Fig. 2) convey the concept that all
cardiac arrest victims are in 1 of 2 `rhythms': VF/VT
rhythms and non-VF rhythms.
Begin Primary ABCD Survey. Unresponsive; not
breathing. Boxes 1 and 2 cover the steps of the BLS Algorithm and cover the Primary ABCD Survey. The survey is a
memory aid and conveys no therapeutic value as stated and
displayed. The Primary and Secondary ABCD Surveys are
simple mnemonics that assist initial learning. They also
provide a useful mental `hook' for later review and recall.
Listing more details within the algorithm provides easy
review of the steps, especially when the learner has not
participated routinely in actual resuscitation attempts.
2 (Fig. 2)
VF/VT: attempt de®brillation (up to 3 shocks if VF
persists). Rhythm assessment and continued CPR are at the
center of the Comprehensive ECC Algorithm. The metaphor
of a clock ticking away for a cardiac arrest victim in VF is
overused but accurate. With each minute of persistent VF,
the probability of survival declines. Two clocks are racing.
One is the clock that measures the therapeutic interval
(from collapse to arrival of the de®brillator). One is the
clock that measures the irreversible damage interval
(from cessation of blood ¯ow to the brain to the start of
permanent, irreversible brain death).
² Non-VF comprises asystole and PEA, which are treated
alike.
² Therefore, there is no critical need to separate the
subjects into VF, pulseless VT, PEA, or asystole.
All cardiac arrest victims receive the same 4 treatments
²
²
²
²
CPR
Secure airway
Vasoconstrictors
Antiarrhythmics
The only distinguishing treatment for arrest victims is that
rescuers treat VF/VT patients with de®brillatory shocks.
The algorithms in Figs. 1 and 2 demonstrate a simple
concept. The ILCOR Universal Algorithm and the Comprehensive ECC Algorithm are the only teaching/learning
Part 6: Advanced Cardiovascular Life Support
Here is an observation that will put the racing clocks into
perspective. Several experts have observed that great
amounts of time and money are spent on the development
of new de®brillation waveforms, novel antiarrhythmics,
innovative vasopressors, and fresh approaches to ventilation
and oxygenation. The total combined effect on survival of
these interventions is equivalent to nothing more than
cutting the interval from collapse to de®brillatory shock
by 2 minutes[1].
3 (Fig. 2)
Non-VF/VT. The ILCOR recommendation is to consider
the non-VF/VT rhythms as one rhythm when the patient is
in cardiac arrest. Consider non-VF/VT as either asystole or
PEA. The treatment in the algorithm is the same for both:
epinephrine, atropine, transcutaneous pacing. Electrical
activity on the monitor screen is a more positive rhythm
than asystole. Later in this discussion PEA and asystole
are presented in much greater detail.
Both rhythms have a `differential diagnosis' in terms of
what entities can produce a PEA and an asystolic rhythm.
Responders must aggressively evaluate PEA victims to
discover a potential reversible cause. There is a narrow
diagnostic interval of just a few minutes at the discovery
of PEA. Asystole, on the other hand, is rarely salvaged
unless a reversible cause (eg, severe hyperkalemia, overdose of phenothiazine) is found. Only occasionally does
asystole respond to epinephrine in higher doses, atropine,
or pacing, because the patient is simply destined to die,
given the nature of the original precipitating event.
4 (Fig. 2)
Secondary ABCD Survey. Use of a vasopressor:
epinephrine for non-VF/VT, vasopressin for refractory
VF. This section of the algorithm makes the same points
about persistent arrest from VF/VT and non-VF/VT as the
ILCOR Universal Algorithm. The ECC Comprehensive
Algorithm, however, uses the memory aid of the Secondary
ABCD Survey, a device repeated in all the cardiac arrest
algorithms. The algorithm notes expand on these concepts.
5 (Fig. 2)
Potentially reversible causes. Sudden VF/VT arrests are
straightforward in their management. Management consists
of early de®brillation, which can succeed independently of
other interventions and independently of discovery of the
cause of the arrhythmia. With non-VF/VT arrest, however,
successful restoration of a spontaneous pulse depends
almost entirely on recognizing and treating a potentially
reversible cause. As an aide meÂmoire, Fig. 1 places the
following list, referred to as `the 5 Hs and 5 Ts,' in the
algorithm layout:
The `5 Hs'
²
²
²
²
²
Hypovolemia
Hypoxia
Hydrogen ion (acidosis)
Hyperkalemia/hypokalemia and metabolic disorders
Hypothermia/hyperthermia
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The `5 Ts'
²
²
²
²
²
Toxins/tablets (drug overdose, illicit drugs)
Tamponade, cardiac
Tension pneumothorax
Thrombosis, coronary
Thrombosis, pulmonary
Fig. 2, the Comprehensive ECC Algorithm, expands the
table of reversible causes by listing possible therapeutic
interventions next to each of the potential causes.
Consider: Is one of the following conditions playing a
role?
Hypovolemia (volume infusion)
Hypoxia (oxygen, ventilation)
Hydrogen ion±acidosis (buffer, ventilation)
Hyperkalemia (CaCl plus others)
Hypothermia (see Hypothermia Algorithm in Part 8)
`Tablets' (drug overdoses, accidents)
Tamponade, cardiac (pericardiocentesis)
Tension pneumothorax (decompress±needle decompression)
Thrombosis, coronary (®brinolytics)
Thrombosis, pulmonary (®brinolytics, surgical evacuation)
Newly Recommended Agent:Vasopressin for VF/VT
People knowledgeable about the ACLS recommendations
during the 1990s will immediately notice that the recommendations for the requisite vasoconstrictor, epinephrine,
have changed. The ®rst 3 algorithms±the ILCOR Universal
Algorithm, the Comprehensive ECC Algorithm, and Ventricular Fibrillation±each contain the same recommendation
for vasopressin as an adrenergic agent equivalent to
epinephrine for VF/VT cardiac arrest.
This is one of the most important new recommendations
in the International Guidelines 2000. Vasopressin, the
natural substance antidiuretic hormone, becomes a powerful
vasoconstrictor when used at much higher doses than
normally present in the body. Vasopressin possesses positive effects that duplicate the positive effects of epinephrine.
Vasopressin does not duplicate the adverse effects of
epinephrine. (See `Pharmacology II: Agents to Optimize
Cardiac Output and Blood Pressure' for more detailed material on vasopressin.)
Vasopressin received a Class IIb recommendation (acceptable, not harmful, supported by fair evidence) from the panel
of international experts on adrenergics. Notice that vasopressin is recommended as a single, 1-time dose in humans.
Vasopressin requires less frequent administration because
the 10- to 20-minute half-life of vasopressin is much greater
than the 3- to 5-minute half-life of epinephrine.
After the single dose of vasopressin, the algorithms allow
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a return to epinephrine if there is no clinical response to
vasopressin. This return to epinephrine has no speci®c
human evidence to provide support, although at least 1 clinical trial in Europe is under way. In an informal poll of the
experts on the adrenergic panel, every person accepted this
recommendation to return to epinephrine after 10 to 20
minutes. (The possibility of a second dose of vasopressin
in 10 to 20 minutes was discussed and seems rational.
However, this was listed as a Class Indeterminate recommendation because we lack research in humans that
addresses this question.)
The rather imprecise time range between the dose of
vasopressin and the administration of subsequent epinephrine allows ¯exibility in the decisions about when to give
subsequent adrenergics. The dilemma is: give too soon and
cause adverse effects from excessive vasopressin; give too
late and the chances of a positive outcome vanish.
Primary and Secondary ABCD Surveys
In some locations, particularly in courses for ACLS
providers, the learners are taught a memory aid called the
Primary and Secondary ABCD Surveys. These 8 steps apply
to all cardiovascular-cardiopulmonary emergencies. Course
directors crafted the ABCD surveys to help ACLS providers
remember the speci®c action steps. By memorizing the 2
surveys, ACLS students learn speci®c actions in a speci®c
sequence. The surveys use the familiar mnemonic of the ®rst
4 letters of the alphabet, and they maintain the traditional
actions associated with those 4 letters:
A ˆ Airway
B ˆ Breathing
C ˆ Circulation
D ˆ De®brillation (or Differential Diagnosis in the
Secondary ABCD Survey)
Because repetition is a well-documented aid to learning,
the elements of the Primary and Secondary ABCD Surveys
are repeated in several other algorithms: VF/VT, PEA, and
asystole.
Fig. 3, VF/pulseless VT, conveys more details about the
Secondary ABCD Survey:
A ˆ Airway control with a secure airway
B ˆ Breathing effectively: verify with primary and
secondary con®rmation of proper airway placement
C ˆ Circulation, which incorporates vital signs, ECG
monitoring, access to the circulation via IV lines, and
then administration of rhythm-appropriate medications
D ˆ Differential Diagnosis
A directive to `consider the differential diagnoses'
improves the resuscitation protocols, because this is a
recommendation to stop and think: What caused this arrest?
With the addition of this step, resuscitation teams will identify more cardiac arrests with reversible causes. Although
we lack evidence that supports use of this memory aid, its
use has the strong appeal of common sense.
The Secondary ABCD Survey in Fig. 2 states perhaps the
most important new recommendations for out-of-hospital
care providers.
² We make stronger and more explicit recommendations to
con®rm tracheal tube placement.
² We recommend that resuscitation personnel take speci®c
actions to prevent tube dislodgment after an initial
correct placement.
During the years 1999±2000, publications about out-ofhospital pediatric resuscitation documented high rates of
tube dislodgment. The researchers discovered that on arrival
and evaluation in the Emergency Department, 8% to 12% of
tracheal tubes were in the esophagus or hypopharynx. Given
the study design, researchers were unable to determine
whether these possibly lethal mishaps were due to incorrect
initial tube placement or dislodgment after placement. This
information has heightened concerns that ACLS providers
may be committing undetected harm while performing our
most critical interventions.
Fig. 3: VF/Pulseless VT
Fig. 3 covers the treatment of VF/pulseless VT in more
depth than Figs. 1 and 2. Fig. 3 was created as a teaching aid
to convey speci®c details about the Primary and Secondary
ABCD Surveys. The treatments outlined in Figs. 1, 2, and 3
are identical: CPR, de®brillation if VF/VT, advanced
airway control, intravenous access, rhythm-appropriate
medications.
Always Assume VF (Figs. 1±3)
Note that Fig. 1, the ILCOR Universal ACLS Algorithm,
Fig. 2, the ECC Comprehensive Algorithm, and Fig. 3, the
Ventricular Fibrillation/Pulseless VT Algorithm, state this
precept unequivocally: rescuers must assume that all adult
sudden cardiac arrests are caused by VF/pulseless VT. All
training efforts therefore place a strong emphasis on
immediate recognition and treatment of VF/pulseless VT.
Proper treatment with early de®brillatory shocks allows VF/
pulseless VT to provide the majority of adult cardiac arrest
survivors. Several mature EMS systems, such as Seattle/
King County, Washington, USA, have collected data for
.25 years. Year after year VF/VT contributes 85±95% of
the survivors.
Energy Levels for Shock and De®brillation Waveforms
The appearance of biphasic waveform de®brillators has
generated great enthusiasm in the resuscitation community.
Reaching EMS organizations in 1996, the ®rst biphasic de®brillator approved for market shocked at only 1 energy level,
approximately 170 J. Competitive market forces stirred up
Part 6: Advanced Cardiovascular Life Support
considerable controversy over the ef®cacy of biphasic
waveform shocks in general and nonescalating energy
levels in particular. This unseemly chapter in the history
of medical device manufacturers has been reviewed in detail
in a Medical Scienti®c Statement from the Senior Science
Editors and the chairs of the ECC subcommittees[1]. Biphasic waveform de®brillators are conditionally acceptable±
regardless of initial shock energy level and regardless of
the energy level of subsequent shocks (nonescalating).
The condition that must be met is clinical data that con®rms
equivalent or superior effectiveness to monophasic de®brillators when used in the same clinical context. For example,
to meet this condition manufacturers cannot compare rescue
de®brillatory shocks delivered to a ®brillating heart in the
Electrophysiology Stimulation Laboratory versus de®brillatory shocks delivered to patients with 12-minute-old VF in
the absence of CPR efforts from bystanders. (See `De®brillation' in Part 6 for more detail on waveforms and energy
levels.) The International Guidelines 2000 panel experts, the
ILCOR representatives, and other delegates thought that the
class of recommendation for biphasic shocks, nonescalating
energy levels, should be upgraded from Class IIb in 1998 to
Class IIa in 2000.
CPR, VF, and De®brillation
After 3 unsuccessful attempts to achieve de®brillation,
the ®rst 3 algorithms instruct rescuers to provide approximately 1 minute of CPR. This produces some reoxygenation
of the blood and some circulation of this blood to the heart
and brain. The precise effect of this minute of CPR on
refractory VF is unclear.
Stimulated by the 1999 publication of a retrospective
analysis of out-of-hospital cardiac arrest data from the Seattle, Washington, EMS system, the Evidence Evaluation
Conference (September 1999) included this topic on its
agenda. The EMS personnel initially used a protocol in
which arriving EMTs attached an AED and analyzed and
shocked any VF rhythms as quickly as possible. Later the
protocol directed the EMTs to perform 60 to 90 seconds of
CPR before attaching the AED and shocking VF. The survival rates to hospital discharge were signi®cantly higher
during the period of prescribed preshock CPR. Other experts
argued that a ®brillating myocardium suffers unrelenting
deterioration as long as VF continues, CPR or no CPR. A
minute or so of preshock CPR does not prevent this deterioration. This guideline recommendation was classed as
Indeterminate because the quality and amount of evidence,
on both sides of the question, were at lower levels: retrospective data (Level 5) and extrapolation of data from other
sources (Level 7), particularly animal studies (Level 6).
Diminishing Roles for Drugs in VF Arrest
The ILCOR Universal Algorithm, the Comprehensive
175
ECC Algorithm, and similar comments in Fig. 3 relegate
adrenergic agents, antiarrhythmic agents, and buffer therapy
to secondary roles for both VF and non-VF patients. This
secondary role applies to time-honored agents such as
epinephrine, lidocaine, procainamide, and buffer agents
and to newly available agents such as amiodarone. Meticulous, systematic review reveals that relevant, valid, and credible evidence to con®rm a bene®t due to these agents simply
does not exist. This does not mean that resuscitation drugs
were selected capriciously by the pioneers of resuscitation
decades ago. They applied common sense, rational conjecture, and extrapolations from animal studies to arrive at the
antiarrhythmics used over the past decade. If an agent is
shown in animal models to raise the ®brillation threshold
and lower the de®brillation threshold, then a reasonable
assumption would be that the drug would facilitate de®brillation of the human heart to a perfusing rhythm. This sort of
rational conjecture produced the rather eclectic groups of
drugs that have stocked resuscitation kits for more than a
decade.
In addition, it was not until the 1990s that researchers
discovered the dismal truth that antiarrhythmic drugs were
acting more like proarrhythmic agents. Drugs given to
prevent VF/VT arrest appear to generate VF/VT arrest.
With critical reappraisal these disturbing discoveries undermined the validity and credibility of scores of excellently
designed and executed studies. Through the use of critical
appraisal, most researchers in this area realized that the only
proper evaluation of new resuscitation agents had to be
prospective, randomized clinical trials in which the only
acceptable control group had to be placebo.
Designs of studies of new drugs versus standard therapy
were unacceptable for the obvious reason±if both standard
therapy and the new drug made cardiac arrest victims worse,
we could never obtain valid results. The adverse effects
would not be recognized unless one agent was signi®cantly
worse than the other. Ironically, the researchers would
conclude that the less worse drug was actually a superior
agent of positive bene®t to patients. See `Pharmacology I:
Agents for Arrhythmias' and `Pharmacology II: Agents to
Optimize Cardiac Output and Blood Pressure' for more
detailed material that supports these observations.
New Class of Recommendation for Epinephrine and
Lidocaine: Indeterminate
An immense amount of animal research and lower-level
human research exists on epinephrine in cardiac arrest.
These projects are remarkable in the homogeneity of
results±the ®ndings are consistently and invariably positive.
But almost no valid, consistent, and relevant human
evidence exists to support epinephrine over placebo in
human cardiac arrest. Clinical researchers have not
conducted prospective, placebo-controlled, clinical trials
in humans on this topic. Consequently, the international,
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Fig. 3. VF/Pulseless VT
evidence-based guidelines had to conclude that epinephrine
was Class Indeterminate.
Similarly, no study has shown that lidocaine is effective as
an agent to use in human arrest from refractory, shock-resistant VF. Our growing awareness of the proarrhythmic effects
of antiarrhythmics now requires that researchers evaluate
lidocaine and other antiarrhythmics against placebo, and
not against some other antiarrhythmics. No clinical differ-
ences will be observed if 2 antiarrhythmics are equally ineffective or even equally harmful. At this time, therefore,
lidocaine receives a Class Indeterminate recommendation.
Notes to Fig. 3: VF/Pulseless VT Algorithm
Assume that VF/VT persists after each intervention.1
(Fig. 3)
Part 6: Advanced Cardiovascular Life Support
De®brillatory shock waveforms
² Use monophasic shocks at listed energy levels (200 J,
200±300 J, 360 J) or biphasic shocks at energy levels
documented to be clinically equivalent (or superior) to
the monophasic shocks.2 (Fig. 3)
2A Con®rm airway placement with
² Primary physical examination criteria plus
² Secondary con®rmation device (end-tidal CO2, enddiastolic diameter) (Class IIa)
2B Secure airway
² To prevent dislodgment, especially in patients at risk for
movement, use purpose-made (commercially available)
tube holders, which are superior to tie-and-tape methods
(Class IIb)
² Consider cervical collar and backboard for transport
(Class Indeterminate)
² Consider continuous, quantitative end-tidal CO2 monitor
(Class IIa)
2C Con®rm oxygenation and ventilation with
² End-tidal CO2 monitor and
² Oxygen saturation monitor3 (Fig. 3)
3A Epinephrine (Class Indeterminate) 1 mg IV push
every 3 to 5 minutes. If this fails, higher doses of epinephrine (up to 0.2 mg/kg) are acceptable but not recommended
(there is growing evidence that it may be harmful).
3B Vasopressin is recommended only for VF/VT; there
is no evidence to support its use in asystole or PEA. There is
no evidence about the value of repeat vasopressin doses.
There is no evidence about the best approach if there is no
response after a single bolus of vasopressin. The following
Class Indeterminate action is acceptable, but only on the
basis of rational conjecture. If there is no response 5 to 10
minutes after a single IV dose of vasopressin, it is acceptable to resume epinephrine 1 mg IV push every 3 to 5
minutes.4 (Fig. 3)
4A Antiarrhythmics are indeterminate or Class IIb:
acceptable; only fair evidence supports possible bene®t of
antiarrhythmics for shock-refractory VF/VT.
² Amiodarone (Class IIb) 300 mg IV push (cardiac arrest
dose). If VF/pulseless VT recurs, consider administration
of a second dose of 150 mg IV. Maximum cumulative
dose: 2.2 g over 24 hours.
² Lidocaine (Class Indeterminate) 1.0 to 1.5 mg/kg IV
push. Consider repeat in 3 to 5 minutes to a maximum
cumulative dose of 3 mg/kg. A single dose of 1.5 mg/kg
in cardiac arrest is acceptable.
² Magnesium sulfate 1 to 2 g IV in polymorphic VT
(torsades de pointes) and suspected hypomagnesemic
state.
² Procainamide 30 mg/min in refractory VF (maximum
177
total dose: 17 mg/kg) is acceptable but not recommended
because prolonged administration time is unsuitable for
cardiac arrest.
4B Sodium bicarbonate 1 mEq/kg IV is indicated for
several conditions known to provoke sudden cardiac arrest.
See Notes in the Asystole and PEA Algorithms for details.5
(Fig. 3)
Resume de®brillation attempts: use 360-J (or equivalent biphasic) shocks after each medication or after each
minute of CPR. Acceptable patterns: CPR-drug-shock
(repeat) or CPR-drug-shock-shock-shock (repeat).
Fig. 4: Pulseless Electrical Activity
The absence of a detectable pulse and the presence of
some type of electrical activity other than VT or VF de®nes
this group of arrhythmias. When electrical activity is organized and no pulse is detectable, clinicians traditionally
have used the term electromechanical dissociation (EMD).
This term, however, is too speci®c and narrow. Strictly
speaking, EMD means that organized electrical depolarization occurs throughout the myocardium, but no synchronous
shortening of the myocardial ®ber occurs and mechanical
contractions are absent.
In the early 1990s the international resuscitation community began to adopt the summary term pulseless electrical
activity (PEA). PEA would more accurately embrace a
heterogeneous group of rhythms that includes pseudoEMD, idioventricular rhythms, ventricular escape rhythms,
postde®brillation idioventricular rhythms, and bradyasystolic rhythms. Additional research with cardiac ultrasonography and indwelling pressure catheters has con®rmed that
often a pulseless patient with electrical activity also has
associated mechanical contractions. These contractions
are too weak to produce a blood pressure detectable by
the usual methods of palpation or sphygmomanometry.
Of utmost importance, ACLS providers must know that
PEA is often associated with speci®c clinical states that
can be reversed when identi®ed early and treated appropriately.
Notes to Fig. 4: Pulseless Electrical Activity
Both VF/VT and PEA are `rhythms of survival.' People
in VF/VT can be resuscitated by timely arrival of a de®brillator, and people in PEA can be resuscitated if a reversible cause of PEA is identi®ed and treated appropriately.
The PEA algorithm puts great emphasis on searching for
speci®c, reversible causes of PEA. The algorithm features a
table of the top 10 causes of PEA, arranged as the `5 H's
and 5 T's.' If reversible causes are not considered, rescuers
will have little chance of recognition and successful treatment. Sodium bicarbonate provides a good example of how
the cause of the PEA relates to the therapy. Sodium
bicarbonate can vary between being a Class I intervention
178
Part 6: Advanced Cardiovascular Life Support
Fig. 4. Pulseless Electrical Activity
and being a Class III intervention, depending on the
cause.
1 (Fig. 4)Sodium bicarbonate 1 mEq/kg is used as
follows:
Class I (acceptable, supported by de®nitive evidence)
² If patient has known, preexisting hyperkalemiaClass IIa
(acceptable, good evidence supports)
² If known, preexisting bicarbonate-responsive acidosis
² In tricyclic antidepressant overdose
² To alkalinize urine in aspirin or other drug overdoses
Class IIb (acceptable, only fair evidence provides
support)
² In intubated and ventilated patients with long arrest inter-
Part 6: Advanced Cardiovascular Life Support
val
² On return of circulation, after long arrest intervalMay be
harmful (Class III) in hypercarbic acidosis2 (Fig. 4)
Epinephrine: recommended dose is 1 mg IV every 3 to 5
minutes (Class Indeterminate).
² If this approach fails, higher doses of epinephrine (up to
0.2 mg/kg) may be used but are not recommended.
² (Although one dose of vasopressin is acceptable for
persistent or shock-refractory VF, we currently lack
evidence to support routine use of vasopressin in victims
of PEA or asystole.)
3 (Fig. 4)
Atropine: the shorter atropine dose interval (every 3 to 5
minutes) is possibly helpful in cardiac arrest.
² Atropine 1 mg IV if electrical activity is slow (absolute
bradycardia ˆ rate ,60 bpm) or
² Relatively slow (relative bradycardia ˆ rate less than
expected, relative to underlying condition)
Other observed pulseless cardiac arrest arrhythmias are
those in which the electrical activity (QRS complex) is wide
versus narrow and fast versus slow. Most clinical studies
have observed poor survival rates from PEA that is widecomplex and slow. These rhythms often indicate malfunction of the myocardium or the cardiac conduction system,
such as occurs with massive AMI. These rhythms can represent the last electrical activity of a dying myocardium, or
they may indicate speci®c critical rhythm disturbances. For
example, severe hyperkalemia, hypothermia, hypoxia,
preexisting acidosis, and a large variety of drug overdoses
can be wide-complex PEAs. Overdoses of tricyclic antidepressants, b-blockers, calcium channel blockers, and digitalis will produce a slow, wide-complex PEA.
In contrast, a fast, narrow-complex PEA indicates a relatively normal heart responding exactly as it should for
severe hypovolemia, infections, pulmonary emboli, or
cardiac tamponade. These conditions have speci®c interventions.
The major action to take for a cardiac arrest victim in
PEA is to search for possible causes. These rhythms are
often a response to a speci®c condition, and helpful clues
can appear if one simply looks at the electrical activity
width and rate.
Hypovolemia is the most common cause of electrical
activity without measurable blood pressure. Through
prompt recognition and appropriate therapy, the many
causes of hypovolemia can often be corrected, including
hypovolemia from hemorrhage or from anaphylaxisinduced vasodilation. Other causes of PEA are cardiac
tamponade, tension pneumothorax, and massive pulmonary
embolism.
Nonspeci®c therapeutic interventions for PEA include
179
epinephrine and (if the rate is slow) atropine, administered
as presented in Fig. 4. In addition, personnel should provide
proper airway management and aggressive hyperventilation
because hypoventilation and hypoxemia are frequent causes
of PEA. Clinicians can give a ¯uid challenge because the
PEA may be due to hypovolemia.
Immediate assessment of blood ¯ow by Doppler ultrasound may reveal an actively contracting heart and signi®cant blood ¯ow. The blood pressure and ¯ow, however, may
fall below the threshold of detection by simple arterial
palpation. Any PEA patient with a Doppler-detectable
blood ¯ow should be aggressively treated. These patients
need volume expansion, norepinephrine, dopamine, or some
combination of the three. They might bene®t from early
transcutaneous pacing because a healthy myocardium exists
and only a temporarily disturbed cardiac conduction system
stands between survival and death. Although in general PEA
has poor outcomes, reversible causes should always be
targeted and never missed when present.
Fig. 5: Asystole: The Silent Heart Algorithm
Patients in cardiac arrest discovered on the de®brillator's
monitor screen to be in asystole have a dismal rate of survival±usually as low as 1 or 2 people out of 100 cardiac
arrests. During a resuscitation attempt, brief periods of an
organized complex may appear on the monitor screen, but
spontaneous circulation rarely emerges. As with PEA, the
only hope for resuscitation of a person in asystole is to
identify and treat a reversible cause.
Fig. 5, the Asystole Algorithm, outlines an approach
much more in keeping with our current understanding of
the issues surrounding asystole. The Asystole Algorithm
focuses on `not starting' and `when to stop.' With
prolonged, refractory asystole the patient is making the transition from life to death. ACLS providers who try to make
that transition as sensitive and digni®ed as possible serve
their patients well.
Notes to Fig. 5: Asystole
1 (Fig. 5)
Scene Survey: DNAR patient?If Yes: do not start/
attempt resuscitation. Any objective indicators of DNAR
status? Bracelet? Anklet? Written documentation? Family
statements? If Yes: do not start/attempt resuscitation.
² Any clinical indicators that resuscitation attempts are not
indicated, eg, signs of death? If Yes: do not start/attempt
resuscitation.
2 (Fig. 5)
Con®rm true asystole
² Check lead and cable connections
² Monitor power on?
180
Part 6: Advanced Cardiovascular Life Support
Fig. 5. Asystole: The Silent Heart Algorithm
Part 6: Advanced Cardiovascular Life Support
² Monitor gain up?
² Verify asystole in another lead?
3 (Fig. 5)
Sodium bicarbonate 1 mEq/kg
² Indications for use include the following: overdose of
tricyclic antidepressants; to alkalinize urine in overdoses;
patients with tracheal intubation plus long arrest intervals; on return of spontaneous circulation if there is a
long arrest interval.
² Ineffective or harmful in hypercarbic acidosis.
4 (Fig. 5)
Transcutaneous pacing
² To be effective, must be performed early, combined with
drug therapy. Evidence does not support routine use of
transcutaneous pacing for asystole.
5 (Fig. 5)
Epinephrine
² Recommended dose is 1 mg IV every 3 to 5 minutes. If this
approach fails, higher doses of epinephrine (up to 0.2 mg/
kg) may be used but are not recommended.
² We currently lack evidence to support routine use of vasopressin in treatment of asystole.
6 (Fig. 5)
Atropine
² Use the shorter dosing interval (every 3 to 5 minutes) in
asystolic arrest.
7 (Fig. 5)
Review the quality of the resuscitation attempt
² Was there an adequate trial of BLS? of ACLS? Has the
team done the following:
² Achieved secure airway?
² Performed effective ventilation?
² Shocked VF if present?
² Obtained IV access?
² Given epinephrine IV? atropine IV?
² Ruled out or corrected reversible causes?
² Continuously documented asystole .5 to 10 minutes
after all of the above have been accomplished?
8 (Fig. 5)
Reviewed for atypical clinical features?
² Not a victim of drowning or hypothermia?
² No reversible therapeutic or illicit drug overdose?
± 'Yes' to the questions in Notes 7 and 8 means the
resuscitation team complies with recommended
criteria to terminate resuscitative efforts where the
patient lies (Class IIa)
181
± If the response team and patient meet the above
criteria, then withhold urgent ®eld-to-hospital transport with continuing CPR ˆ Class III (harmful; no
bene®t)
9 (Fig. 5)
Withholding or stopping resuscitative efforts out-ofhospital
If criteria in 7 and 8 are ful®lled:
² Field personnel, in jurisdictions where authorized, should
start protocols to cease resuscitative efforts or to
pronounce death outside the hospital (Class IIa).
² In most US settings, the medical control of®cial
must give direct voice-to-voice or on-scene authorization.
² Advance planning for these protocols must occur. The
planning should include speci®c directions for
± Leaving the body at scene
± Death certi®cation
± Transfer to funeral service
± On-scene family advocate±Religious or nondenominational counseling
Asystole most often represents a con®rmation of death
rather than a `rhythm' to be treated. Team leaders can
cease efforts to resuscitate the patient from con®rmed
and persistent asystole when the resuscitation team has
done the following:
² Provided suitable basic CPR
² Eliminated VF
² Achieved a successful secure airway with primary and
secondary con®rmation of tube placement
² Con®rmed throughout the efforts that the tube was
secure and had not been dislodged
² Monitored oxygen saturation and end-tidal CO2 to
ensure that the best possible oxygenation and ventilation
were achieved
² Established successful IV access
² Maintained these interventions for .10 minutes, during
which time the con®rmed rhythm was asystole
² Administered all rhythm-appropriate medications
² Updated waiting family members, spouses, or available
friends about the severity of the patient's condition and
lack of response to interventions
² Discussed the concept of programs to support family
presence during resuscitative attempts and offered that
option to appropriate family members. Note that family
presence at resuscitative efforts is not a spur-of-themoment offer, extended or not extended at the whim
of supervising physicians. Rather, family presence
at resuscitative efforts requires a formal program,
with advance planning, assigned roles, and even rehearsals.
182
Part 6: Advanced Cardiovascular Life Support
Fig. 6. Bradycardia
When to Stop?
Is it possible to state a speci®c time interval beyond which
rescuers have never resuscitated patients? Does every resuscitation attempt have to continue for that length of time to
guarantee that every salvageable person will be identi®ed and
saved? As outlined in the algorithm notes, the resuscitation
team must make a conscientious and competent effort to give
patients `a trial of CPR and ACLS,' provided that the person
had not expressed a decision to forego resuscitative efforts.
The ®nal decision to stop efforts can never be as simple as an
isolated time interval, but clinical judgment and a respect for
human dignity must enter the decision making. Many people
among the resuscitation community strongly believe that we
have erred greatly in the tendency to try prolonged, excessive
resuscitative efforts.
Part 6: Advanced Cardiovascular Life Support
Emergency medical response systems should not require
the ®eld personnel to transport every victim of cardiac arrest
back to a hospital or Emergency Department (ED). In
European countries most out-of-hospital ALS care is
provided by medical doctors, so decisions about stopping
CPR, transportation back to the ED, and pronouncing death
are handled by an authorized medical doctor in the ®eld.
Transportation with continuing CPR is justi®ed if there are
interventions available in the ED that cannot be performed
in the ®eld (such as central core rewarming equipment) or
®eld interventions (such as tracheal intubation) that were
unsuccessful in the ®eld.
In the United States, outdated concepts of EMS care can
linger for years. For example, many systems still dictate the
practice of `scoop and run' on all major medical patients,
not just major trauma. For nontraumatic cardiac arrest solid
evidence con®rms that ACLS care in the ED offers no
advantage over ACLS care in the ®eld. Stated succinctly±
if ACLS care in the ®eld cannot resuscitate the victim,
neither will ED care. Civil rules, administrative concerns,
medical insurance requirements, and even reimbursement
enhancement have frequently led to requirements to transport all cardiac arrest victims back to a hospital or ED. If
these are unselective requirements, they are inappropriate,
futile, and ethically unacceptable. There should be no
requirements for ambulance transport of all patients who
suffer an out-of-hospital cardiac arrest. This is especially
true when the patient is pulseless and CPR is continued
during transport. Researchers and EMS experts continue
to publish observational studies on this practice of transporting all ®eld resuscitations back to an ED, most often for
pronouncement of death. To have the resuscitation team
succeed with one of these victims and then have the victim
survive to hospital discharge is extremely rare±usually
,1%.
Likewise, it is inappropriate for clinicians to apply
routine `stopping rules' without thinking about the particular situation. `Part 2: Ethical Aspects of ECC and CPR'
provides a more detailed discussion of these issues. Cessation of efforts in the prehospital setting, following systemspeci®c criteria and under direct medical control, should be
standard practice in all EMS systems.
Fig. 6: Bradycardia
Notes to Fig. 6: Bradycardia
1 (Fig. 6)
If the patient has serious signs or symptoms, make sure
they are related to the slow rate.
2 (Fig. 6)
Clinical manifestations include
² Symptoms (chest pain, shortness of breath, decreased
level of consciousness)
183
² Signs (low blood pressure, shock, pulmonary congestion,
congestive heart failure)
3 (Fig. 6)
If the patient is symptomatic, do not delay transcutaneous
pacing while awaiting IV access or for atropine to take
effect.
4 (Fig. 6)
Denervated transplanted hearts will not respond to atropine. Go at once to pacing, catecholamine infusion, or both.
5 (Fig. 6)
Atropine should be given in repeat doses every 3 to 5
minutes up to a total of 0.03 to 0.04 mg/kg. Use the shorter
dosing interval (3 minutes) in severe clinical conditions.
6 (Fig. 6)
Never treat the combination of third-degree heart block
and ventricular escape beats with lidocaine (or any agent
that suppresses ventricular escape rhythms).
7 (Fig. 6)
Verify patient tolerance and mechanical capture. Use
analgesia and sedation as needed.
Transcutaneous pacing is a Class I intervention for all
symptomatic bradycardias. If clinicians are concerned about
the use of atropine in higher-level blocks, they should
remember that transcutaneous pacing is always appropriate,
although not as readily available as atropine. If the bradycardia is severe and the clinical condition is unstable, implement transcutaneous pacing immediately.
There are several other cautions to remember about treatment of symptomatic bradycardias. Lidocaine may be lethal
if the bradycardia is a ventricular escape rhythm and unwary
clinicians think they are treating preventricular contractions
or slow VT. In addition, transcutaneous pacing can be painful
and may fail to produce effective mechanical contractions.
Sometimes the patient's `symptom' is not due to the bradycardia. For example, hypotension, associated with bradycardia, may be due to myocardial dysfunction or hypovolemia
rather than to conducting system or autonomic problems.
Fig. 6 lists interventions in a sequence based on the
assumption of worsening clinical severity. Give patients
who are `precardiac arrest,' or moving in that direction,
multiple interventions in rapid sequence. Begin preparations
for pacing, IV atropine, and administration of an epinephrine infusion. If the patient displays only mild problems due
to the bradycardia, then atropine 0.5 to 1.0 mg IV can be
given in a repeat dose every 3 to 5 minutes, to a total of 0.03
mg/kg. (For severe bradycardia or asystole, a maximum
dose of 0.04 mg/kg is advisable.) Selection of the dosing
interval (3 to 5 minutes) requires judgment about the severity of the patient's symptoms. The provider should repeat
atropine at shorter intervals for more distressed patients.
Dopamine (at rates of 2to 5 mg/kg per minute) can be
added and increased quickly to 5 to 20 mg/kg per minute
if low blood pressure is associated with the bradycardia. If
the patient displays severe symptoms, clinicians can go
directly to an epinephrine infusion.
184
Part 6: Advanced Cardiovascular Life Support
Transcutaneous pacing should be initiated quickly in
patients who do not respond to atropine or who are severely
symptomatic, especially when the block is at or below the
His-Purkinje level. Newer de®brillator/monitors have the
capability to perform transcutaneous pacing. This intervention, unlike insertion of transvenous pacemakers, is available to and can be performed by almost all ECC providers.
This gives transcutaneous pacing enormous advantages over
transvenous pacing because transcutaneous pacing can be
started quickly and conveniently at the bedside.
References
[1] Cummins RO, Hazinski MF, Kerber RE, Kudenchuk P, Becker L,
Nichol G, Malanga B, Aufderheide TP, Stapleton EM, Kern K, Ornato
JP, Sanders A, Valenzuela T, Eisenberg M. Low-energy biphasic
waveform de®brillation: evidence-based review applied to emergency
cardiovascular care guidelines: a statement for healthcare professionals
from the American Heart Association Committee on Emergency Cardiovascular Care and the Subcommittees on Basic Life Support,
Advanced Cardiac Life Support, and Pediatric Resuscitation. Circulation. 1998;97:1654±1667. Circulation 2000;102(Suppl I):I142±I157.
The Ne w E n g l a nd Jour n a l o f Me d ic i ne
EARLY GOAL-DIRECTED THERAPY IN THE TREATMENT OF SEVERE SEPSIS
AND SEPTIC SHOCK
EMANUEL RIVERS, M.D., M.P.H., BRYANT NGUYEN, M.D., SUZANNE HAVSTAD, M.A., JULIE RESSLER, B.S.,
ALEXANDRIA MUZZIN, B.S., BERNHARD KNOBLICH, M.D., EDWARD PETERSON, PH.D., AND MICHAEL TOMLANOVICH, M.D.,
FOR THE EARLY GOAL-DIRECTED THERAPY COLLABORATIVE GROUP*
ABSTRACT
Background Goal-directed therapy has been used
for severe sepsis and septic shock in the intensive care
unit. This approach involves adjustments of cardiac
preload, afterload, and contractility to balance oxygen
delivery with oxygen demand. The purpose of this
study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit.
Methods We randomly assigned patients who arrived at an urban emergency department with severe
sepsis or septic shock to receive either six hours of
early goal-directed therapy or standard therapy (as a
control) before admission to the intensive care unit.
Clinicians who subsequently assumed the care of the
patients were blinded to the treatment assignment.
In-hospital mortality (the primary efficacy outcome),
end points with respect to resuscitation, and Acute
Physiology and Chronic Health Evaluation (APACHE II)
scores were obtained serially for 72 hours and compared between the study groups.
Results Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133
to standard therapy; there were no significant differences between the groups with respect to base-line
characteristics. In-hospital mortality was 30.5 percent
in the group assigned to early goal-directed therapy, as
compared with 46.5 percent in the group assigned to
standard therapy (P=0.009). During the interval from
7 to 72 hours, the patients assigned to early goaldirected therapy had a significantly higher mean (±SD)
central venous oxygen saturation (70.4±10.7 percent
vs. 65.3±11.4 percent), a lower lactate concentration
(3.0±4.4 vs. 3.9±4.4 mmol per liter), a lower base deficit (2.0±6.6 vs. 5.1±6.7 mmol per liter), and a higher
pH (7.40±0.12 vs. 7.36±0.12) than the patients assigned
to standard therapy (P«0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed
therapy than in those assigned to standard therapy
(13.0±6.3 vs. 15.9±6.4, P<0.001).
Conclusions Early goal-directed therapy provides
significant benefits with respect to outcome in patients
with severe sepsis and septic shock. (N Engl J Med
2001;345:1368-77.)
Copyright © 2001 Massachusetts Medical Society.
T
HE systemic inflammatory response syndrome can be self-limited or can progress to
severe sepsis and septic shock.1 Along this
continuum, circulatory abnormalities (intravascular volume depletion, peripheral vasodilatation,
myocardial depression, and increased metabolism) lead
to an imbalance between systemic oxygen delivery and
oxygen demand, resulting in global tissue hypoxia or
shock.2 An indicator of serious illness, global tissue
hypoxia is a key development preceding multiorgan
failure and death.2 The transition to serious illness occurs during the critical “golden hours,” when definitive recognition and treatment provide maximal benefit in terms of outcome. These golden hours may
elapse in the emergency department,3 hospital ward,4
or the intensive care unit.5
Early hemodynamic assessment on the basis of physical findings, vital signs, central venous pressure,6 and
urinary output7 fails to detect persistent global tissue
hypoxia. A more definitive resuscitation strategy involves goal-oriented manipulation of cardiac preload,
afterload, and contractility to achieve a balance between systemic oxygen delivery and oxygen demand.2
End points used to confirm the achievement of such
a balance (hereafter called resuscitation end points) include normalized values for mixed venous oxygen saturation, arterial lactate concentration, base deficit, and
pH.8 Mixed venous oxygen saturation has been shown
to be a surrogate for the cardiac index as a target for
hemodynamic therapy.9 In cases in which the insertion
of a pulmonary-artery catheter is impractical, venous
oxygen saturation can be measured in the central circulation.10
Whereas the incidence of septic shock has steadily
increased during the past several decades, the associated mortality rates have remained constant or have
decreased only slightly.11 Studies of interventions such
as immunotherapy,12 hemodynamic optimization,9,13
or pulmonary-artery catheterization14 enrolled patients
up to 72 hours after admission to the intensive care
unit. The negative results of studies of the use of hemodynamic variables as end points (“hemodynamic
From the Departments of Emergency Medicine (E.R., B.N., J.R., A.M.,
B.K., M.T.), Surgery (E.R.), Internal Medicine (B.N.), and Biostatistics and
Epidemiology (S.H., E.P.), Henry Ford Health Systems, Case Western Reserve University, Detroit. Address reprint requests to Dr. Rivers at the Department of Emergency Medicine, Henry Ford Hospital, 2799 West Grand
Blvd., Detroit, MI 48202, or at [email protected].
*The members of the Early Goal-Directed Therapy Collaborative Group
are listed in the Appendix.
1368 · N Engl J Med, Vol. 345, No. 19 · November 8, 2001 · www.nejm.org
EARLY GOAL-DIREC TED THERAPY IN THE TREATMENT OF SEVERE SEPSIS AND SEP TIC SHOCK
optimization”), in particular, prompted suggestions
that future studies involve patients with similar causes
of disease13 or with global tissue hypoxia (as reflected
by elevated lactate concentrations)15 and that they examine interventions begun at an earlier stage of disease.16,17
We examined whether early goal-directed therapy
before admission to the intensive care unit effectively
reduces the incidence of multiorgan dysfunction, mor-
tality, and the use of health care resources among patients with severe sepsis or septic shock.
METHODS
Approval of Study Design
This prospective, randomized study was approved by the institutional review board for human research and was conducted under
the auspices of an independent safety, efficacy, and data monitoring
committee.
SIRS criteria and systolic
blood pressure «90 mm Hg
or lactate »4 mmol/liter
Assessment
and
consent
Standard therapy in
emergency department
(n=133)
Early goaldirected therapy
(n=130)
Randomization
(n=263)
Vital signs, laboratory
data, cardiac monitoring,
pulse oximetry, urinary
catheterization, arterial and
central venous catheterization
CVP »8–12 mm Hg
CVP »8–12 mm Hg
MAP »65 mm Hg
Continuous
ScvO2 monitoring
and
early goal-directed
therapy for »6 hr
Standard
care
Urine output
»0.5 ml/kg/hr
Hospital
admission
Follow-up
Urine output
»0.5 ml/kg/hr
ScvO2 »70%
SaO2 »93%
Vital signs and laboratory
data obtained every
12 hr for 72 hr
Did not
complete 6 hr
(n=14)
MAP »65 mm Hg
Hematocrit »30%
Did not
complete 6 hr
(n=13)
Cardiac index
◊O2
Figure 1. Overview of Patient Enrollment and Hemodynamic Support.
SIRS denotes systemic inflammatory response syndrome, CVP central venous pressure, MAP mean arterial pressure, ScvO2 central
venous oxygen saturation, SaO2 arterial oxygen saturation, and ◊O2 systemic oxygen consumption. The criteria for a diagnosis of
SIRS were temperature greater than or equal to 38°C or less than 36°C, heart rate greater than 90 beats per minute, respiratory rate
greater than 20 breaths per minute or partial pressure of arterial carbon dioxide less than 32 mm Hg, and white-cell count greater
than 12,000 per cubic millimeter or less than 4000 per cubic millimeter or the presence of more than 10 percent immature band forms.
N Engl J Med, Vol. 345, No. 19 · November 8, 2001 · www.nejm.org · 1369
The Ne w E n g l a nd Jour n a l o f Me d ic i ne
Eligibility
Eligible adult patients who presented to the emergency department of an 850-bed academic tertiary care hospital with severe sepsis, septic shock, or the sepsis syndrome from March 1997 through
March 2000 were assessed for possible enrollment according to
the inclusion18,19 and exclusion criteria (Fig. 1). The criteria for inclusion were fulfillment of two of four criteria for the systemic inflammatory response syndrome and a systolic blood pressure no
higher than 90 mm Hg (after a crystalloid-fluid challenge of 20 to
30 ml per kilogram of body weight over a 30-minute period) or
a blood lactate concentration of 4 mmol per liter or more. The criteria for exclusion from the study were an age of less than 18 years,
pregnancy, or the presence of an acute cerebral vascular event, acute
coronary syndrome, acute pulmonary edema, status asthmaticus,
cardiac dysrhythmias (as a primary diagnosis), contraindication to
central venous catheterization, active gastrointestinal hemorrhage,
seizure, drug overdose, burn injury, trauma, a requirement for immediate surgery, uncured cancer (during chemotherapy), immunosuppression (because of organ transplantation or systemic disease),
do-not-resuscitate status, or advanced directives restricting implementation of the protocol.
The clinicians who assessed the patients at this stage were unaware
of the patients’ treatment assignments. After written informed consent was obtained (in compliance with the Helsinki Declaration 20),
the patients were randomly assigned either to early goal-directed
therapy or to standard (control) therapy in computer-generated
blocks of two to eight. The study-group assignments were placed
in sealed, opaque, randomly assorted envelopes, which were opened
by a hospital staff member who was not one of the study investigators.
Treatment
The patients were treated in a nine-bed unit in the emergency
department by an emergency physician, two residents, and three
nurses.3 The study was conducted during the routine treatment of
other patients in the emergency department. After arterial and central venous catheterization, patients in the standard-therapy group
were treated at the clinicians’ discretion according to a protocol for
hemodynamic support21 (Fig. 1), with critical-care consultation, and
were admitted for inpatient care as soon as possible. Blood, urine,
and other relevant specimens for culture were obtained in the emergency department before the administration of antibiotics. Antibiotics were given at the discretion of the treating clinicians. Antimicrobial therapy was deemed adequate if the in vitro sensitivities
of the identified microorganisms matched the particular antibiotic
ordered in the emergency department.22
The patients assigned to early goal-directed therapy received a
central venous catheter capable of measuring central venous oxygen
saturation (Edwards Lifesciences, Irvine, Calif.); it was connected
to a computerized spectrophotometer for continuous monitoring.
Patients were treated in the emergency department according to
a protocol for early goal-directed therapy (Fig. 2) for at least six
hours and were transferred to the first available inpatient beds.
Monitoring of central venous oxygen saturation was then discontinued. Critical-care clinicians (intensivists, fellows, and residents
providing 24-hour in-house coverage) assumed the care of all the
patients; these physicians were unaware of the patients’ study-group
assignments. The study investigators did not influence patient care
in the intensive care unit.
The protocol was as follows. A 500-ml bolus of crystalloid was
given every 30 minutes to achieve a central venous pressure of 8 to
12 mm Hg. If the mean arterial pressure was less than 65 mm Hg,
vasopressors were given to maintain a mean arterial pressure of at
least 65 mm Hg. If the mean arterial pressure was greater than
90 mm Hg, vasodilators were given until it was 90 mm Hg or below. If the central venous oxygen saturation was less than 70 percent, red cells were transfused to achieve a hematocrit of at least
30 percent. After the central venous pressure, mean arterial pressure,
and hematocrit were thus optimized, if the central venous oxygen
saturation was less than 70 percent, dobutamine administration was
started at a dose of 2.5 µg per kilogram of body weight per minute, a dose that was increased by 2.5 µg per kilogram per minute
every 30 minutes until the central venous oxygen saturation was
70 percent or higher or until a maximal dose of 20 µg per kilogram
per minute was given. Dobutamine was decreased in dose or discontinued if the mean arterial pressure was less than 65 mm Hg or if
the heart rate was above 120 beats per minute. To decrease oxygen
consumption, patients in whom hemodynamic optimization could
not be achieved received mechanical ventilation and sedatives.
Outcome Measures
The patients’ temperature, heart rate, urine output, blood pressure, and central venous pressure were measured continuously for
the first 6 hours of treatment and assessed every 12 hours for 72
hours. Arterial and venous blood gas values (including central
venous oxygen saturation measured by in vitro co-oximetry; Nova
Biomedical, Waltham, Mass.), lactate concentrations, and coagulation-related variables and clinical variables required for determination of the Acute Physiology and Chronic Health Evaluation
(APACHE II) score (on a scale from 0 to 71, with higher scores
indicating more severe organ dysfunction), 23 the Simplified Acute
Physiology Score II (SAPS II, on a scale from 0 to 174, with higher
scores indicating more severe organ dysfunction), 24 and the Multiple Organ Dysfunction Score (MODS, on a scale from 0 to 24,
with higher scores indicating more severe organ dysfunction)25 were
obtained at base line (0 hours) and at 3, 6, 12, 24, 36, 48, 60,
and 72 hours.2,26 The results of laboratory tests required only for
purposes of the study were made known only to the study investigators. Patients were followed for 60 days or until death. The
consumption of health care resources (indicated by the duration of
vasopressor therapy and mechanical ventilation and the length of
the hospital stay) was also examined.
Statistical Analysis
In-hospital mortality was the primary efficacy end point. Secondary end points were the resuscitation end points, organ-dysfunction
scores, coagulation-related variables, administered treatments, and
the consumption of health care resources. Assuming a rate of refusal
or exclusion of 10 percent, a two-sided type I error rate of 5 percent,
and a power of 80 percent, we calculated that a sample size of 260
patients was required to permit the detection of a 15 percent reduction in in-hospital mortality. Kaplan–Meier estimates of mortality, along with risk ratios and 95 percent confidence intervals, were
used to describe the relative risk of death. Differences between the
two groups at base line were tested with the use of Student’s t-test,
the chi-square test, or Wilcoxon’s rank-sum test. Incremental analyses of the area under the curve were performed to quantify differences during the interval from base line to six hours after the start
of treatment. For the data at six hours, analysis of covariance was
used with the base-line values as the covariates. Mixed models were
used to assess the effect of treatment on prespecified secondary variables during the interval from 7 to 72 hours after the start of
treatment.27 An independent, 12-member external safety, efficacy,
and data monitoring committee reviewed interim analyses of the
data after one third and two thirds of the patients had been enrolled
and at both times recommended that the trial be continued. To adjust for the two interim analyses, the alpha spending function of
DeMets and Lan 28 was used to determine that a P value of 0.04 or
less would be considered to indicate statistical significance.
RESULTS
Base-Line Characteristics
We evaluated 288 patients; 8.7 percent were excluded or did not consent to participate. The 263 patients
enrolled were randomly assigned to undergo either
standard therapy or early goal-directed therapy; 236
patients completed the initial six-hour study period.
1370 · N Engl J Med, Vol. 345, No. 19 · November 8, 2001 · www.nejm.org
EARLY GOAL-DIREC TED THERAPY IN THE TREATMENT OF SEVERE SEPSIS AND SEP TIC SHOCK
Supplemental oxygen ±
endotracheal intubation and
mechanical ventilation
Central venous and
arterial catheterization
Sedation, paralysis
(if intubated),
or both
<8 mm Hg
CVP
Crystalloid
Colloid
8–12 mm Hg
<65 mm Hg
MAP
>90 mm Hg
Vasoactive agents
»65 and «90 mm Hg
ScvO2
<70%
»70%
Transfusion of red cells
until hematocrit »30%
<70%
»70%
Inotropic agents
No
Goals
achieved
Yes
Hospital admission
Figure 2. Protocol for Early Goal-Directed Therapy.
CVP denotes central venous pressure, MAP mean arterial pressure, and ScvO2 central venous oxygen saturation.
All 263 were included in the intention-to-treat analyses. The patients assigned to standard therapy stayed
a significantly shorter time in the emergency department than those assigned to early goal-directed therapy (mean [±SD], 6.3±3.2 vs. 8.0±2.1 hours; P<
0.001). There was no significant difference between
the groups in any of the base-line characteristics, including the adequacy and duration of antibiotic therapy (Table 1). Vital signs, resuscitation end points,
organ-dysfunction scores, and coagulation-related variables were also similar in the two study groups at base
line (Table 2).
Twenty-seven patients did not complete the initial
six-hour study period (14 assigned to standard therapy and 13 assigned to early goal-directed therapy),
for the following reasons: discontinuation of aggressive medical treatment (in 5 patients in each group),
discontinuation of aggressive surgical treatment (in
2 patients in each group), a need for immediate surgery (in 4 patients assigned to standard therapy and in
3 assigned to early goal-directed therapy), a need for
interventional urologic, cardiologic, or angiographic
procedures (in 2 patients in each group), and refusal
to continue participation (in 1 patient in each group)
(P=0.99 for all comparisons). There were no significant differences between the patients who completed
N Engl J Med, Vol. 345, No. 19 · November 8, 2001 · www.nejm.org · 1371
The Ne w E n g l a nd Jour n a l o f Me d ic i ne
TABLE 1. BASE-LINE CHARACTERISTICS
VARIABLE
Age (yr)
Sex (%)
Female
Male
Time from arrival at emergency department to
enrollment
Mean (hr)
Median (min)
Entry criteria
Temperature (°C)
Heart rate (beats/min)
Systolic blood pressure (mm Hg)
Respiratory rate (breaths/min)
Partial pressure of carbon dioxide (mm Hg)
White-cell count (per mm3)
Lactate (mmol/liter)
Base-line laboratory values
Anion gap (mmol/liter)
Creatinine (mg/dl)
Blood urea nitrogen (mg/dl)
Total bilirubin (mg/dl)
g-Glutamyltransferase (U/liter)
Albumin (g/dl)
Chronic coexisting conditions (%)†
Alcohol use
Congestive heart failure
Coronary artery disease
Chronic obstructive pulmonary disease or
emphysema
Diabetes
Human immunodeficiency virus infection
Hypertension
Liver disease
History of cancer
Neurologic disease
Renal insufficiency
Smoking
Diagnosis (%)†
Medical condition
Pneumonia
Urosepsis
Peritonitis
Other
Surgical condition
Intraabdominal process
Abscess of the arms or legs
Types and features of sepsis (%)
Severe sepsis
Septic shock
Sepsis syndrome
Culture positive
Culture negative
Blood culture positive
Antibiotic therapy
Antibiotics given in the first 6 hr (%)
Antibiotics adequate (%)
Duration (days)
OF THE
PATIENTS.*
STANDARD THERAPY
(N=133)
EARLY GOAL-DIRECTED
THERAPY (N=130)
64.4±17.1
67.1±17.4
49.6
50.4
49.2
50.8
1.5±1.7
50.5
1.3±1.5
59.0
36.6±2.3
114±27
109±34
30.2±10.6
30.6±15.1
14,200±9,600
6.9±4.5
35.9±3.2
117±31
106±36
31.8±10.8
31.5±15.7
13,600±8,300
7.7±4.7
21.4±8.5
2.6±2.0
45.4±33.0
1.9±3.0
123±130
2.8±0.7
21.7±7.6
2.6±2.0
47.1±31.3
1.3±1.7
117±159
2.8±0.7
38.7
30.2
23.5
13.4
38.5
36.7
26.5
18.0
31.9
1.7
66.4
23.5
10.1
31.9
21.9
31.1
30.8
4.3
68.4
23.1
12.8
34.2
21.4
29.9
93.3
39.5
27.7
4.2
21.9
6.7
5.9
0.8
90.6
38.5
25.6
3.4
23.1
9.4
7.7
1.7
48.7
51.3
71.4
76.5
23.5
36.1
45.3
54.7
75.2
76.1
23.9
34.2
92.4
94.3
11.3±15.8
86.3
96.7
11.7±16.2
*Plus–minus values are means ±SD. There were no significant differences between groups in any
of the variables. To convert the values for creatinine to micromoles per liter, multiply by 88.4; to
convert the values for blood urea nitrogen to millimoles per liter, multiply by 0.357; and to convert
the values for total bilirubin to micromoles per liter, multiply by 17.1.
†Values sum to more than 100% because patients could have more than one condition.
1372 · N Engl J Med, Vol. 345, No. 19 · November 8, 2001 · www.nejm.org
EARLY GOAL-DIREC TED THERAPY IN THE TREATMENT OF SEVERE SEPSIS AND SEP TIC SHOCK
TABLE 2. VITAL SIGNS, RESUSCITATION END POINTS, ORGAN-DYSFUNCTION SCORES,
VARIABLE AND
TREATMENT GROUP
BASE LINE
(0 hr)
HOURS
AFTER
6
Heart rate (beats/min)
Standard therapy
EGDT
P value
Central venous pressure
(mm Hg)
Standard therapy
EGDT
P value
Mean arterial pressure
(mm Hg)
Standard therapy
EGDT
P value
Central venous oxygen
saturation (%)
Standard therapy
EGDT
P value
Lactate (mmol/liter)
Standard therapy
EGDT
P value
Base deficit (mmol/liter)
Standard therapy
EGDT
P value
Arterial pH
Standard therapy
EGDT
P value
APACHE II score
Standard therapy
EGDT
P value
SAPS II
Standard therapy
EGDT
P value
START
0–6†
OF
THERAPY
COAGULATION VARIABLES.*
BASE LINE
(0 hr)
7–72‡
114±27
117±31
0.45
105±25
103±19
0.12
108±23
105±19
0.25
99±18
96±18
0.04
6.1±7.7
5.3±9.3
0.57
11.8±6.8
13.8±4.4
0.007
10.5±6.8
11.7±5.1
0.22
11.6±6.1
11.9±5.6
0.68
76±24
74±27
0.60
81±18
95±19
<0.001
81±16
88±16
<0.001
80±15
87±15
<0.001
49.2±13.3
48.6±11.2
0.49
VARIABLE AND
TREATMENT GROUP
AND
66.0±15.5 65.4±14.2 65.3±11.4
77.3±10.0 71.6±10.2 70.4±10.7
<0.001
<0.001
<0.001
6.9±4.5
7.7±4.7
0.17
4.9±4.7
4.3±4.2
0.01
5.9±4.2
5.5±4.2
0.62
3.9±4.4
3.0±4.4
0.02
8.9±7.5
8.9±8.1
0.81
8.0±6.4
4.7±5.8
<0.001
8.6±6.0
6.7±5.6
0.006
5.1±6.7
2.0±6.6
<0.001
7.32±0.19
7.31±0.17
0.40
7.31±0.15 7.31±0.12 7.36±0.12
7.35±0.11 7.33±0.13 7.40±0.12
<0.001
0.26
<0.001
20.4±7.4
21.4±6.9
0.27
17.6±6.2
16.0±6.9
<0.001
—
—
15.9±6.4
13.0±6.3
<0.001
48.8±11.1
51.2±11.1
0.08
45.5±12.3
42.1±13.2
<0.001
—
—
42.6±11.5
36.9±11.3
<0.001
MODS
Standard therapy
EGDT
P value
Hematocrit (%)
Standard therapy
EGDT
P value
Prothrombin time
(sec)
Standard therapy
EGDT
P value
Partial-thromboplastin time (sec)
Standard therapy
EGDT
P value
Fibrinogen (mg/dl)
Standard therapy
EGDT
P value
Fibrin-split products
(µg/dl)
Standard therapy
EGDT
P value
D -Dimer (µg/ml)
Standard therapy
EGDT
P value
Platelet count
(per mm3)
Standard therapy
EGDT
P value
HOURS
AFTER
START
OF
THERAPY
6
0–6†
7–72‡
7.3±3.1
7.6±3.1
0.44
6.8±3.7
5.9±3.7
<0.001
—
—
6.4±4.0
5.1±3.9
<0.001
34.7±8.5
34.6±8.3
0.91
32.0±6.9
33.3±4.8
0.03
—
—
30.1±4.1
32.1±4.2
<0.001
16.5±6.3
15.8±5.0
0.17
17.5±8.1
16.0±3.6
0.02
—
—
17.3±6.1
15.4±6.1
0.001
32.9±12.0
33.3±20.4
0.17
37.6±21.0
32.6±8.7
0.01
—
—
37.0±14.2
34.6±14.1
0.06
361±198
370±209
0.51
319±142
300±157
0.01
—
—
358±134
342±134
0.21
39.0±61.6
44.8±71.3
0.76
54.9±84.0
45.8±66.0
0.13
—
—
62.0±71.4
39.2±71.2
<0.001
3.66±8.45 5.48±11.95
4.46±10.70 3.98±9.41
0.71
0.05
—
—
5.65±9.06
3.34±9.02
0.006
205,000±
110,000
220,000±
135,000
0.65
—
144,000±
84,000
139,000±
82,000
0.51
164,000±
84,000
156,000±
90,000
0.001
—
*Plus–minus values are means ±SD. EGDT denotes early goal-directed therapy, APACHE II Acute Physiology and Chronic Health Evaluation, SAPS
II Simplified Acute Physiology Score II, and MODS Multiple Organ Dysfunction Score.
†For the period from base line (0 hours) to 6 hours, the area under the curve was calculated, except for noncontinuous variables (as indicated by dashes).
‡For the period from 7 to 72 hours, the adjusted mean value was obtained from a mixed model.
the initial six-hour study period and those who did
not in any of the base-line characteristics or base-line
vital signs, resuscitation end points, organ-dysfunction scores, or coagulation-related variables (data not
shown).
Vital Signs and Resuscitation End Points
During the initial six hours after the start of therapy, there was no significant difference between the
two study groups in the mean heart rate (P=0.25)
or central venous pressure (P=0.22) (Table 2). During this period, the mean arterial pressure was significantly lower in the group assigned to standard therapy than in the group assigned to early goal-directed
therapy (P<0.001), but in both groups the goal of
65 mm Hg or higher was met by all the patients. The
goal of 70 percent or higher for central venous oxygen
saturation was met by 60.2 percent of the patients in
the standard-therapy group, as compared with 94.9
percent of those in the early-therapy group (P<0.001).
The combined hemodynamic goals for central venous
pressure, mean arterial pressure, and urine output
(with adjustment for patients with end-stage renal
failure) were achieved in 86.1 percent of the standard-therapy group, as compared with 99.2 percent of
the early-therapy group (P<0.001). During this period, the patients assigned to standard therapy had a
significantly lower central venous oxygen saturation
(P<0.001) and a greater base deficit (P=0.006) than
those assigned to early goal-directed therapy; the two
N Engl J Med, Vol. 345, No. 19 · November 8, 2001 · www.nejm.org · 1373
The Ne w E n g l a nd Jour n a l o f Me d ic i ne
ference between the groups in mortality at 60 days
primarily reflected the difference in in-hospital mortality. Similar results were obtained after data from
the 27 patients who did not complete the initial sixhour study period were excluded from the analysis
(data not shown). The rate of in-hospital death due to
sudden cardiovascular collapse was significantly higher in the standard-therapy group than in the earlytherapy group (P=0.02); the rate of death due to multiorgan failure was similar in the two groups (P=0.27).
groups had similar lactate concentrations (P=0.62)
and similar pH values (P=0.26).
During the period from 7 to 72 hours after the
start of treatment, the patients assigned to standard
therapy had a significantly higher heart rate (P=0.04)
and a significantly lower mean arterial pressure (P<
0.001) than the patients assigned to early goal-directed
therapy; the two groups had a similar central venous
pressure (P=0.68). During this period, those assigned
to standard therapy also had a significantly lower central venous oxygen saturation than those assigned to
early goal-directed therapy (P<0.001), as well as a
higher lactate concentration (P=0.02), a greater base
deficit (P<0.001), and a lower pH (P<0.001).
Administered Treatments
During the initial six hours, the patients assigned
to early goal-directed therapy received significantly
more fluid than those assigned to standard therapy
(P<0.001) and more frequently received red-cell transfusion (P<0.001) and inotropic support (P<0.001),
whereas similar proportions of patients in the two
groups required vasopressors (P=0.62) and mechanical ventilation (P=0.90) (Table 4). During the period
from 7 to 72 hours, however, the patients assigned to
standard therapy received significantly more fluid than
those assigned to early goal-directed therapy (P=0.01)
and more often received red-cell transfusion (P<
0.001) and vasopressors (P=0.03) and underwent
mechanical ventilation (P<0.001) and pulmonaryartery catheterization (P=0.04); the rate of use of inotropic agents was similar in the two groups (P=0.14)
(Table 4). During the overall period from base line
to 72 hours after the start of treatment, there was no
significant difference between the two groups in the
total volume of fluid administered (P=0.73) or the
rate of use of inotropic agents (P=0.15), although a
greater proportion of the patients assigned to standard therapy than of those assigned to early goal-direct-
Organ Dysfunction and Coagulation Variables
During the period from 7 to 72 hours, the
APACHE II score, SAPS II, and MODS were significantly higher in the patients assigned to standard therapy than in the patients assigned to early goal-directed
therapy (P<0.001 for all comparisons) (Table 2). During this period, the prothrombin time was significantly greater in the patients assigned to standard therapy
than in those assigned to early goal-directed therapy
(P=0.001), as was the concentration of fibrin-split
products (P<0.001) and the concentration of D-dimer
(P=0.006). The two groups had a similar partialthromboplastin time (P=0.06), fibrinogen concentration (P=0.21), and platelet count (P=0.51) (Table 2).
Mortality
In-hospital mortality rates were significantly higher
in the standard-therapy group than in the early-therapy group (P=0.009), as was the mortality at 28 days
(P=0.01) and 60 days (P=0.03) (Table 3). The dif-
TABLE 3. KAPLAN–MEIER ESTIMATES
VARIABLE
OF
MORTALITY
STANDARD THERAPY
(N=133)
AND
CAUSES
OF IN-HOSPITAL
EARLY
GOAL-DIRECTED
THERAPY
(N=130)
DEATH.*
RELATIVE RISK
(95% CI)
P VALUE
no. (%)
In-hospital mortality†
All patients
Patients with severe sepsis
Patients with septic shock
Patients with sepsis syndrome
28-Day mortality†
60-Day mortality†
Causes of in-hospital death‡
Sudden cardiovascular collapse
Multiorgan failure
59
19
40
44
61
70
(46.5)
(30.0)
(56.8)
(45.4)
(49.2)
(56.9)
25/119 (21.0)
26/119 (21.8)
38
9
29
35
40
50
(30.5)
(14.9)
(42.3)
(35.1)
(33.3)
(44.3)
0.58
0.46
0.60
0.66
0.58
0.67
12/117 (10.3)
19/117 (16.2)
(0.38–0.87)
(0.21–1.03)
(0.36–0.98)
(0.42–1.04)
(0.39–0.87)
(0.46–0.96)
—
—
0.009
0.06
0.04
0.07
0.01
0.03
0.02
0.27
*CI denotes confidence interval. Dashes indicate that the relative risk is not applicable.
†Percentages were calculated by the Kaplan–Meier product-limit method.
‡The denominators indicate the numbers of patients in each group who completed the initial six-hour study period.
1374 · N Engl J Med, Vol. 345, No. 19 · November 8, 2001 · www.nejm.org
EARLY GOAL-DIREC TED THERAPY IN THE TREATMENT OF SEVERE SEPSIS AND SEP TIC SHOCK
a significantly longer time in the hospital than those
assigned to early goal-directed therapy (18.4±15.0 vs.
14.6±14.5 days, P=0.04).
TABLE 4. TREATMENTS ADMINISTERED.*
TREATMENT
HOURS
0–6
AFTER THE
START
7–72
OF
THERAPY
0–72
Total fluids (ml)
Standard therapy
3499±2438 10,602±6,216 13,358±7,729
EGDT
4981±2984 8,625±5,162 13,443±6,390
P value
<0.001
0.01
0.73
Red-cell transfusion (%)
Standard therapy
18.5
32.8
44.5
EGDT
64.1
11.1
68.4
P value
<0.001
<0.001
<0.001
Any vasopressor (%)†
Standard therapy
30.3
42.9
51.3
EGDT
27.4
29.1
36.8
P value
0.62
0.03
0.02
Inotropic agent (dobutamine) (%)
Standard therapy
0.8
8.4
9.2
EGDT
13.7
14.5
15.4
P value
<0.001
0.14
0.15
Mechanical ventilation (%)
Standard therapy
53.8
16.8
70.6
EGDT
53.0
2.6
55.6
P value
0.90
<0.001
0.02
Pulmonary-artery catheterization (%)‡
Standard therapy
3.4
28.6
31.9
EGDT
0
18.0
18.0
P value
0.12
0.04
0.01
*Plus–minus values are means ±SD. Because some patients received a
specific treatment both during the period from 0 to 6 hours and during
the period from 7 to 72 hours, the cumulative totals for those two periods
do not necessarily equal the values for the period from 0 to 72 hours.
EGDT denotes early goal-directed therapy.
†Administered vasopressors included norepinephrine, epinephrine, dopamine, and phenylephrine hydrochloride.
‡All pulmonary-artery catheters were inserted while patients were in the
intensive care unit.
ed therapy received vasopressors (P=0.02) and mechanical ventilation (P=0.02) and underwent pulmonary-artery catheterization (P=0.01), and a smaller
proportion required red-cell transfusion (P<0.001).
Though similar between the groups at base line (P=
0.91), the mean hematocrit during this 72-hour period was significantly lower in the standard-therapy
group than in the early-therapy group (P<0.001).
Despite the transfusion of red cells, it was significantly
lower than the value obtained at base line in each
group (P<0.001 for both comparisons) (Table 2).
Consumption of Health Care Resources
There were no significant differences between the
two groups in the mean duration of vasopressor therapy (2.4±4.2 vs. 1.9±3.1 days, P=0.49), the mean
duration of mechanical ventilation (9.0±13.1 vs. 9.0±
11.4 days, P=0.38), or the mean length of stay in the
hospital (13.0±13.7 vs. 13.2±13.8 days, P=0.54).
However, of the patients who survived to hospital discharge, those assigned to standard therapy had stayed
DISCUSSION
Severe sepsis and septic shock are common and are
associated with substantial mortality and substantial
consumption of health care resources. There are an
estimated 751,000 cases (3.0 cases per 1000 population) of sepsis or septic shock in the United States
each year, and they are responsible for as many deaths
each year as acute myocardial infarction (215,000, or
9.3 percent of all deaths).29 In elderly persons, the
incidence of sepsis or septic shock and the related
mortality rates are substantially higher than those in
younger persons. The projected growth of the elderly population in the United States will contribute
to an increase in incidence of 1.5 percent per year,
yielding an estimated 934,000 and 1,110,000 cases
by the years 2010 and 2020, respectively.29 The
present annual cost of this disease is estimated to be
$16.7 billion.29
The transition from the systemic inflammatory response syndrome to severe sepsis and septic shock
involves a myriad of pathogenic changes, including
circulatory abnormalities that result in global tissue
hypoxia.1,2 These pathogenic changes have been the
therapeutic target of previous outcome studies.12 Although this transition occurs over time, both out of
the hospital and in the hospital, in outcome studies
interventions have usually been initiated after admission to the intensive care unit.12 In studies of goaldirected hemodynamic optimization, in particular,
there was no benefit in terms of outcome with respect
to normal and supranormal hemodynamic end points,
as well as those guided by mixed venous oxygen saturation.9,13 In contrast, even though we enrolled patients with lower central venous oxygen saturation and
lower central venous pressure than those studied by
Gattinoni et al.9 and with a higher lactate concentration than those studied by Hayes et al.,13 we found
significant benefits with respect to outcome when
goal-directed therapy was applied at an earlier stage
of disease. In patients with septic shock, for example,
Hayes et al. observed a higher in-hospital mortality
rate with aggressive hemodynamic optimization in the
intensive care unit (71 percent) than with control therapy (52 percent), whereas we observed a lower mortality rate in patients with septic shock assigned to early goal-directed therapy (42.3 percent) than in those
assigned to standard therapy (56.8 percent).
The benefits of early goal-directed therapy in terms
of outcome are multifactorial. The incidence of death
due to sudden cardiovascular collapse in the standardtherapy group was approximately double that in the
group assigned to early goal-directed therapy, suggesting that an abrupt transition to severe disease is an important cause of early death. The early identification
N Engl J Med, Vol. 345, No. 19 · November 8, 2001 · www.nejm.org · 1375
The Ne w E n g l a nd Jour n a l o f Me d ic i ne
of patients with insidious illness (global tissue hypoxia
accompanied by stable vital signs) makes possible the
early implementation of goal-directed therapy. If sudden cardiovascular collapse can be prevented, the subsequent need for vasopressors, mechanical ventilation,
and pulmonary-artery catheterization (and their associated risks) diminishes. In addition to being a stimulus of the systemic inflammatory response syndrome,
global tissue hypoxia independently contributes to
endothelial activation and disruption of the homeostatic balance among coagulation, vascular permeability, and vascular tone.30 These are key mechanisms
leading to microcirculatory failure, refractory tissue
hypoxia, and organ dysfunction.2,30 When early therapy is not comprehensive, the progression to severe
disease may be well under way at the time of admission to the intensive care unit.16 Aggressive hemodynamic optimization and other therapy12 undertaken
thereafter may be incompletely effective or even deleterious.13
The value of measurements of venous oxygen saturation at the right atrium or superior vena cava (central venous oxygen saturation) instead of at the pulmonary artery (mixed venous oxygen saturation) has
been debated,31 in particular, when saturation values
are above 65 percent. In patients in the intensive care
unit who have hyperdynamic septic shock, the mixed
venous oxygen saturation is rarely below 65 percent.32
In contrast, our patients were examined during the
phase of resuscitation in which the delivery of supplemental oxygen is required (characterized by a decreased mixed venous oxygen saturation and an increased lactate concentration), when the central venous
oxygen saturation generally exceeds the mixed venous
oxygen saturation.33,34 The initial central venous oxygen saturation was less than 50 percent in both study
groups. The mixed venous oxygen saturation is estimated to be 5 to 13 percent lower in the pulmonary
artery33 and 15 percent lower in the splanchnic bed.35
Though not numerically equivalent, these ranges of
values are pathologically equivalent and are associated with high mortality.32,36 Among all the patients in
the current study in whom the goals with respect to
central venous pressure, mean arterial pressure, and
urine output during the first six hours were met, 39.8
percent of those assigned to standard therapy were
still in this oxygen-dependent phase of resuscitation
at six hours, as compared with 5.1 percent of those assigned to early goal-directed therapy. The combined
56.5 percent in-hospital mortality of this 39.8 percent of patients, who were at high risk for hemodynamic compromise, is consistent with the results of
previous studies in the intensive care unit.32,36
In an open, randomized, partially blinded trial,
there are unavoidable interactions during the initial period of the study. As the study progressed, the patients
in the standard-therapy group may have received some
form of goal-directed therapy, reducing the treatment
effect. This reduction may have been offset by the
slight but inherent bias resulting from the direct influence of the investigators on the care of the patients
in the treatment group. The potential period of bias
was 9.9±19.5 percent of the overall hospital stay in
the standard-therapy group and 7.2±12.0 percent of
that in the group assigned to early goal-directed therapy (P=0.20). This interval was minimal in comparison with those in previous studies9,13 because the clinicians who assumed responsibility for the remainder
of hospitalization were completely blinded to the randomization order.
We conclude that goal-directed therapy provided
at the earliest stages of severe sepsis and septic shock,
though accounting for only a brief period in comparison with the overall hospital stay, has significant
short-term and long-term benefits. These benefits
arise from the early identification of patients at high
risk for cardiovascular collapse and from early therapeutic intervention to restore a balance between oxygen delivery and oxygen demand. In the future, investigators conducting outcome trials in patients with
sepsis should consider the quality and timing of the
resuscitation before enrollment as an important outcome variable.
Supported by the Henry Ford Health Systems Fund for Research, a Weatherby Healthcare Resuscitation Fellowship, Edwards Lifesciences (which provided oximetry equipment and catheters), and Nova Biomedical (which provided equipment for laboratory assays).
We are indebted to the nurses, residents, senior staff attending physicians, pharmacists, patient advocates, technicians, and billing and
administrative personnel of the Department of Emergency Medicine;
to the nurses and technicians of the medical and surgical intensive care
units; and to the staff members of the Department of Respiratory Therapy, Department of Pathology, Department of Medical Records, and
Department of Admitting and Discharge for their patience and
their cooperation in making this study possible.
APPENDIX
The following persons participated in the study: External Safety, Efficacy, and Data Monitoring Committee: A. Connors (Charlottesville, Va.),
S. Conrad (Shreveport, La.), L. Dunbar (New Orleans), S. Fagan (Atlanta),
M. Haupt (Portland, Oreg.), R. Ivatury (Richmond, Va.), G. Martin (Detroit), D. Milzman (Washington, D.C.), E. Panacek (Palo Alto, Calif.), M.
Rady (Scottsdale, Ariz.), M. Rudis (Los Angeles), and S. Stern (Ann Arbor,
Mich.); the Early-Goal-Directed-Therapy Collaborative Group: B. Derechyk, W. Rittinger, G. Hayes, K. Ward, M. Mullen, V. Karriem, J. Urrunaga, M. Gryzbowski, A. Tuttle, W. Chung, P. Uppal, R. Nowak, D. Powell,
T. Tyson, T. Wadley, G. Galletta, K. Rader, A. Goldberg, D. Amponsah,
D. Morris, K. Kumasi-Rivers, B. Thompson, D. Ander, C. Lewandowski,
J. Kahler, K. Kralovich, H. Horst, S. Harpatoolian, A. Latimer, M. Schubert,
M. Fallone, B. Fasbinder, L. Defoe, J. Hanlon, A. Okunsanya, B. Sheridan,
Q. Rivers, H. Johnson, B. Sessa-Boji, K. Gunnerson, D. Fritz, K. Rivers,
S. Moore, D. Huang, and J. Farrerer (Henry Ford Hospital, Detroit).
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Copyright © 2001 Massachusetts Medical Society.
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N Engl J Med, Vol. 345, No. 19 · November 8, 2001 · www.nejm.org · 1377
Vasopressor and inotropic support in septic shock: An evidencebased review
Richard J. Beale, MBBS; Steven M. Hollenberg, MD, FCCM; Jean-Louis Vincent, MD, PhD, FCCM;
Joseph E. Parrillo, MD, FCCM
Objective: In 2003, critical care and infectious disease experts
representing 11 international organizations developed management
guidelines for vasopressor and inotropic support in septic shock that
would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to
increase awareness and to improve outcome in severe sepsis.
Design: The process included a modified Delphi method, a
consensus conference, several subsequent smaller meetings of
subgroups and key individuals, teleconferences, and electronicbased discussion among subgroups and among the entire committee.
Methods: The modified Delphi methodology used for grading
recommendations built on a 2001 publication sponsored by the
International Sepsis Forum. We undertook a systematic review of
the literature graded along five levels to create recommendation
grades from A to E, with A being the highest grade. Pediatric
S
hock may be defined as an impairment of the normal relationship between oxygen demand and oxygen supply. As a
consequence, there are detrimental alterations in tissue perfusion, resulting in a
reduction in the delivery of oxygen and
other nutrients to tissue beds and causing cellular and then organ dysfunction.
In hypovolemic, cardiogenic, and obstructive forms of shock, the primary defect is a fall in cardiac output, leading to
hypoperfusion, hypotension, and anaerobic metabolism. In septic shock, however,
there is a complex interaction between
pathologic vasodilatation, relative and absolute hypovolemia, direct myocardial
depression, and altered blood flow distribution, which occur as a consequence of
the inflammatory response to infection.
Even after the restoration of circulating
From Guy’s and St. Thomas’ NHS Foundation Trust,
London, UK (RJB, SMH, JEP); Klinik für Anaesthesie,
Operative Intensivmedizin und Schmerztherapie,
Vivantes-Klinikum Neukölin, Berlin, Germany (J-LV).
Copyright © 2004 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000142909.86238.B1
Crit Care Med 2004 Vol. 32, No. 11 (Suppl.)
considerations to contrast adult and pediatric management are in
the article by Parker et al. on p. S591.
Conclusion: An arterial catheter should be placed as soon as
possible in patients with septic shock. Vasopressors are indicated
to maintain mean arterial pressure of <65 mm Hg, both during
and following adequate fluid resuscitation. Norepinephrine or
dopamine are the vasopressors of choice in the treatment of
septic shock. Norepinephrine may be combined with dobutamine
when cardiac output is being measured. Epinephrine, phenylephrine, and vasopressin are not recommended as first-line agents in
the treatment of septic shock. Vasopressin may be considered for
salvage therapy. Low-dose dopamine is not recommended for the
purpose of renal protection. Dobutamine is recommended as the
agent of choice to increase cardiac output but should not be used
for the purpose of increasing cardiac output above physiologic
levels. (Crit Care Med 2004; 32[Suppl.]:S455–S465)
volume, maldistribution of a normal or
increased cardiac output typically persists
as a consequence of microvascular abnormalities. In addition, cellular and organ
injury also occur as direct consequences
of the inflammatory response in sepsis
and as a consequence of hypoperfusion.
Making recommendations about the
choice of individual vasopressor agents in
septic shock is made difficult by the paucity of controlled trials and by the clinical
reality that agents are frequently used in
combination. In modern practice, norepinephrine and dopamine are the vasopressors used most frequently, although dopamine has more marked inotropic
effects. The relatively small inotropic effect of norepinephrine, and concerns
about regional blood flow, mean that it is
frequently used in combination with dobutamine. Epinephrine may also be used
as an alternative and, again, combines
vasopressor and inotropic effects. Phenylephrine, which has virtually only vasopressor actions, is also sometimes used.
Dopamine and epinephrine in particular
have important metabolic and endocrine
effects that may complicate their use and
be potentially detrimental. This review of
the literature enables recommendations
to be established and graded according to
the strength of the available evidence.
End Points of Resuscitation and
Monitoring in Septic Shock
The complexity of the pathophysiology
and the limitations of routinely used hemodynamic monitoring techniques have
made defining the end points of hemodynamic management of sepsis difficult.
Nevertheless, the available literature does
provide important guidance as to a basic
approach to the use of vasopressors and
inotropes in sepsis, although this will undoubtedly change as our understanding
improves further. Septic shock is characterized by hypotension, which in adults
generally refers to a mean arterial pressure below 65–70 mm Hg, and altered
tissue perfusion. Poor tissue perfusion
may be manifest clinically by reduced
capillary refill, oliguria, and altered sensorium. Some caution is necessary in interpreting these signs, however, because
signs of peripheral vasoconstriction may
be absent in some patients who may seem
S455
deceptively well in the early phases of
severe sepsis.
Other global markers of tissue perfusion that are used clinically include the
acid-base status (base excess and blood
lactate) and the mixed venous or central
venous oxygen saturations. The adequacy
of regional perfusion is usually assessed
by evaluating indices of specific organ
function, although none of these alone
has been validated as a reliable indicator
of adequate resuscitation. These include
coagulation abnormalities (disseminated
intravascular coagulation); altered renal
function with increased blood urea nitrogen and creatinine; altered liver parenchymal function with increased serum
levels of transaminases, lactate dehydrogenase, and bilirubin; and altered gut
perfusion, manifest by ileus and malabsorption. A number of approaches may be
employed to monitor the hemodynamic
and perfusion status of patients with septic shock. The variables measured provide
potential end points for the resuscitation
process and information about the
progress of the patient in response to
treatment.
Arterial Blood Pressure. Because hypotension is a primary feature of septic
shock and improving blood pressure is
frequently a therapeutic goal, accurate
and continuous measurement of blood
pressure is essential. It is therefore customary to use an arterial catheter to enable continuous invasive blood pressure
monitoring. The radial artery is the site
most frequently chosen, but the femoral
artery is also often used. It is important
to note that there may be marked differences in the blood pressure recordings at
the two sites, especially in patients who
are in shock, receiving vasopressors, and
still hypovolemic.
Intravascular Volume Status. Adequate fluid resuscitation is a fundamental
aspect of the hemodynamic management
of patients with septic shock. Ideally, this
should be achieved before vasopressors
and inotropes are used, although it is
frequently necessary to employ vasopressors early as an emergency measure in
patients with severe shock. In fluidresponsive hearts, in which the FrankStarling mechanism is intact, fluid administration increases preload and
therefore stroke volume and cardiac output. Depending on the degree of vasodilatation, there may also be an increase in
blood pressure. There are a number of
approaches to monitoring intravascular
filling that are employed currently. These
S456
include the use of traditional cardiac filling pressures (central venous pressure
and pulmonary artery occlusion pressure), which are limited by errors in routine measurement, the confounding effects of mechanical ventilation, and
uncertainties about the compliance of the
left ventricle. Alternatives employed with
increasing frequency in modern practice
include central blood volume measurements using the transpulmonary indicator dilution technique and analysis of patterns of dynamic changes in the arterial
waveform in response to mechanical ventilation (systolic pressure variation,
stroke volume variation) as a predictor of
volume responsiveness. This issue is addressed in more detail in the section on
fluid resuscitation.
Cardiac Output. Cardiac output is frequently measured in patients with septic
shock, both as a guide to the adequacy of
resuscitation and to allow calculation of
oxygen transport variables. It is also useful diagnostically in confirming the typical hyperdynamic picture of septic shock,
although this is not always present, especially if the patient is still hypovolemic or
has co-existing cardiac disease.
Mixed Venous Oxygen Saturation and
Central Venous Oxygen Saturation.
Mixed venous oxygen saturation (SV៮ O2)
can be measured in patients with a pulmonary artery catheter in place. SV៮ O2 is
dependent on cardiac output, oxygen demand, hemoglobin, and arterial oxygen
saturation. The normal SV៮ O2 value is 70 –
75% in critically ill patients but can be
elevated in septic patients due to maldistribution of blood flow. Frequently, however, it may be low or even normal, and
the value must be interpreted carefully in
the context of the wider hemodynamic
picture. Nevertheless, it is useful to measure SV៮ O2 because if cardiac output becomes inadequate, SV៮ O2 decreases. Moreover, if SV៮ O2 remains low even though
other end points of resuscitation have
been corrected, this suggests increased
oxygen extraction and therefore potentially incomplete resuscitation. Ronco et
al. (1) studied terminally ill patients in
whom treatment was withdrawn; SV៮ O2
decreased dramatically before oxygen
consumption started to fall, indicating
that oxygen extraction capabilities are
not necessarily profoundly altered even in
patients in the final stage of the disease
process. Hence, SV៮ O2, if normal or high,
does not necessarily indicate adequate resuscitation, whereas a low SV៮ O2 should
prompt rapid intervention to increase ox-
ygen delivery to the tissues. The advent of
continuous SV៮ O2 monitoring using fiberoptic pulmonary artery catheters has
greatly increased the value of this variable as a real-time monitor, so long as the
systems are recalibrated appropriately.
Central venous oxygen saturation is
becoming increasingly popular as an alternative to SV៮ O2 because the measurement provides a clinically useful approximation to SV៮ O2 and can be obtained from
a central venous catheter without the
need for pulmonary artery catheterization. In a recent study in patients with
severe sepsis presenting to the emergency department, Rivers et al. (2) randomized 263 patients with severe sepsis
or septic shock to receive either standard
resuscitation or early goal-directed therapy for the first 6 hrs after admission.
Central venous oxygen saturation was
used as an intrinsic part of the early goaldirected therapy protocol, targeting a
value of 70%. The mortality in the early
goal-directed therapy group was 30.5%
compared with 46.5% in the standard
care group (p ⫽ .009).
Blood Lactate Levels. Hyperlactatemia
(⬎2 mEq/L) is typically present in patients with septic shock and may be secondary to anaerobic metabolism due to
hypoperfusion. However, the interpretation of blood lactate levels in septic patients is not always straightforward. Experimental studies have not always been
able to show a reduction in high-energy
phosphate levels in animal models of sepsis (3). The differences between studies
may be related to the severity of the septic model, with more severe sepsis being
associated with depletion of adenosine
triphosphate, despite maintenance of systemic oxygen delivery and tissue oxygenation. Also, measurements of tissue PO2
in septic patients have not demonstrated
tissue hypoxia in the presence of lactic
acidosis (4). However, if inhomogeneity
in blood flow distribution is a real phenomenon, it is likely that cell hypoperfusion also exists with ischemia/reperfusion. A number of studies have suggested
that elevated lactate levels may result
from cellular metabolic failure rather
than from global hypoperfusion in sepsis.
Some organs may produce more lactate
than others, in particular, the lungs in
acute lung injury or acute respiratory distress syndrome (5, 6). Elevated lactate
levels can also result from decreased
clearance by the liver, and patients with
septic shock may have a more severe liver
injury than conventional liver function
Crit Care Med 2004 Vol. 32, No. 11 (Suppl.)
tests may suggest (7). Nonetheless, the
prognostic value of raised blood lactate
levels has been well established in septic
shock patients (8), particularly if the high
levels persist (9, 10). It is also of interest
to note that blood lactate levels are of
greater prognostic value than oxygenderived variables (11).
Gut Tonometry. The measurement of
regional perfusion as a means of detecting inadequate tissue oxygenation has focused on the splanchnic circulation, as
the hepatosplanchnic circulation is particularly sensitive to changes in blood
flow and oxygenation for several reasons.
First, under normal conditions, the gut
mucosa receives the majority of total intestinal blood flow. However, in sepsis,
there is a redistribution of flow away from
the mucosa toward the serosa and muscularis (12), resulting in mucosal hypoxia. Any further reduction in splanchnic
flow has a correspondingly greater effect
on gut hypoxia. Second, the gut may have
a higher critical oxygen delivery threshold than other organs (13). Third, the tip
of the villus is supplied by a central arteriole and drained by venules passing away
from the tip. A countercurrent exchange
mechanism operates in the villus,
whereby a base-to-tip PO2 gradient exists,
making the tip particularly sensitive to
changes in regional flow and oxygenation. Fourth, constriction of the villus
arteriole occurs during sepsis (14), rendering the villus even more sensitive to
reductions in blood flow. Fifth, the capillary density at the villus tip is reduced
during sepsis (15), impeding the transfer
of oxygen. Finally, gut ischemia increases
intestinal permeability, which may increase translocation of bacteria or cytokines. This mechanism is frequently suggested as a possible trigger or “motor” of
the sepsis response and multiple organ
failure, and recent work has suggested
that the lymphatic drainage of the gut
may be an important route by which inflammatory mediators released by injured
gut reach the systemic circulation (16).
Gastric tonometry has been proposed
as a method to assess regional perfusion
in the gut by measuring intragastric
⌬PCO2. Originally, the PCO2 value was
used, together with the arterial bicarbonate, to calculate gastric intramucosal pH
(pHi), but arterial bicarbonate represents
global conditions, is nonspecific, and is
measured only intermittently. Consequently, pHi measurement has become
obsolete, and the change in the PCO2 signal itself is considered more representaCrit Care Med 2004 Vol. 32, No. 11 (Suppl.)
tive of conditions in the gut. Gastric mucosal P CO 2 is influenced directly by
systemic arterial PCO2, and some clinicians have proposed using the gastricarterial PCO2 difference as the primary
tonometric variable of interest (17). Even
this measure is not a simple measure of
gastric mucosal hypoxia because either
anaerobic metabolism, decreased gastric
blood flow in the absence of anaerobic
metabolism, or a combination of the two
can increase gastric mucosal PCO2 (17).
An early trial suggested that tonometryderived variables might be useful in
guiding therapy (18), but these findings
were not confirmed recently (19), and
many investigators have emphasized
the limited sensitivity and specificity of
these measurements. Various vasoactive agents have been shown to have
divergent effects on gastric PCO2 and
pHi that are neither consistent nor predictable (20). Perhaps most problematic, tonometric PCO2 measurement is
confounded by enteral feeding, which is
often started relatively early in modern
intensive care practice. Taken together,
these limitations make gastric tonometry of interest largely as a research tool
rather than as a useful clinical monitor
for routine use.
Sublingual Capnometry. Sublingual
capnometry is a new technique just beginning the process of clinical evaluation.
It is based on the principle that reduced
perfusion leading to an increase in tissue
PCO2 occurs in areas of the gastrointestinal tract other than just the stomach,
including the readily accessible sublingual mucosa (21). The device itself uses a
PCO2-sensitive optode placed under the
tongue to detect changes in the local CO2
tension. Recently, in an observational
study of 54 unstable critically ill patients,
of whom 21 had either severe sepsis or
septic shock and 27 died, Marik and
Bankov (22) demonstrated that the initial
sublingual PCO2–PCO2 gap was the best
predictor of outcome (p ⫽ .0004), followed by the initial sublingual PCO2 reading itself (p ⫽ .004). The area under the
receiver operating characteristic curve
for the sublingual PCO2–PCO2 gap was
0.75, and the best threshold for discriminating between survivors and nonsurvivors was a gap of ⬍25 mm Hg. Data were
obtained at admission (after insertion of a
pulmonary artery catheter), at 4 hrs, and
at 8 hrs, and there were no differences
between either blood lactate or SV៮ O2 between survivors and nonsurvivors during
this period. Clearly, although initial re-
ports are encouraging, much more experience is required to establish whether
this technique will have a role as a routine clinical monitor in the future.
Question: Is it recommended to monitor
arterial blood pressure continuously in
septic shock by using an arterial catheter?
Yes; Grade E
Recommendations: All patients with septic shock requiring vasopressors should
have an arterial catheter placed as soon as
practical if resources are available.
Grade E
Rationale: In shock states, measurement
of blood pressure using a cuff is commonly inaccurate, whereas use of an arterial catheter provides a more accurate
and reproducible measurement of arterial
pressure. Monitoring using these catheters also allows beat-to-beat analysis so
that decisions regarding therapy can be
based on immediate blood pressure information (23). Placement of an arterial
catheter in the emergency department is
typically not possible or practical. It is
important to appreciate the complications of arterial catheter placement,
which include hemorrhage and damage
to arterial vessels.
Question: Does vasopressor support improve outcome from septic shock?
Yes; Grade E
Recommendations: When an appropriate
fluid challenge fails to restore an adequate arterial pressure and organ perfusion, therapy with vasopressor agents
should be started. Vasopressor therapy
may also be required transiently to sustain life and maintain perfusion in the
face of life-threatening hypotension, even
when hypovolemia has not been resolved.
Grade E
Rationale: Adequate fluid resuscitation is
a prerequisite for the successful and appropriate use of either vasopressors or
inotropes in patients with septic shock,
and in general, the end points of fluid
resuscitation are the same as those for
the use of pharmacologic hemodynamic
support. Sometimes, fluid resuscitation
alone may suffice. The choice of fluid
remains a matter of debate, but patients
with septic shock can be successfully resuscitated with either crystalloid or colloid, or a combination of both. It is also
S457
necessary to maintain a minimum hemoglobin concentration to ensure adequate
blood oxygen carriage and oxygen dispatch to the tissues. These aspects of the
management of the patient with septic
shock are discussed in detail elsewhere.
Four agents with vasopressor activity
are commonly used in the treatment of
patients with septic shock. These are dopamine, norepinephrine, epinephrine,
and phenylephrine. More recently, there
has been an increasing trend to use lowdose hydrocortisone as an adjunct to vasopressor therapy, especially in patients
who exhibit a poor response to the primary vasopressor agent. The other recent
change in practice is the increasing interest in the possible role of vasopressin
as an alternative vasopressor agent in patients with septic shock.
Although all the vasopressor agents
mentioned generally result in an increase
in blood pressure, concerns remain in
clinical practice about their potentially
inappropriate or detrimental use. The
most obvious of these relates to the inadequately volume-resuscitated patient, in
whom vasopressor use may worsen already inadequate organ perfusion. Even
when volume resuscitation has been performed, discussion continues as to
whether vasopressor agents may raise
blood pressure at the expense of the perfusion of vulnerable organs, most particularly, the kidneys and the gut. A further
concern relates to the possibility that
overenthusiastic use, especially if an unnecessarily high blood pressure is targeted, may increase left ventricular work
to an unsustainable degree and so worsen
cardiac output and end-organ perfusion.
Although this is much more likely to
occur in patients with cardiogenic shock,
cardiac depression is a feature of severe
sepsis, and a number of patients presenting with septic shock may already have
significant underlying cardiac disease.
The precise level of mean arterial pressure to aim for is not certain and is likely
to vary between individual patients. In
animal studies, a mean arterial pressure
of ⬍60 mm Hg is associated with compromised autoregulation in the coronary,
renal, and central nervous system vascular beds, and blood flow may be reduced.
Some patients, however, especially the
elderly, may require higher blood pressures to maintain adequate organ perfusion. To address this question specifically,
LeDoux et al. (24) studied ten patients
with septic shock who had been fluid
resuscitated to a pulmonary artery occluS458
sion pressure of ⱖ12 mm Hg and were
requiring vasopressors to maintain mean
arterial pressures of ⱖ60 mm Hg. Norepinephrine infusions were used to raise
the blood pressure incrementally from 65
to 75 mm Hg and then to 85 mm Hg,
with detailed global and regional hemodynamic and metabolic measurements
being taken at each stage. Cardiac index
increased from 4.7 ⫾ 0.5 L·min⫺1·m⫺2 to
5.5 ⫾ 0.5 L·min⫺1·m⫺2 (p ⫽ .07), and left
ventricular stroke work index increased
accordingly (p ⫽ .01). There were no
significant changes in urine output,
blood lactate, tonometric PCO2 gap, skin
capillary blood flow, or red blood cell
velocity and, thus, no suggestion of either
harm or benefit from the maneuver. Although fascinating, the wider applicability of these results is limited by the small
number of patients and the short-term
nature of the norepinephrine infusion.
Nevertheless, it further reinforces the
need to assess perfusion in patients on an
individualized basis by a combination of
the methods outlined previously.
Question: Is the combination of norepinephrine and dobutamine superior to dopamine in the treatment of septic shock?
Uncertain; Grade D
Recommendations: Either norepinephrine or dopamine (through a central
catheter as soon as possible) is the firstchoice vasopressor agent to correct hypotension in septic shock.
Grade D
Rationale: The effects of dopamine on
cellular oxygen supply in the gut remain
incompletely defined, and the effects of
norepinephrine alone on splanchnic circulation may be difficult to predict. The
combination of norepinephrine and dobutamine seems to be more predictable
and more appropriate to the goals of septic shock therapy than norepinephrine
alone. Dopamine is the natural precursor
of norepinephrine and epinephrine, and
it possesses several dose-dependent pharmacologic effects. Generally, at doses of
⬍5 ␮g·kg⫺1·min⫺1, dopamine stimulates
dopaminergic DA1 receptors in the renal,
mesenteric, and coronary beds, resulting
in vasodilation. Infusion of low doses of
dopamine causes an increase in glomerular filtration rate, renal blood flow, and
sodium excretion. At doses of 5–10
␮g·kg⫺1·min⫺1, ␤-adrenergic effects become predominant, resulting in an increase in cardiac contractility and heart
rate. Dopamine also causes the release of
norepinephrine from nerve terminals,
contributing to its cardiac effects. At
higher doses (⬎10 ␮g·kg ⫺1 ·min ⫺1 ),
␣-adrenergic effects predominate, leading to arterial vasoconstriction and an
increase in blood pressure.
The systemic hemodynamic effects of
dopamine in patients with septic shock
are well established. Dopamine increases
mean arterial pressure primarily by increasing cardiac index with minimal effects on systemic vascular resistance. The
increase in cardiac index is due to an
increase in stroke volume and, to a lesser
extent, to increased heart rate (25–36).
Patients receiving dopamine at rates of
⬎20 ␮g·kg⫺1·min⫺1 show increases in
right heart pressures and in heart rate,
and therefore, doses should not usually
exceed 20 ␮g·kg⫺1·min⫺1, at least not
without adequate hemodynamic monitoring.
Splanchnic perfusion and the integrity
of the gut mucosa may play an important
role in the pathogenesis of multiple organ failure. The effect of dopamine on
gastric tonometric and splanchnic variables has been evaluated with mixed results. At low doses, dopamine increases
splanchnic oxygen delivery by 65% but
splanchnic oxygen consumption by only
16%. Despite this, dopamine may decrease pHi, perhaps by a direct effect on
the gastric mucosal cell. The effects of
dopamine on cellular oxygen supply in
the gut remain incompletely defined.
Ruokonen et al. (33) and Meier-Hellmann
et al. (36) have documented that dopamine increases splanchnic blood flow.
Neviere et al. (37) reported that dopamine is associated with a reduction in
gastric mucosal blood flow; there were
changes in gastric PCO2, gastric-arterial
PCO2 difference, and calculated pHi. They
(37) concluded that they could not determine whether the reduction in gastric
mucosal blood flow was critical because
there were no changes in the acid-base
variables of the patients. More recently,
Jakob et al. (38) demonstrated that dopamine increased splanchnic blood flow in
septic patients but that this did not correlate with changes in monoethylglycinexylidide formation (the cytochrome
P450 – dependent conversion of lidocaine
to monoethylglycinexylidide in the liver).
The same group also demonstrated that
the dopamine infusion resulted in a decrease in splanchnic oxygen consumption, despite the increase in blood flow.
They then performed a post hoc comparCrit Care Med 2004 Vol. 32, No. 11 (Suppl.)
ison with septic patients receiving dobutamine infusions, in whom splanchnic
blood flow also increased, but without
any change in splanchnic oxygen consumption, leading the authors to conclude that dopamine resulted in an
impairment of hepatosplanchnic metabolism that may be detrimental (39).
In contrast, De Backer et al. (40) compared the effects of dopamine, norepinephrine, and epinephrine on measures
of splanchnic perfusion in ten patients
with a moderate degree of septic shock.
The gradient between mixed-venous and
hepatic-venous oxygen saturations was
lower with dopamine, although there
were no other significant differences,
leading to the authors to conclude that
overall effects of all three drugs were similar in the small study group, although, if
anything, dopamine had the most beneficial profile of effects on splanchnic circulation.
Recent studies have shown that dopamine may alter the inflammatory response in septic shock by decreasing the
release of a number of hormones, including prolactin (41). Other potentially
harmful endocrine effects have been
demonstrated in trauma patients (42–
45). In a study of 12 stable mechanically
ventilated patients, Dive et al. (46) used
intestinal manometry to demonstrate that
dopamine infused at 4 ␮g·kg⫺1·min⫺1 resulted in impaired gastroduodenal motility.
Concerns remain that these and other
poorly understood biological effects of dopamine might potentially have harmful effects in patients with septic shock.
Norepinephrine is a potent ␣-adrenergic agonist with some ␤-adrenergic agonist effects. The effects of norepinephrine
have been examined in a number of studies on patients with septic shock. In
open-label trials, norepinephrine has
been shown to increase mean arterial
pressure in patients with hypotension resistant to fluid resuscitation and dopamine, although the potential that norepinephrine may have negative effects on
blood flow in the splanchnic and renal
vascular beds, with resultant regional
ischemia, has meant that in the past norepinephrine was commonly reserved for
use as a last resort, with predictably poor
results. However, recent experience with
the use of norepinephrine in patients
with septic shock suggests that it can
successfully increase blood pressure
without causing the feared deterioration
in organ function. Many studies have
given septic patients fluid to correct hyCrit Care Med 2004 Vol. 32, No. 11 (Suppl.)
povolemia before starting dopamine, with
or without dobutamine, titrated to doses
of 7–25 ␮g·kg⫺1·min⫺1 to achieve the
target blood pressure. Only if this regime
failed was norepinephrine added (33, 47–
53). In older studies, norepinephrine was
added after the use of metaraminol, methoxamine, or isoproterenol (25, 54). A
few studies have used norepinephrine as
the only adrenergic agent to correct sepsis-induced hemodynamic abnormalities
(32, 33, 35, 55, 56). In most studies, the
mean dose of norepinephrine was 0.2–1.3
␮g·kg⫺1·min⫺1, although the initial dose
can be as low as 0.01 ␮g·kg⫺1·min⫺1 (48),
and the highest reported norepinephrine
dose was up to 5.0 ␮g·kg⫺1·min⫺1 (57).
Thus, large doses of the drug can be required in some patients with septic
shock, which may be due to adrenergic
receptor “down-regulation” in sepsis
(58).
Norepinephrine therapy usually
causes a statistically and clinically significant increase in mean arterial pressure
due to the vasoconstrictive effects, with
little change in heart rate or cardiac output, leading to increased systemic vascular resistance. Several studies have demonstrated increases in cardiac output
ranging from 10% to 20% and increases
in stroke volume index of 10% to 15%
(25, 35, 50), which may have been due
either to ␤-receptor agonist effects or to
improved cardiac performance as a result
of a better coronary perfusion pressure.
Other studies, however, have observed no
significant changes in either cardiac output or stroke volume index after the use
of norepinephrine in the presence of a
significant increase in vascular resistance, suggesting that norepinephrine is
exerting predominantly ␣1-receptor agonist effects (47– 49, 53, 59, 60). Obviously, because cardiac index is either increased or unchanged and mean arterial
pressure is consistently increased, left
ventricular stroke work index is always
statistically increased with norepinephrine. With regard to pulmonary artery
occlusion pressure, no clinically significant changes are reported.
Norepinephrine should be used only
to restore adequate values of mean arterial blood pressure, which might be regarded as values sufficient to restore
urine output (being cognizant of the premorbid blood pressure) or toward the
lower part of the normal range. Higher
values should be avoided during norepinephrine therapy because elevated cardiac afterload may be deleterious, espe-
cially in cases of severe underlying
cardiac dysfunction. Mean arterial pressure is a better target for the titration of
therapy than systemic vascular resistance
due to the methodologic problems of the
use of systemic vascular resistance as the
sole measurement of peripheral resistance.
Norepinephrine seems to be more effective than dopamine at reversing hypotension in septic shock patients. Martin
et al. (32) carried out a study with the
most striking findings. They prospectively randomized 32 volume-resuscitated patients with hyperdynamic sepsis
syndrome to receive either dopamine
(2.5–25 ␮g·kg⫺1·min⫺1) or norepinephrine (0.5–5.0 ␮g·kg⫺1·min⫺1) to achieve
and maintain normal hemodynamic
and oxygen transport variables for at
least 6 hrs. If the goals were not
achieved with one agent, the other was
added. The groups were similar at baseline. Dopamine administration (10 –25
␮g·kg⫺1·min⫺1) was successful in only
31% of patients (5 of 16), whereas norepinephrine (0.5–1.2 ␮g·kg⫺1·min⫺1) resulted in success in 93% of patients (15 of
16; p ⬍ .001). Of the 11 patients who did
not respond to dopamine, ten responded
when norepinephrine was added. In contrast, the one patient who did not respond to norepinephrine failed to respond to dopamine. The survival rate
differed between the two groups (59% for
norepinephrine vs. 17% for dopamine),
although the study was not statistically
designed to examine this issue. In a recent larger study from the same group,
97 patients with septic shock were entered into an observational study, in
which they were treated in a standardized
fashion. After antibiotic treatment, respiratory support, and fluid resuscitation,
dopamine (5–15 ␮g·kg⫺1·min⫺1) was
used to support the blood pressure, and
dobutamine (5–25 ␮g·kg⫺1·min⫺1) was
added if the SV៮ O2 was ⬍70%. If hypotension, oliguria, or lactic acidosis persisted,
patients then received either high-dose
dopamine (16 –25 ␮g·kg⫺1·min⫺1) or
norepinephrine (0.5–5.0 ␮g·kg⫺1·min⫺1),
although this choice was left to the discretion of the individual clinician and was
not randomized. If the patients remained
in shock, epinephrine could then be
added. The results were analyzed statistically with the aim of establishing which
aspects of therapy were associated with
outcome. Four factors were significantly
associated with a poor outcome (pneumonia as the cause of septic shock, organ
S459
system failure index of ⱕ3, low urine
output at study entry, and admission
blood lactate level of ⬎4 mmol/L). The
only factor that was associated with a
favorable outcome was the use of norepinephrine as part of the hemodynamic
support of the patient, with these 57 patients having a significantly lower hospital mortality (62% vs. 82%; p ⬍ .001;
relative risk, 0.68; 95% confidence interval, 0.54 – 0.87) than the 40 patients who
received support with high-dose dopamine or epinephrine, or both.
Concern is frequently expressed with
regard to the effect of norepinephrine on
the kidney. In patients with hypotension
and hypovolemia during hemorrhagic
shock, for example, norepinephrine and
other vasoconstrictor agents may have
severe detrimental effects on renal hemodynamics. Despite the improvement in
blood pressure, renal blood flow does not
increase, and renal vascular resistance
continues to rise (61). However, in hyperdynamic septic shock, during which
urine flow is believed to decrease mainly
as a result of lowered renal glomerular
perfusion pressure, the situation is
different. In an elegant study in a dog
model, Bellomo et al. (62) were able to
demonstrate that during endotoxic
shock, norepinephrine infused at 0.3
␮g·kg⫺1·min⫺1 resulted in an increase in
renal blood flow. Under baseline conditions, however, the effect of norepinephrine was to reduce renal blood flow.
The effects of norepinephrine on renal
function in patients with sepsis have been
evaluated in four studies. Desjars et al.
(59) studied 22 septic shock patients
treated with norepinephrine (0.5–1.5
␮g·kg ⫺1 ·min ⫺1 ) and dopamine (2–3
␮g·kg⫺1·min⫺1). Serum creatinine, blood
urea nitrogen, free water clearance, and
fractional excretion of sodium decreased
significantly, whereas urine output, creatinine clearance, and osmolar clearance
increased significantly. In this study (59),
six of seven patients considered at risk for
developing acute renal failure had improved renal function during norepinephrine treatment, and only one developed nonoliguric acute renal failure
requiring dialysis. Martin et al. (56) studied 24 septic shock patients treated with
norepinephrine (1.1 ␮g·kg⫺1·min⫺1) plus
dobutamine (8 –14 ␮g·kg⫺1·min⫺1) plus
dopamine (6 –17 ␮g·kg⫺1·min⫺1). No
patient received low-dose dopamine or
furosemide. Normalization of systemic
hemodynamics was followed by reestablishment of urine flow, decrease in
S460
serum creatinine, and increase in creatinine clearance. Fukuoka et al. (55)
studied 15 patients with septic shock
treated with norepinephrine (0.05–
0.24 ␮g·kg ⫺1 ·min ⫺1 ), dopamine (9
␮g·kg ⫺1 ·min ⫺1 ), and dobutamine (5
␮g·kg⫺1·min⫺1). Only patients with a
normal serum lactate concentration
had an increase in systemic vascular
resistance and an increase in urine
flow. Creatinine clearance was not affected (18.8 ⫾ 5.5 mL/min before and
20.1 ⫾ 6.6 mL/min after norepinephrine). Patients with elevated serum lactate concentrations had no change in
vascular resistance, a decrease in creatinine clearance (32.6 ⫾ 6.4 to 11.9 ⫾
4.9 mL/min), and required higher doses
of furosemide. The authors concluded
that the serum lactate concentration
may predict which patients will experience potentially adverse renal effects
with norepinephrine. However, this
study included only a very limited number of patients and is at variance with
the findings of other studies (25, 32, 35,
50, 52) in which vascular resistance and
urine flow were increased in patients
with elevated lactate concentrations (as
high as 4.8 ⫾ 1.6 mmol/L) (32). RedlWenzl et al. (50) studied 56 patients
with septic shock treated with norepinephrine (0.1–2.0 ␮g·kg⫺1·min⫺1) and
dopamine (2.5 ␮g·kg⫺1·min⫺1). During
norepinephrine infusion, creatinine
clearance increased significantly from
75 ⫾ 37 to 102 ⫾ 43 mL/min after 48
hrs of treatment. The authors concluded that mean arterial pressure
could be increased by norepinephrine
with a positive effect on organ perfusion and oxygenation.
The effects of norepinephrine on serum lactate concentrations have been assessed in several studies. Four studies
assessed changes in serum lactate concentrations over a relatively short period
of time (i.e., 1–3 hrs). Hesselvik and Brodin (49) reported unchanged lactate levels during norepinephrine therapy, but
the actual values were not given. In the
other three studies (33, 35, 52), mean
values of serum lactate concentrations
did not change over the 1- to 3-hr study
period. It should be noted that initial
values were not very high (1.8 –2.3 mmol/
L). Because blood flow tended to improve
significantly and lactic acid concentrations decreased (but not significantly) in
one study, it is unclear whether sufficient
time elapsed between measurements to
see a significant norepinephrine-induced
change in serum lactate concentrations.
Martin et al. (32) infused norepinephrine
into patients with septic shock in whom
initial lactate concentrations were elevated (4.8 ⫾ 1.6 mmol/L), and a statistically and clinically significant decrease in
lactate levels was observed at the end of
the 6-hr study period. Zhou et al. (63)
infused dopamine into 16 patients with
septic shock and then switched to norepinephrine, epinephrine, and a norepinephrine-dobutamine combination to maintain the same blood pressure in a random
fashion. There was a trend toward a lower
lactate level with norepinephrine compared with dopamine or epinephrine, and
this difference became significant with
the norepinephrine-dobutamine combination. Once again, however, the lactate
values were already low (all were ⬍2.6 ⫾
2.2 mmol/L), and the infusion of each
drug was for only 120 mins. Norepinephrine thus does not worsen, and may even
improve, tissue oxygenation, as assessed
by serum lactate levels, in patients with
septic shock. Very recently, De Backer et
al. (40) compared norepinephrine, epinephrine, and dopamine in patients with
moderate and severe septic shock and
found no effect of norepinephrine on arterial lactate levels.
The effects of norepinephrine alone on
the splanchnic circulation are difficult to
predict. The combination of norepinephrine and dobutamine seems to be
more predictable and more appropriate
to the goals of septic shock therapy than
the effects of epinephrine alone.
Ruokonen et al. (33) measured splanchnic blood flow and splanchnic oxygen
consumption in septic shock patients receiving either norepinephrine (0.07– 0.23
␮g·kg⫺1·min⫺1) or dopamine (7.6 –33.8
␮g·kg⫺1·min⫺1) to correct hypotension.
With norepinephrine, no overall changes
in splanchnic blood flow and splanchnic
oxygen consumption or extraction were
noted, and in individual patients, its effects on splanchnic blood flow were unpredictable (increased in three patients,
decreased in two). Dopamine caused a
consistent and statistically significant increase in splanchnic blood flow. MeierHellmann et al. (36) studied patients
changed from dobutamine to norepinephrine. They observed a significant decrease in hepatic venous oxygen saturation. In another group of patients, they
studied the effects of switching from dobutamine plus norepinephrine to the latter drug alone. They observed the previously reported changes in hepatic venous
Crit Care Med 2004 Vol. 32, No. 11 (Suppl.)
oxygen saturation together with a decrease in splanchnic blood flow (indocyanine green dye dilution technique) and in
cardiac output. Splanchnic oxygen consumption remained unchanged due to a
regional increase in oxygen extraction.
The decrease in splanchnic blood flow
paralleled the decrease in cardiac output.
The authors concluded that as long as
cardiac output is maintained, treatment
with norepinephrine alone has no negative effects on splanchnic tissue oxygenation. This finding was confirmed by
Marik and Mohedin (35), who observed a
significant increase in pHi (from 7.16 ⫾
0.07 to 7.23 ⫾ 0.07) over 3 hrs of norepinephrine treatment. During treatment
with dopamine, pHi decreased significantly (7.24 ⫾ 0.04 to 7.18 ⫾ 0.05).
Reinelt et al. (64) tested the hypothesis that when dobutamine is added to
norepinephrine to obtain a 20% increase
in cardiac index in septic shock patients,
splanchnic blood flow and oxygen consumption increases and hepatic metabolic activity (hepatic glucose production) improves. Splanchnic blood flow
and cardiac index increased in parallel,
but there was no effect on splanchnic
oxygen consumption, and hepatic glucose production decreased. The conclusion of the authors was that splanchnic
oxygen consumption was not dependent
on delivery in septic shock patients well
resuscitated with norepinephrine. Levy et
al. (51) studied the effects of the combination of norepinephrine and dobutamine on gastric tonometric variables in
30 septic shock patients. pHi and gastric
PCO2 gap were normalized within 6 hrs,
whereas in epinephrine-treated patients,
pHi decreased and gastric PCO2 gap increased. Changes in the epinephrine
group were only transient and were corrected within 24 hrs but could potentially
have caused splanchnic ischemia. The authors concluded that the combination of
norepinephrine with dobutamine was
more predictable than epinephrine. Zhou
et al. (63) demonstrated that the combination of norepinephrine and dobutamine was associated with higher pHi
values than epinephrine alone in septic
patients.
Summarizing the results of studies of
norepinephrine, it can be concluded that
norepinephrine markedly improves mean
arterial pressure and glomerular filtration. This is particularly true in the highoutput–low-resistance state of many septic shock patients. After restoration of
systemic hemodynamics, urine flow reapCrit Care Med 2004 Vol. 32, No. 11 (Suppl.)
pears in most patients and renal function
improves without the use of low-dose dopamine or furosemide. This fact supports
the hypothesis that the renal ischemia
observed during hyperdynamic septic
shock is not worsened by norepinephrine
infusion and even suggests that this
drug may be effective in improving renal blood flow and renal vascular resistance. Clinical experience with norepinephrine in septic shock patients
suggests that this drug can successfully
increase blood pressure without causing
deterioration in cardiac index or organ
function. Norepinephrine (at doses of
0.01–3 ␮g·kg⫺1·min⫺1) consistently improves hemodynamic variables in the
large majority of patients with septic
shock. The effects of norepinephrine on
oxygen transport variables remain undefined from the available data, but most
studies find other clinical variables of peripheral perfusion to be significantly improved. There is some evidence that outcome may be better with norepinephrine
than with high-dose dopamine. Unfortunately only one published study was controlled (32), and a prospective, randomized clinical trial is still required to assess
whether the use of norepinephrine in
septic shock patients affects mortality
compared with other vasopressors.
Question: Should low-dose dopamine be
routinely administered for renal protection?
No; Grade B
Recommendations: Low-dose dopamine
should not be used for renal protection as
part of the treatment of severe sepsis.
Grade B
Rationale: Although no prospective, randomized studies have demonstrated a significant improvement in renal function
with vasopressors, a number of openlabel clinical series support an increase in
renal perfusion pressure (47–50, 55, 56,
59, 65, 66). Excessive doses of vasopressors may shift the renal autoregulation
curve to the right, necessitating a greater
perfusion pressure for a specified renal
blood flow. The precise target mean blood
pressure level depends on the premorbid
blood pressure, but it can be as high as 75
mm Hg (47, 49, 50, 55, 56, 59, 65, 66).
However, individual levels should be kept
at the minimum needed to reestablish
urine flow, and in some patients, this can
be achieved with a mean arterial pressure
of 60 or 65 mm Hg. Certain patients may
remain oliguric, despite normalization of
systemic hemodynamic variables (48, 50,
55, 56, 59). This may be due to the absence of an increase in renal blood flow, a
decrease in glomerular perfusion pressure, or because renal failure has become
established.
Although in nonseptic conditions
combination therapy with the use of lowdose dopamine (1– 4 ␮g·kg⫺1·min⫺1) in
addition to norepinephrine in an anesthetized dog model and in healthy volunteers resulted in significantly higher renal blood flow and lower renal vascular
resistance (67, 68), such effects have not
been conclusively demonstrated in septic
shock. The Australian and New Zealand
Intensive Care Society Clinical Trials
Group (69) recently performed the only
large randomized, clinical trial of the effect of low-dose dopamine on the development of renal failure in a general intensive care unit population of patients
with systemic inflammatory response
syndrome and early renal dysfunction. A
total of 328 patients, including patients
with sepsis, were randomized either to
receive dopamine at 2 ␮g·kg⫺1·min⫺1 or
placebo, but no protective effect on renal
function or other outcomes was found.
Question: Should epinephrine or phenylephrine be administered as firstline vasopressors in septic shock?
No; Grade D
Recommendations: Epinephrine or phenylephrine should not be used as firstline
vasopressors as part of the treatment of
septic shock. Epinephrine decreases
splanchnic blood flow, increases gastric
mucosal PCO2 production, and decreases
pHi, suggesting that the drug alters oxygen supply in the splanchnic circulation.
Phenylephrine was reported to reduce
splanchnic blood flow and oxygen delivery in septic shock patients.
Grade D
Rationale: Epinephrine can increase arterial pressure in patients who fail to respond to fluid administration or other
vasopressors, primarily by increasing cardiac index and stroke volume (66, 70 –
72). Moran et al. (72) reported a linear
relationship between epinephrine dose
and heart rate, mean arterial pressure,
cardiac index, left ventricular stroke work
index, and oxygen delivery and consumption. Epinephrine, however, has variable
and often detrimental effects on splanchnic blood flow and causes transient deS461
creases in pHi and increases in the PCO2
gap (51, 63, 73). De Backer et al. (40)
demonstrated in septic patients with severe shock that epinephrine increased
cardiac index when compared with norepinephrine but that splanchnic blood
flow was reduced and the mixed-venous–
to– hepatic venous oxygenation gradient
was increased, although PCO2 gap remained unchanged, leading these authors to conclude that epinephrine was
potentially detrimental.
Epinephrine administration has also
been associated with increases in systemic and regional lactate concentrations
(51, 71, 74), although the cause of these
increases is unclear. As the monitoring
periods in all these studies were short, it
is unclear whether these increases are a
transient phenomenon. In an animal sepsis model, Levy et al. (75) demonstrated
that these changes may well be due to a
direct effect on carbohydrate metabolism.
Other adverse effects of epinephrine include tachyarrhythmias. In summary,
epinephrine clearly increases blood pressure and cardiac output in patients unresponsive to other agents. However, because of its potentially negative effects on
gastric blood flow and blood lactate concentrations, its use should be limited.
Phenylephrine is a selective ␣ 1 adrenergic agonist and has been used in
septic shock, although there are concerns about its potential to reduce cardiac output and lower heart rate in
these patients. Doses of phenylephrine
start at 0.5 ␮g·kg⫺1·min⫺1 and reach a
maximum dose of 5– 8 ␮g·kg⫺1·min⫺1.
A few studies have evaluated the clinical
use of phenylephrine in septic shock
(76 –78). Reinelt et al. (78) reported reduced splanchnic blood flow and oxygen delivery in six septic shock patients
treated with phenylephrine compared
with norepinephrine.
0.04 units/min. It may decrease stroke
volume.
Question: Should vasopressin be administered as vasopressor in septic shock
when conventional vasopressor therapy
fails?
Recommendations: In patients with low
cardiac output despite adequate fluid resuscitation, dobutamine may be used to
increase cardiac output. If used in the
presence of low blood pressure, it should
be combined with vasopressor therapy.
Uncertain; Grade E
Recommendations: Vasopressin use may
be considered in patients with refractory
shock despite adequate fluid resuscitation
and high-dose conventional vasopressors.
Pending the outcome of ongoing trials, it
is not recommended as a replacement for
norepinephrine or dopamine as a firstline agent. If used in adults, it should be
administered at infusion rates of 0.01–
S462
Grade E
Rationale: There is increasing interest in
the possible role of vasopressin as a therapeutic vasopressor in patients with septic shock. Landry et al. (79) reported that
patients with severe septic shock had reduced vasopressin levels and demonstrated a marked response to exogenous
infusion. Subsequently, there have been
several small case series of the use of
vasopressin to raise the blood pressure in
septic patients (80, 81). Recently, Dunser
et al. (82) prospectively randomized 48
patients with vasodilatory shock to receive either norepinephrine or norepinephrine plus vasopressin at 4 units/hr
for 48 hrs. Mean arterial pressure, cardiac
index, and left ventricular stroke work
index were all significantly higher in the
vasopressin group. Splanchnic perfusion
as assessed by tonometry was better preserved in the vasopressin group, although
serum bilirubin levels were also higher
and increased significantly during the infusion period. However, in a separate report, the same group described a 30.2%
rate (19 of 63 patients) of ischemic skin
lesions in patients with septic shock receiving vasopressin infusions (83). Although these preliminary results are fascinating, there is still inadequate
understanding as to the mechanisms and
potential therapeutic risk/benefit ratio of
the use of vasopressin in septic shock. At
this stage, vasopressin should only be
used as part of properly constructed clinical trials until more information is available.
Question: Is dobutamine the pharmacologic agent of choice to increase cardiac
output in the treatment of septic shock?
Yes; Grade E
Grade E
Rationale: Although the cardiac index is
usually maintained in the volumeresuscitated septic shock patient, cardiac
function is impaired (84). Characterized
by ventricular dilation, a decreased ejection fraction, an impaired contractile response to volume loading, and a low peak
systolic pressure/end-systolic volume (85,
86), the mechanism of the myocardial
dysfunction is complex. Coronary blood
flow is usually normal, and there is no
net lactate production across the coronary vascular bed, so myocardial ischemia is not implicated. Alterations in intracellular calcium homeostasis and in
␤-adrenergic signal transduction may be
contributory factors. Several inflammatory mediators have been shown to cause
myocardial depression in various animal
models, including cytokines (87), platelet-activating factor, and nitric oxide (88).
Inotropic therapy in septic shock is thus
not straightforward. Cardiac output is
usually not decreased, and multiple factors may be involved in the depressed
cardiac function.
Dobutamine is an adrenergic agonist
that stimulates ␤1- and ␤2-adrenergic receptors. A number of studies have investigated the effect of dobutamine on cardiac function during sepsis or septic
shock (89 –93). The doses utilized ranged
from 2 to 28 ␮g·kg⫺1·min⫺1. The majority of these studies found increases in
cardiac index combined with increases in
stroke volume and heart rate.
Dopexamine is a dopamine analog that
stimulates adrenergic and dopamine 1
and 2 receptors. It is not approved for use
in the United States. Several studies have
evaluated short-term infusions of dopexamine in sepsis or septic shock and demonstrated significant improvements in
cardiac index and left ventricular stroke
work index (94 –96). In addition, mesenteric perfusion, as assessed by gastric
tonometry, was improved compared with
baseline values in initial studies (95), but
this has not been confirmed in subsequent studies (97).
Phosphodiesterase inhibitors alone,
such as amrinone and milrinone, have
little place in the treatment of septic
shock. They may be considered in combination with adrenergic agents. One
study evaluating milrinone in pediatric
patients with sepsis observed that cardiac
index and right and left ventricular stroke
work indices improved significantly, with
little change in heart rate (98).
Calcium supplementation has been
proposed in the management of myocardial dysfunction in septic shock. However, no consistent beneficial hemodynamic effect of calcium administration in
septic patients has been reported (99),
and increased mortality has been reported in animal models (100, 101).
Digoxin has been reported to significantly
Crit Care Med 2004 Vol. 32, No. 11 (Suppl.)
improve cardiac performance in hypodynamic septic patients (102). The new
calcium-sensitizing agent levosimendan
may also prove to have a role in the
future, but there are no available data at
present.
Question: Is it recommended to use inotropic agents for increasing cardiac output above physiologic levels?
5.
6.
7.
No; Grade A
Recommendations: A strategy of increasing cardiac index to achieve an arbitrarily
predefined elevated level is not recommended.
Grade A
Rationale: In patients with decreased cardiac output, the goals of therapy are relatively clear and are aimed at restoring
normal physiology. Because of the complexity of assessment of clinical variables
in septic patients, direct measurement of
cardiac output by invasive hemodynamic
monitoring is advisable, but other end
points of global perfusion should be followed as well. When global hypoperfusion
is manifest by a decreased SV៮ O2, monitoring of SV៮ O2 can be helpful to guide response to therapy. Similarly, although
lactate production in sepsis is complex, a
fall in blood lactate levels during inotropic therapy is a good prognostic sign
(103).
In contrast to former reports (104,
105), two large prospective clinical trials
that included critically ill patients who
had severe sepsis failed to demonstrate
benefit from increasing oxygen delivery
to supranormal levels by use of dobutamine (106, 107). The goal of resuscitation should instead be to achieve adequate levels of oxygen delivery to avoid
flow-dependent tissue hypoxia.
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S465
The New England
Journal of Medicine
© Co py r ig ht , 2 0 0 0 , by t he Ma s s ac h u s e t t s Me d ic a l S o c ie t y
MAY 4, 2000
VOLUME 342
NUMBER 18
VENTILATION WITH LOWER TIDAL VOLUMES AS COMPARED WITH
TRADITIONAL TIDAL VOLUMES FOR ACUTE LUNG INJURY
AND THE ACUTE RESPIRATORY DISTRESS SYNDROME
THE ACUTE RESPIRATORY DISTRESS SYNDROME NETWORK*
ABSTRACT
Background Traditional approaches to mechanical
ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced
lung injury in patients with acute lung injury and the
acute respiratory distress syndrome. We therefore
conducted a trial to determine whether ventilation
with lower tidal volumes would improve the clinical
outcomes in these patients.
Methods Patients with acute lung injury and the
acute respiratory distress syndrome were enrolled in
a multicenter, randomized trial. The trial compared
traditional ventilation treatment, which involved an
initial tidal volume of 12 ml per kilogram of predicted
body weight and an airway pressure measured after
a 0.5-second pause at the end of inspiration (plateau
pressure) of 50 cm of water or less, with ventilation
with a lower tidal volume, which involved an initial
tidal volume of 6 ml per kilogram of predicted body
weight and a plateau pressure of 30 cm of water or
less. The first primary outcome was death before a
patient was discharged home and was breathing
without assistance. The second primary outcome
was the number of days without ventilator use from
day 1 to day 28.
Results The trial was stopped after the enrollment
of 861 patients because mortality was lower in the
group treated with lower tidal volumes than in the
group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of
days without ventilator use during the first 28 days
after randomization was greater in this group (mean
[±SD], 12±11 vs. 10±11; P=0.007). The mean tidal
volumes on days 1 to 3 were 6.2±0.8 and 11.8±0.8 ml
per kilogram of predicted body weight (P<0.001), respectively, and the mean plateau pressures were
25±6 and 33±8 cm of water (P<0.001), respectively.
Conclusions In patients with acute lung injury and
the acute respiratory distress syndrome, mechanical
ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use. (N Engl
J Med 2000;342:1301-8.)
©2000, Massachusetts Medical Society.
T
HE mortality rate from acute lung injury
and the acute respiratory distress syndrome1
is approximately 40 to 50 percent.2-4 Although substantial progress has been made
in elucidating the mechanisms of acute lung injury,5
there has been little progress in developing effective
treatments.
Traditional approaches to mechanical ventilation
use tidal volumes of 10 to 15 ml per kilogram of body
weight.6 These volumes are larger than those in normal subjects at rest (range, 7 to 8 ml per kilogram),
but they are frequently necessary to achieve normal
values for the partial pressure of arterial carbon dioxide and pH. Since atelectasis and edema reduce aerated lung volumes in patients with acute lung injury
and the acute respiratory distress syndrome,7,8 inspiratory airway pressures are often high, suggesting the
presence of excessive distention, or “stretch,” of the
aerated lung. In animals, ventilation with the use of
large tidal volumes caused the disruption of pulmonary epithelium and endothelium, lung inflammation,
atelectasis, hypoxemia, and the release of inflammatory mediators.9-14 The release of inflammatory mediators could increase lung inflammation and cause injury to other organs.10,15 Thus, the traditional approach
to mechanical ventilation may exacerbate or perpetuate lung injury in patients with acute lung injury and
the acute respiratory distress syndrome and increase
the risk of nonpulmonary organ or system failure.
The writing committee (Roy G. Brower, M.D., Johns Hopkins University, Baltimore; Michael A. Matthay, M.D., University of California, San
Francisco; Alan Morris, M.D., LDS Hospital, Salt Lake City; David
Schoenfeld, Ph.D., and B. Taylor Thompson, M.D., Massachusetts General
Hospital, Boston; and Arthur Wheeler, M.D., Vanderbilt University, Nashville) assumes responsibility for the overall content and integrity of the
manuscript. Address reprint requests to Dr. Brower at the Division of
Pulmonary and Critical Care Medicine, Johns Hopkins University, 600
N. Wolfe St., Baltimore, MD 21287.
*Members of the Acute Respiratory Distress Syndrome (ARDS) Network are listed in the Appendix.
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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
The use of lower tidal volumes during ventilation
in patients with acute lung injury and the acute respiratory distress syndrome may reduce injurious lung
stretch and the release of inflammatory mediators.16-18
However, this approach may cause respiratory acidosis16,17 and decrease arterial oxygenation19,20 and
may therefore require changes in the priority of some
objectives in the care of these patients. With the traditional approach, the attainment of normal partial
pressure of arterial carbon dioxide and pH is given
a higher priority than is protection of the lung from
excessive stretch. With an approach that involves lower tidal volumes, the reverse is true. Uncontrolled
studies suggested that the use of a lower tidal volume
would reduce mortality in patients with acute lung
injury and the acute respiratory distress syndrome,17
but the results of four randomized trials of lungprotecting ventilation strategies have been conflicting.21-24 The present trial was conducted to determine whether the use of a lower tidal volume with
mechanical ventilation would improve important clinical outcomes in such patients.
METHODS
Patients
Patients were recruited from March 1996 through March 1999
at the 10 university centers of the Acute Respiratory Distress Syndrome Network of the National Heart, Lung, and Blood Institute
(the centers are listed in the Appendix). The protocol was approved
by the institutional review board at each hospital, and informed
consent was obtained from the patients or surrogates at all but
one hospital, where this requirement was waived. A complete description of the methods is available on the World Wide Web (at
www.ardsnet.org) or from the National Auxiliary Publications
Service (NAPS).*
Patients who were intubated and receiving mechanical ventilation were eligible for the study if they had an acute decrease in
the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen to 300 or less (indicating the onset of hypoxemia;
values were adjusted for altitude in Denver and Salt Lake City),
bilateral pulmonary infiltrates on a chest radiograph consistent with
the presence of edema, and no clinical evidence of left atrial hypertension or (if measured) a pulmonary-capillary wedge pressure
of 18 mm Hg or less.1 Patients were excluded if 36 hours had
elapsed since they met the first three criteria; they were younger
than 18 years of age; they had participated in other trials within
30 days before the first three criteria were met; they were pregnant; they had increased intracranial pressure, neuromuscular disease that could impair spontaneous breathing, sickle cell disease,
or severe chronic respiratory disease; they weighed more than 1 kg
per centimeter of height; they had burns over more than 30
percent of their body-surface area; they had other conditions with
an estimated 6-month mortality rate of more than 50 percent; they
had undergone bone marrow or lung transplantation; they had
chronic liver disease (as defined by Child–Pugh class C)25; or their
attending physician refused or was unwilling to agree to the use
of full life support.
A centralized interactive voice system was used for randomization. Patients were randomly assigned to receive mechanical ventilation involving either traditional tidal volumes or lower tidal
volumes.
*See NAPS document no. 05542 for 15 pages of supplementary material. To order, contact NAPS, c/o Microfiche Publications, 248 Hempstead
Tpk., West Hempstead, NY 11552.
1302 ·
Ventilator Procedures
The volume-assist–control mode was used for the ventilator until the patient was weaned from the device or for 28 days after
randomization on day 0. Because normal lung volumes are predicted on the basis of sex and height, 26,27 a predicted body weight
was calculated for each patient from these data. 28 The predicted
body weight of male patients was calculated as equal to 50+
0.91(centimeters of height¡152.4); that of female patients was
calculated as equal to 45.5+0.91(centimeters of height¡152.4).
In the group treated with traditional tidal volumes, the initial tidal volume was 12 ml per kilogram of predicted body weight. This
was subsequently reduced stepwise by 1 ml per kilogram of predicted body weight if necessary to maintain the airway pressure
measured after a 0.5-second pause at the end of inspiration (plateau
pressure) at a level of 50 cm of water or less. The minimal tidal volume was 4 ml per kilogram of predicted body weight. If the plateau pressure dropped below 45 cm of water, the tidal volume was
increased in steps of 1 ml per kilogram of predicted body weight
until the plateau pressure was at least 45 cm of water or the tidal
volume was 12 ml per kilogram of predicted body weight.
In the group treated with lower tidal volumes, the tidal volume
was reduced to 6 ml per kilogram of predicted body weight within
four hours after randomization and was subsequently reduced
stepwise by 1 ml per kilogram of predicted body weight if necessary to maintain plateau pressure at a level of no more than 30 cm
of water. The minimal tidal volume was 4 ml per kilogram of predicted body weight. If plateau pressure dropped below 25 cm of
water, tidal volume was increased in steps of 1 ml per kilogram of
predicted body weight until the plateau pressure was at least 25 cm
of water or the tidal volume was 6 ml per kilogram of predicted
body weight. For patients with severe dyspnea, the tidal volume
could be increased to 7 to 8 ml per kilogram of predicted body
weight if the plateau pressure remained 30 cm of water or less.
Plateau pressures were measured with a half-second inspiratory
pause at four-hour intervals and after changes in the tidal volume
or positive end-expiratory pressure. Plateau pressures of more than
50 cm of water in the patients in the group treated with traditional tidal volumes and of more than 30 cm of water in patients
in the group treated with lower tidal volumes were allowed if the
tidal volume was 4 ml per kilogram of predicted body weight or
if arterial pH was less than 7.15.
All other objectives and ventilation procedures, including weaning, were identical in the two study groups (Table 1). If a patient
became able to breathe without assistance but subsequently required additional mechanical ventilation within a period of 28 days,
the same tidal-volume protocol was resumed.
Organ or System Failure
Patients were monitored daily for 28 days for signs of the failure of nonpulmonary organs and systems.29 Circulatory failure
was defined as a systolic blood pressure of 90 mm Hg or less or
the need for treatment with any vasopressor; coagulation failure as
a platelet count of 80,000 per cubic millimeter or less; hepatic failure as a serum bilirubin concentration of at least 2 mg per deciliter
(34 µmol per liter); and renal failure as a serum creatinine concentration of at least 2 mg per deciliter (177 µmol per liter). We calculated the number of days without organ or system failure by subtracting the number of days with organ failure from the lesser of 28
days or the number of days to death. Organs and systems were considered failure-free after patients were discharged from the hospital.
Plasma Interleukin-6 Concentrations
Blood samples were obtained from 204 of the first 234 patients
on day 0 and on day 3 for measurement of plasma interleukin-6
by immunoassay (R & D Systems, Minneapolis).30 Blood samples
were stored in sterile EDTA-treated glass tubes.
Data Collection
Data on demographic, physiologic, and radiographic characteristics, coexisting conditions, and medications were recorded with-
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TABLE 1. SUMMARY
OF
VARIABLE
Ventilator mode
Initial tidal volume (ml/kg of predicted body
weight)†
Plateau pressure (cm of water)
Ventilator rate setting needed to achieve a pH
goal of 7.3 to 7.45 (breaths/min)
Ratio of the duration of inspiration to the
duration of expiration
Oxygenation goal
Allowable combinations of FiO2 and PEEP
(cm of water)‡
Weaning
VENTILATOR PROCEDURES.*
GROUP RECEIVING
TRADITIONAL TIDAL
VOLUMES
Volume assist–control
12
GROUP RECEIVING
LOWER TIDAL
VOLUMES
Volume assist–control
6
«50
6–35
«30
6–35
1:1–1:3
1:1–1:3
PaO2, 55–80 mm Hg,
or SpO2, 88–95%
0.3 and 5
0.4 and 5
0.4 and 8
0.5 and 8
0.5 and 10
0.6 and 10
0.7 and 10
0.7 and 12
0.7 and 14
0.8 and 14
0.9 and 14
0.9 and 16
0.9 and 18
1.0 and 18
1.0 and 20
1.0 and 22
1.0 and 24
By pressure support; required by protocol
when FiO2 «0.4
PaO2, 55–80 mm Hg,
or SpO2, 88–95%
0.3 and 5
0.4 and 5
0.4 and 8
0.5 and 8
0.5 and 10
0.6 and 10
0.7 and 10
0.7 and 12
0.7 and 14
0.8 and 14
0.9 and 14
0.9 and 16
0.9 and 18
1.0 and 18
1.0 and 20
1.0 and 22
1.0 and 24
By pressure support; required by protocol
when FiO2 «0.4
*PaO2 denotes partial pressure of arterial oxygen, SpO2 oxyhemoglobin saturation measured by
pulse oximetry, FiO2 fraction of inspired oxygen, and PEEP positive end-expiratory pressure.
†Subsequent adjustments in tidal volume were made to maintain a plateau pressure of «50 cm of
water in the group receiving traditional tidal volumes and «30 cm of water in the group receiving
lower tidal volumes.
‡Further increases in PEEP, to 34 cm of water, were allowed but were not required.
in four hours before the ventilator settings were changed on day 0.
Physiologic and radiographic data, medication use, and use of other investigational treatments were recorded between 6 and 10 a.m.
on days 1, 2, 3, 4, 7, 14, 21, and 28. Data were transmitted weekly
to the network coordinating center. Patients were followed until
day 180 or until they were breathing on their own at home.
Assessment of Compliance
Randomly selected ventilator and blood gas variables were analyzed for compatibility with the protocol. Quarterly reports of
these data from each of the 10 centers were used by investigators
to assess compliance.
Statistical Analysis
The first primary outcome was death before a patient was discharged home and was breathing without assistance. Patients who
were in other types of health care facilities at 180 days were considered to have been discharged from the hospital and to be breathing without assistance. The second primary outcome was ventilator-free days, defined as the number of days from day 1 to day 28
on which a patient breathed without assistance, if the period of
unassisted breathing lasted at least 48 consecutive hours. A differ-
ence in ventilator-free days could reflect a difference in mortality,
ventilator days among survivors, or both. Other outcomes were
the number of days without organ or system failure and the occurrence of barotrauma, defined as any new pneumothorax, pneumomediastinum, or subcutaneous emphysema, or a pneumatocele
that was more than 2 cm in diameter. Interim analyses were conducted by an independent data and safety monitoring board after
the enrollment of each successive group of approximately 200 patients. Stopping boundaries (with a two-sided a level of 0.05) were
designed to allow early termination of the study if the use of lower
tidal volumes was found to be either efficacious31 or ineffective.32
The comparison of traditional with lower tidal volumes was
one of two trials conducted simultaneously in the same patients
in a factorial experimental design. Ketoconazole was compared with
placebo in the first 234 patients, and lisofylline was compared with
placebo in the last 194 patients; no drugs were assessed in the
middle 433 patients.
We used Student’s t-test or Fisher’s exact test to compare baseline variables. We used analysis of covariance to compare log-transformed plasma interleukin-6 values. We used Wilcoxon’s test to
compare the day 0 and day 3 plasma interleukin-6 concentrations,
ventilator-free days, and organ-failure–free days, which had skewed
distributions. We used the 180-day cumulative incidence of mor-
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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
tality to compare the proportion of patients in each group who
died before being discharged home and breathing without assistance,33 after stratification for other experimental interventions:
treatment with ketoconazole, the ketoconazole placebo, lisofylline,
the lisofylline placebo, or no other agent. We used a chi-square
test to determine whether there was an interaction between the
study group and the other experimental interventions with respect to the mean (±SE) mortality rates at 180 days. All P values
are two-sided.
RESULTS
The trial was stopped after the fourth interim analysis because the use of lower tidal volumes was found
to be efficacious (P=0.005 for the difference in mortality between groups; P value for the stopping boundary, 0.023). The base-line characteristics of the 861
patients who were enrolled were similar, except that
minute ventilation was slightly but significantly higher (P=0.01) in the group treated with lower tidal
volumes (Table 2).
The tidal volumes and plateau pressures were sig-
TABLE 2. BASE-LINE CHARACTERISTICS
CHARACTERISTIC
OF THE
PATIENTS.*
GROUP RECEIVING
LOWER
TIDAL VOLUMES
(N=432)
GROUP RECEIVING
TRADITIONAL
TIDAL VOLUMES
(N=429)
51±17
40
52±18
41
75
16
5
4
81±28
138±64
82
676±119
13.4±4.3¶
1.8±1.1
71
19
7
3
84±28
134±58‡
85
665±125
12.7±4.3
1.8±1.0
33
27
15
13
10
2
36
26
14
9
11
3
Age (yr)
Female sex (%)
Race or ethnic group (%)
White
Black
Hispanic
Other or unknown
APACHE III score†
PaO2:FiO2
PaO2:FiO2 «200 (%)
Tidal volume (ml)§
Minute ventilation (liters/min)
No. of nonpulmonary organ or
system failures¿
Lung injury (%)
Pneumonia
Sepsis
Aspiration
Trauma
Other causes
Multiple transfusions
*Plus–minus values are means ±SD. Because of rounding, not all percentages total 100. PaO2 denotes partial pressure of arterial oxygen, and
FiO2 fraction of inspired oxygen.
†APACHE III denotes Acute Physiology, Age, and Chronic Health Evaluation. Scores can range from 0 to 299, with higher scores indicating more
severe illness.34
‡Data were missing for one patient.
§Data were available for 300 patients in the group treated with lower tidal volumes and for 290 patients in the group treated with traditional tidal
volumes.
¶P=0.01.
¿Organ and system failures were defined as described in the Methods
section.
1304 ·
nificantly lower on days 1, 3, and 7 in the group
treated with lower tidal volumes than in the group
treated with traditional tidal volumes (Table 3). The
mean (±SD) tidal volumes on days 1 to 3 were 6.2±
0.8 and 11.8±0.8 ml per kilogram of predicted body
weight (P<0.001), respectively, and the mean plateau pressures were 25±6 and 33±8 cm of water
(P<0.001), respectively. The partial pressure of arterial oxygen was similar in the two groups at all three
times, but the positive end-expiratory pressure and
fraction of inspired oxygen were significantly higher
and the ratio of partial pressure of arterial oxygen to
fraction of inspired oxygen was significantly lower in
the group treated with lower tidal volumes on days
1 and 3. On day 7, positive end-expiratory pressure
and the fraction of inspired oxygen were significantly
higher in the group treated with traditional tidal volumes. The respiratory rate was significantly higher in
the group treated with lower tidal volumes on days
1 and 3, but minute ventilation was similar in the two
groups on these days. The partial pressure of arterial
carbon dioxide was significantly higher on days 1, 3,
and 7 and arterial pH was significantly lower on days
1 and 3 in the group treated with lower tidal volumes.
The probability of survival and of being discharged
home and breathing without assistance during the
first 180 days after randomization is shown in Figure
1. The mortality rate was 39.8 percent in the group
treated with traditional tidal volumes and 31.0 percent in the group treated with lower tidal volumes
(P=0.007; 95 percent confidence interval for the
difference between groups, 2.4 to 15.3 percent). The
interaction between the study group and stratification for other experimental interventions was not significant (P=0.16).
Data were available to calculate the static compliance of the respiratory system at base line in 517 patients (Fig. 2). The interaction between the quartile
of static compliance at base line and the study group
with respect to the risk of death was not significant
(P=0.49).
The number of ventilator-free days was significantly
higher in the group treated with lower tidal volumes
than in the group treated with traditional tidal volumes (Table 4). The median duration of ventilation
was 8 days among patients in both groups who were
discharged from the hospital after weaning and 10.5
and 10 days, respectively, among those who died in
the group treated with lower tidal volumes and the
group treated with traditional tidal volumes. The number of days without nonpulmonary organ or system
failure was significantly higher in the group treated
with lower tidal volumes (P=0.006). This group had
more days without circulatory failure (mean [±SD],
19±10 vs. 17±11 days; P=0.004), coagulation failure (21±10 vs. 19±11 days, P=0.004), and renal
failure (20±11 vs. 18±11 days, P=0.005) than did
the group treated with traditional tidal volumes. The
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TABLE 3. RESPIRATORY VALUES
DURING THE FIRST SEVEN DAYS OF TREATMENT IN PATIENTS WITH
AND THE ACUTE RESPIRATORY DISTRESS SYNDROME.*
VARIABLE
DAY 1
DAY 3
GROUP
Tidal volume (ml/kg of predicted
body weight)
No. of patients
Plateau pressure (cm of water)
No. of patients
Peak inspiratory pressure (cm of water)
No. of patients
Mean airway pressure (cm of water)
No. of patients
Respiratory rate (breaths/min)
No. of patients
Minute ventilation (liters/min)
No. of patients
FiO2
No. of patients
PEEP (cm of water)
No. of patients
PaO2:FiO2
No. of patients
PaO2 (mm Hg)
No. of patients
PaCO2 (mm Hg)
No. of patients
Arterial pH
No. of patients
ACUTE LUNG INJURY
GROUP
RECEIVING
DAY 7
GROUP
GROUP
RECEIVING
GROUP
GROUP
RECEIVING
TRADITIONAL
RECEIVING
TRADITIONAL
RECEIVING
TRADITIONAL
RECEIVING
LOWER TIDAL
TIDAL
LOWER TIDAL
TIDAL
LOWER TIDAL
TIDAL
VOLUMES
VOLUMES
VOLUMES
VOLUMES
VOLUMES
VOLUMES
6.2±0.9
11.8±0.8
6.2±1.1
11.8±0.8
6.5±1.4
11.4±1.4
387
25±7
384
32±8
382
17±13
369
29±7
389
12.9±3.6
387
0.56±0.19
390
9.4±3.6
390
158±73
350
76±23
350
40±10
351
7.38±0.08
351
405
33±9
399
39±10
401
17±12
385
16±6
406
12.6±4.5
401
0.51±0.17
406
8.6±3.6
406
176±76
369
77±19
369
35±8
369
7.41±0.07
369
294
26±7
294
33±9
295
17±14
288
30±7
296
13.4±3.5
296
0.54±0.18
296
9.2±3.6
296
160±68
284
74±22
284
43±12
285
7.38±0.08
285
307
34±9
307
40±10
308
19±17
301
17±7
308
13.4±4.8
307
0.51±0.18
308
8.6±4.2
308
177±81
297
76±23
297
36±9
297
7.41±0.07
297
181
26±7
168
33±9
178
17±14
176
30±7
185
13.7±3.8
182
0.50±0.17
185
8.1±3.4
185
165±71
148
73±17
148
44±12
147
7.40±0.07
148
179
37±9
173
44±10
177
20±10
173
20±7
181
14.9±5.3
177
0.54±0.20
181
9.1±4.2
181
164±88
160
75±21
160
40±10
160
7.41±0.08
160
*Plus–minus values are means (±SD) of the values recorded between 6 and 10 a.m. on days 1, 3, and 7 after enrollment. The numbers of
patients refers to those who were receiving ventilation and for whom data were available. FiO2 denotes fraction of inspired oxygen, PEEP
positive end-expiratory pressure, PaO2 partial pressure of arterial oxygen, and PaCO2 partial pressure of arterial carbon dioxide. All differences
between study groups were significant on each day (P<0.05) except for mean airway pressure on days 1, 3, and 7; the PaO2:FiO2 on day 7;
minute ventilation on days 1 and 3; pH on day 7; and PaO2 on days 1, 3, and 7.
incidence of barotrauma after randomization was similar in the two groups.
There were no significant differences between
groups in the percentages of days on which neuromuscular-blocking drugs were used among patients
who were discharged home and breathing without
assistance (6±14 percent in the group treated with
lower tidal volumes and 6±15 percent in the group
treated with traditional tidal volumes) or among those
who died (20±32 percent and 16±28 percent, respectively), or in the percentages of days on which sedatives were used among patients who were discharged
home and breathing without assistance (65±26 percent and 65±24 percent, respectively) or those who
died (73±24 percent and 71±28 percent, respectively). Investigational treatments for acute lung injury and the acute respiratory distress syndrome that
were not included in the factorial design of the experimental interventions were given to 15 patients
in the group treated with lower tidal volumes and 12
patients in the group treated with traditional tidal
volumes. These included prone positioning in 14 and
9 patients, respectively.
The mean log-transformed plasma interleukin-6
values decreased from 2.5±0.7 pg per milliliter on
day 0 to 2.3±0.7 pg per milliliter on day 3 in the
group treated with traditional tidal volumes and from
2.5±0.7 pg per milliliter to 2.0±0.5 pg per milliliter
in the group treated with lower tidal volumes. The
decrease was greater in the group treated with lower
tidal volumes (P<0.001), and the day 3 plasma interleukin-6 concentrations were also lower in this
group (P=0.002).
DISCUSSION
In this large study of patients with acute lung injury and the acute respiratory distress syndrome, mortality was reduced by 22 percent and the number of
ventilator-free days was greater in the group treated
with lower tidal volumes than in the group treated
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Proportion of Patients
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
TABLE 4. MAIN OUTCOME VARIABLES.*
Lower tidal volumesI
mmnSurvivalI
mmnDischargeI
Traditional tidal volumesI
mmnSurvivalI
mmnDischarge
0
20
40
60
80
100 120 140 160 180
Days after Randomization
Figure 1. Probability of Survival and of Being Discharged Home
and Breathing without Assistance during the First 180 Days after Randomization in Patients with Acute Lung Injury and the
Acute Respiratory Distress Syndrome.
The status at 180 days or at the end of the study was known for
all but nine patients. Data on these 9 patients and on 22 additional patients who were hospitalized at the time of the fourth
interim analysis were censored.
0.6
Lower tidal volumesI
Traditional tidal volumes
Mortality
0.5
0.4
0.3
0.2
0.1
0.0
0.15–0.40
0.41–0.50
0.51–0.62
0.63–1.5
Quartile of Static ComplianceI
(ml/cm of water/kg of predicted body weight)
Figure 2. Mean (+SE) Mortality Rate among 257 Patients with
Acute Lung Injury and the Acute Respiratory Distress Syndrome
Who Were Assigned to Receive Traditional Tidal Volumes and
260 Such Patients Who Were Assigned to Receive Lower Tidal
Volumes, According to the Quartile of Static Compliance of the
Respiratory System before Randomization.
The interaction between the study group and the quartile of
static compliance at base line was not significant (P=0.49).
with traditional tidal volumes. These results are consistent with the results of experiments in animals9-14
and observational studies in humans.16,17
These benefits occurred despite the higher requirements for positive end-expiratory pressure and fraction of inspired oxygen and the lower ratio of partial
pressure of arterial oxygen to fraction of inspired oxygen in the group treated with lower tidal volumes
1306 ·
VARIABLE
Death before discharge home
and breathing without
assistance (%)
Breathing without assistance
by day 28 (%)
No. of ventilator-free days,
days 1 to 28
Barotrauma, days 1 to 28 (%)
No. of days without failure
of nonpulmonary organs
or systems, days 1 to 28
GROUP
RECEIVING
LOWER TIDAL
VOLUMES
GROUP
RECEIVING
TRADITIONAL
TIDAL VOLUMES
31.0
39.8
0.007
65.7
55.0
<0.001
12±11
10±11
0.007
10
15±11
11
12±11
0.43
0.006
P VALUE
*Plus–minus values are means ±SD. The number of ventilator-free days
is the mean number of days from day 1 to day 28 on which the patient had
been breathing without assistance for at least 48 consecutive hours. Barotrauma was defined as any new pneumothorax, pneumomediastinum, or
subcutaneous emphysema, or a pneumatocele that was more than 2 cm in
diameter. Organ and system failures were defined as described in the Methods section.
on days 1 and 3. These results, coupled with the greater reductions in plasma interleukin-6 concentrations,
suggest that the group treated with lower tidal volumes had less lung inflammation.35 The greater reductions in plasma interleukin-6 concentrations may
also reflect a reduced systemic inflammatory response
to lung injury, which could contribute to the higher
number of days without organ or system failure and
the lower mortality in the group treated with lower
tidal volumes.15
Several factors could explain the difference in results between our trial and other trials of ventilation
using lower tidal volumes in patients with acute lung
injury and the acute respiratory distress syndrome.22-24
First, our study had a greater difference in tidal volumes between groups. In one earlier trial, the traditional tidal volume was equivalent to approximately
12.2 ml per kilogram of predicted body weight and
the lower tidal volume was equivalent to approximately 8.1 ml per kilogram of predicted body weight.23
In a second study, the traditional and lower tidal volumes were approximately 10.3 and 7.1 ml per kilogram of dry body weight (calculated as the measured
weight minus the estimated weight gain from fluid
retention), respectively.22 In the present trial, measured weight exceeded predicted body weight by approximately 20 percent. Assuming a similar difference,
and assuming that half the difference was dry weight
in excess of predicted body weight, tidal volumes in
the second trial would have been approximately 11.3
and 7.8 ml per kilogram of predicted body weight.
Therefore, the traditional tidal volume of 11.8 ml
per kilogram of predicted body weight in our study
was similar to the values in the previous two trials.
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However, the tidal volume of 6.2 ml per kilogram of
predicted body weight in the group receiving lower
tidal volumes was lower than the values in the previous two trials.
If one assumes that measured weights also exceeded predicted body weights by 20 percent in the earlier trials, the tidal volumes in the traditional groups
were approximately 10.2 and 9.4 ml per kilogram of
measured weight, respectively, as compared with 9.9
ml per kilogram of measured weight in our study.
Therefore, the tidal volumes in the traditional groups
in each of the three trials were consistent with traditional recommendations.6,36
A second possible explanation for the different results is that the previous trials were designed to detect
larger differences in mortality between groups.22-24
Hence, they lacked the statistical power to demonstrate the moderate effects of lower tidal volumes that
we found.
A third difference in the trials was in the treatment of acidosis. Increases in the ventilator rate were
required and bicarbonate infusions were allowed to
correct mild-to-moderate acidosis in our study, which
resulted in smaller differences in the partial pressure
of arterial carbon dioxide and pH between the study
groups than in the previous trials.22-24 The deleterious effects of acidosis in the previous studies may
have counteracted a protective effect of the lower
tidal volumes.
In addition to being caused by excessive stretch,
lung injury may also result from repeated opening
and closing of small airways or from excessive stress
at margins between aerated and atelectatic regions of
the lungs.37 These types of lung injury may be prevented by the use of a higher positive end-expiratory
pressure.10,13,37,38 A slightly higher positive end-expiratory pressure was necessary in the group treated with
lower tidal volumes during the first few days to maintain arterial oxygenation at a level similar to that in
the group treated with traditional tidal volumes, but
positive end-expiratory pressure was not increased as
a means of protecting the lungs.
In a recent trial in 53 patients with acute respiratory distress syndrome, 28-day mortality was significantly lower with a ventilation strategy that used
a higher positive end-expiratory pressure combined
with limited peak inspiratory pressure than with a
strategy of traditional ventilation.21 These results suggest that both increased positive end-expiratory pressure and reduced inspiratory stretch could have beneficial effects.
Stretch-induced lung injury may not occur if lung
compliance is not greatly reduced. However, the benefit of ventilation with a lower tidal volume was independent of the static compliance of the respiratory
system at base line, suggesting that the lower tidal volume was advantageous regardless of lung compliance.
Variations in chest-wall compliance, which contrib-
utes to compliance of the respiratory system and is
reduced in many patients with acute lung injury and
the acute respiratory distress syndrome,39 may have
obscured a true interaction between tidal volume and
base-line lung compliance.
Barotrauma occurred with similar frequency in
the two study groups, a finding consistent with the
results of other studies in which the incidence of barotrauma was independent of airway pressures.22-24,40,41
The most common manifestation of barotrauma was
pneumothorax, which could have been the result of
invasive procedures. Pneumothorax is not a sensitive
or specific marker of stretch-induced injury with the
tidal volumes used in this study.
The similarity in the number of days of ventilator
use among the survivors in both groups suggests that
the higher number of ventilator-free days in the group
treated with lower tidal volumes resulted from reduced mortality rather than from a reduced number
of days of ventilation among the survivors. However,
the comparison of the number of days of ventilator
use among the survivors could be misleading.42 Some
patients who would have survived in the group treated with traditional tidal volumes might have needed
the ventilator on fewer days had they been in the
group treated with lower tidal volumes. This beneficial effect would have been obscured if prolonged
ventilation was required before recovery among patients who otherwise would have died in the group
treated with traditional tidal volumes. For similar
reasons, it is also difficult to compare the number of
days with organ or system failure among the survivors in the two study groups.
We found that treatment with a ventilation approach designed to protect the lungs from excessive
stretch resulted in improvements in several important clinical outcomes in patients with acute lung injury and the acute respiratory distress syndrome. On
the basis of these results, high priority should be
given to preventing excessive lung stretch during adjustments to mechanical ventilation, and this lowertidal-volume protocol should be used in patients with
acute lung injury and the acute respiratory distress
syndrome.
Supported by contracts (NO1-HR 46054, 46055, 46056, 46057,
46058, 46059, 46060, 46061, 46062, 46063, and 46064) with the National Heart, Lung, and Blood Institute.
Presented in part at the International Conference of the American Lung
Association and the American Thoracic Society, San Diego, Calif., April
26, 1999.
We are indebted to the intensive care unit nurses, respiratory therapists, and physicians, as well as our patients and their families, who
supported this trial.
APPENDIX
In addition to the members of the Writing Committee, the members of
the National Heart, Lung, and Blood Institute ARDS Network were as follows: Network Participants: Cleveland Clinic Foundation — H.P. Wiedemann, A.C. Arroliga, C.J. Fisher, Jr., J.J. Komara, Jr., P. Perez-Trepichio;
Vo l u m e 3 4 2
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Copyright © 2000 Massachusetts Medical Society. All rights reserved.
Nu m b e r 18
·
1307
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Denver Health Medical Center — P.E. Parsons, R. Wolkin; Denver Veterans
Affairs Medical Center — C. Welsh; Duke University Medical Center — W.J.
Fulkerson, Jr., N. MacIntyre, L. Mallatratt, M. Sebastian, R. McConnell,
C. Wilcox, J. Govert; Johns Hopkins University — D. Thompson; LDS Hospital — T. Clemmer, R. Davis, J. Orme, Jr., L. Weaver, C. Grissom, M.
Eskelson; McKay–Dee Hospital — M. Young, V. Gooder, K. McBride, C.
Lawton, J. d’Hulst; MetroHealth Medical Center of Cleveland — J.R. Peerless, C. Smith, J. Brownlee; Rose Medical Center — W. Pluss; San Francisco
General Hospital Medical Center — R. Kallet, J.M. Luce; Jefferson Medical
College — J. Gottlieb, M. Elmer, A. Girod, P. Park; University of California,
San Francisco — B. Daniel, M. Gropper; University of Colorado Health Sciences Center — E. Abraham, F. Piedalue, J. Glodowski, J. Lockrem, R.
McIntyre, K. Reid, C. Stevens, D. Kalous; University of Maryland — H.J.
Silverman, C. Shanholtz, W. Corral; University of Michigan — G.B. Toews,
D. Arnoldi, R.H. Bartlett, R. Dechert, C. Watts; University of Pennsylvania
— P.N. Lanken, H. Anderson III, B. Finkel, C.W. Hanson; University of
Utah Hospital — R. Barton, M. Mone; University of Washington–Harborview Medical Center — L.D. Hudson, C. Lee, G. Carter, R.V. Maier, K.P.
Steinberg; Vanderbilt University — G. Bernard, M. Stroud, B. Swindell, L.
Stone, L. Collins, S. Mogan; Clinical Coordinating Center: Massachusetts
General Hospital and Harvard Medical School — M. Ancukiewicz, D. Hayden, F. Molay, N. Ringwood, G. Wenzlow, A.S. Kazeroonian; National
Heart, Lung, and Blood Institute Staff: D.B. Gail, C.H. Bosken, P.
Randall, M. Waclawiw; Data and Safety Monitoring Board: R.G.
Spragg, J. Boyett, J. Kelley, K. Leeper, M. Gray Secundy, A. Slutsky; Protocol Review Committee: T.M. Hyers, S.S. Emerson, J.G.N. Garcia, J.J.
Marini, S.K. Pingleton, M.D. Shasby, W.J. Sibbald.
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May 4 , 2 0 0 0
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Copyright © 2000 Massachusetts Medical Society. All rights reserved.
Anaesthesia, 2004, 59, pages 675–694
.....................................................................................................................................................................................................................
SPECIAL ARTICLE
Difficult Airway Society guidelines for management
of the unanticipated difficult intubation
J. J. Henderson,1 M. T. Popat,2 I. P. Latto3 and A. C. Pearce4
1
2
3
4
Anaesthetic Department, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK
Nuffield Department of Anaesthetics, John Radcliffe Hospital, Headington, Oxford OX3 9 DU, UK
Anaesthetic Department, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK
Anaesthetic Department, Guy’s Hospital, London SE1 9RT, UK
Summary
Problems with tracheal intubation are infrequent but are the most common cause of anaesthetic
death or brain damage. The clinical situation is not always managed well. The Difficult Airway
Society (DAS) has developed guidelines for management of the unanticipated difficult tracheal
intubation in the non-obstetric adult patient without upper airway obstruction. These guidelines
have been developed by consensus and are based on evidence and experience. We have produced
flow-charts for three scenarios: routine induction; rapid sequence induction; and failed intubation,
increasing hypoxaemia and difficult ventilation in the paralysed, anaesthetised patient. The flowcharts are simple, clear and definitive. They can be fully implemented only when the necessary
equipment and training are available. The guidelines received overwhelming support from the
membership of the DAS.
Disclaimer: It is not intended that these guidelines should constitute a minimum standard of practice,
nor are they to be regarded as a substitute for good clinical judgement.
Keywords
Intubation, intratracheal. Practice guidelines. Cricothyroidotomy. Laryngeal mask airway.
. ......................................................................................................
Correspondence to: John Henderson
E-mail: [email protected]
*The guidelines and algorithms were presented in part at annual
Difficult Airway Society meetings (DAS). A version of the algorithm
has been displayed on the DAS website – http://www.das.uk.com
since March 2004.
Accepted: 11 March 2004
Problems with tracheal intubation were the most frequent
causes of anaesthetic death in the published analyses of
records of the UK medical defence societies [1, 2]. The
true number is likely to be substantially greater than those
published.
Most cases of unanticipated difficult intubation are
managed satisfactorily, but problems with tracheal intubation can cause serious soft tissue damage [3] and are the
principal cause of hypoxaemic anaesthetic death and brain
damage [1, 2, 4]. Management of the unanticipated
difficult tracheal intubation must therefore concentrate on
maintenance of oxygenation and prevention of airway
trauma.
2004 Blackwell Publishing Ltd
Guidelines for management of the difficult airway have
been published recently by North American [5, 6],
French [7], Canadian [8] and Italian [9] national societies
or groups. A limitation of the American guidelines is the
use of flow-charts which allow a wide choice of
techniques at each stage. This wide choice makes them
less useful for management of airway emergencies than
simple and definitive flow-charts such as those in the
European [10, 11] or American Heart Association [12]
Advanced Life Support guidelines.
In the UK there are no national guidelines for
management of unanticipated difficult intubation in the
non-obstetric patient. The Royal College of Anaesthetists
675
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J. J. Henderson et al.
Management of unanticipated difficult intubation guidelines
Anaesthesia, 2004, 59, pages 675–694
. ....................................................................................................................................................................................................................
has encouraged individual departments to display national
guidelines for management of a number of emergencies.
In the case of failed intubation and ventilation they
suggest that guidelines are developed locally. However,
general concern has been expressed about the quality of
local guidelines [13, 14].
The Difficult Airway Society (DAS) has developed
guidelines for management of the unanticipated difficult
intubation in an adult non-obstetric patient. The purpose
of this article is to present these guidelines, to justify
the choice of techniques, and to discuss alternative
management strategies. Paediatric and obstetric patients,
and patients with upper airway obstruction, are excluded.
Methods
The need for airway guidelines was first discussed at the
Annual Scientific Meeting of DAS in 1999. The following
year, members of DAS considered a structured approach
to airway guidelines and initiated development of such
guidelines for the management of unanticipated difficult
intubation. The aim was to produce simple, clear and
definitive guidelines, similar in structure to those of the
Advanced Life Support groups. Such guidelines could be
used in training drills and could be followed easily in an
emergency situation. Definitive guidelines imply the use
of recommended techniques at every stage. These techniques must be of proven value and relatively easy to learn.
A prototype flow-chart was presented at the DAS
Annual Scientific Meeting in November 2000. There was
debate and criticism, and constructive suggestions were
received at the meeting and subsequently by electronic
mail. The DAS executive committee examined the flowcharts in detail at several meetings. Development was
based on evidence, experience and consensus. The
published literature on difficult and failed tracheal intubation was reviewed with extensive Medline searches and
use of personal bibliographies. Advice was sought from
members who had particular expertise or knowledge.
Revised flow-charts were presented at the DAS Annual
Scientific Meetings in November 2001 and 2002. There
was overwhelming support for the concept and content of
the flow-charts. A late version of the paper was sent for
comments to 27 DAS members who had been particularly involved in the guidelines discussions. Their
comments were considered during preparation of the
final version.
These guidelines are concerned primarily with difficulty with tracheal intubation when the larynx cannot be
seen with conventional direct laryngoscopy. Even when
the larynx can be visualised, it is sometimes difficult to
pass the tracheal tube. Use of optimum shape of the
tracheal tube, with [15–19] or without [20] a stylet,
676
or passage of an introducer (‘bougie’) under vision
(‘visual bougie’ technique) with subsequent ‘railroading’
of the tube into the trachea, are recommended [21].
The Difficult Airway Society guidelines
The essence of the DAS guidelines for management of
unanticipated difficult tracheal intubation is a series of
flow-charts. They should be used in conjunction with this
paper.
The DAS flow-charts are based on a series of plans. The
philosophy of having a series of plans is well established in
airway management as no single technique is always
effective [22, 23]. Effective airway management requires
careful planning so that back up plans (plan B, C, D) can
be executed when the primary technique (plan A) fails.
This philosophy forms the basis of the DAS guidelines. It
is hoped that anaesthetists will always make back up plans
before performing primary techniques so that adequate
expertise, equipment and assistance are available.
Two other principles are particularly important. Maintenance of oxygenation takes priority over everything else
during the execution of each plan. Anaesthetists should
seek the best assistance available as soon as difficulty with
laryngoscopy is experienced.
The basic structure of the DAS flow-charts is shown in
Fig. 1. This contains the plans and core techniques, and
shows the possible outcomes. The plans are labelled A–D:
Plan A Initial tracheal intubation plan.
Plan B Secondary tracheal intubation plan, when Plan A
has failed.
Plan C Maintenance of oxygenation and ventilation,
postponement of surgery, and awakening the patient,
when earlier plans fail.
Plan D Rescue techniques for ‘can’t intubate, can’t
ventilate’ (CICV) situation.
Not all these plans are appropriate to every possible
scenario (vide infra). The outcome of each plan determines
progress to subsequent plans. In some situations, progress
depends upon clinical factors, such as the best view of the
larynx. Subdivision [24] of the Cormack & Lehane [25]
grade 3 into 3a (epiglottis can be lifted) and 3b (epiglottis
cannot be lifted from the posterior pharyngeal wall) has a
significant effect on the success of the introducer (bougie)
[24] and fibreoptic techniques [26].
It was not possible to develop a single detailed flowchart to cover all clinical scenarios. Detailed flow-charts
have therefore been developed for each of the following:
1 Unanticipated difficult tracheal intubation – during
routine induction of anaesthesia in an adult patient.
2 Unanticipated difficult tracheal intubation – during
rapid sequence induction of anaesthesia (with succinylcholine) in a non-obstetric patient.
2004 Blackwell Publishing Ltd
Æ
Anaesthesia, 2004, 59, pages 675–694
J. J. Henderson et al.
Management of unanticipated difficult intubation guidelines
. ....................................................................................................................................................................................................................
Plan A:
Initial tracheal
intubation plan
succeed
Tracheal intubation
Direct laryngoscopy
failed intubation
Plan B:
Secondary tracheal
intubation plan
succeed
ILMATM or LMATM
Confirm - then
fibreoptic tracheal
intubation through
ILMATM or LMATM
failed oxygenation
failed intubation
Plan C:
Maintenance of
oxygenation, ventilation,
postponement of
surgery and awakening
Plan D:
Rescue techniques
for "can't intubate,
can't ventilate" situation
Revert to face mask
Oxygenate & ventilate
succeed
Postpone surgery
Awaken patient
failed oxygenation
improved
oxygenation
LMATM
Awaken patient
increasing hypoxaemia
or
Figure 1 Basic structure of DAS
Guidelines flow-chart.
Cannula
cricothyroidotomy
3 Failed intubation, increasing hypoxaemia, and difficult
ventilation in the paralysed, anaesthetised patient, the
‘can’t intubate, can’t ventilate’ situation.
The principal points of these plans are discussed in
more detail. Practical details of some techniques are
outlined, but full descriptions should be sought in the
references and textbooks. The techniques should be
practised under supervision in elective situations, where
appropriate, and in manikins.
Scenario 1: Unanticipated difficult tracheal
intubation – during routine induction of
anaesthesia in an adult patient (Fig. 2)
This is the clinical scenario of difficult intubation in an
adult patient after induction of general anaesthesia and
muscle paralysis, usually with a non-depolarising neuromuscular blocking drug.
Plan A: Initial tracheal intubation plan
The first attempt at direct laryngoscopy should always
be performed in optimal conditions after ensuring
adequate muscle relaxation and appropriate position of
the head and neck (normally the ‘sniffing’ position of
head extension and neck flexion) [27]. Use of optimum
external laryngeal manipulation (OELM) [28–32] or
BURP (backward, upward, and rightward pressure on
the thyroid cartilage) [33–35], if required, applied with
2004 Blackwell Publishing Ltd
fail
Surgical
cricothyroidotomy
the anaesthetist’s right hand, should be an integral part
of this first attempt [27]. If, despite these measures,
there is still a grade 3 or 4 [25] view, then alternative
techniques will be needed. These techniques include
use of an introducer (‘gum elastic bougie’) [21] and ⁄ or
a different laryngoscope. Alternative direct laryngoscopes of proven value include the McCoy [36–40]
and straight [41, 42] laryngoscopes. The choice of
technique depends upon the experience of the anaesthetist with a particular technique. Oxygenation is
maintained with mask ventilation between intubation
attempts.
The Eschmann tracheal tube introducer (‘gum elastic
bougie’) was designed for multiple use and was marketed
in the UK in the early 1970s [43]. It differs from previous
introducers in its greater length (60 cm), angled tip and
the combination of flexibility and malleability. It is
inexpensive and readily available and the technique
combines simplicity of operation with a high success rate.
It is passed blindly into the trachea when the laryngeal
inlet is not visible. The most widely used technique in the
UK is the combination of the multiple-use bougie
(introducer) with the Macintosh laryngoscope [44]. There
is evidence that the bougie is more effective than the stylet
when the best view of the larynx is grade 3 [45].
The bougie technique should be used in an optimal
way. The Macintosh laryngoscope is left in the mouth
677
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J. J. Henderson et al.
Management of unanticipated difficult intubation guidelines
Anaesthesia, 2004, 59, pages 675–694
. ....................................................................................................................................................................................................................
Unanticipated difficult tracheal intubationduring routine induction of anaesthesia in an adult patient
Direct
laryngoscopy
Any
problems
Call
for help
Plan A: Initial tracheal intubation plan
Direct laryngoscopy - check:
Neck flexion and head extension
Laryngoscope technique and vector
External laryngeal manipulation by laryngoscopist
Vocal cords open and immobile
If poor view: Introducer (bougie) seek clicks or hold-up
and/or Alternative laryngoscope
Not more
than 4 attempts,
maintaining:
(1) oxygenation
with face mask and
(2) anaesthesia
succeed
Tracheal intubation
Verify tracheal intubation
(1) Visual, if possible
(2) Capnograph
(3) Oesophageal detector
"If in doubt, take it out"
failed intubation
Plan B: Secondary tracheal intubation plan
ILMATM or LMATM
Not more than 2 insertions
Oxygenate and ventilate
succeed
failed oxygenation
(e.g. SpO2 < 90% with FiO2 1.0)
via ILMATM or LMATM
Confirm: ventilation, oxygenation,
anaesthesia, CVS stability and muscle
relaxation - then fibreoptic tracheal intubation
through IMLATM or LMATM - 1 attempt
If LMATM, consider long flexometallic,nasal
RAE or microlaryngeal tube
Verify intubation and proceed with surgery
failed intubation via ILMATM or LMATM
Plan C: Maintenance of oxygenation, ventilation,
postponement of surgery and awakening
Revert to face mask
Oxygenate and ventilate
Reverse non-depolarising relaxant
1 or 2 person mask technique
(with oral ± nasal airway)
succeed
Postpone surgery
Awaken patient
failed ventilation and oxygenation
Figure 2 Management of unanticipated
Plan D: Rescue techniques for
"can't intubate, can't ventilate" situation
Difficult Airway Society Guidelines Flow-chart 2004 (use with DAS guidelines paper)
and attempts are made to insert the bougie blindly into
the trachea. It is important to maximise the chance of
the bougie entering the trachea. The anaesthetist will
not see the bougie entering the larynx when the
laryngoscopy view is grade 3 or 4. Therefore it is
important to be able to recognise whether the bougie is
in the trachea or the oesophagus. Clicks can often be felt
by the anaesthetist when the bougie is passed into the
trachea [46–48]. These are caused by the tip of the
bougie hitting the tracheal cartilages. Clicks are more
likely to be elicited if the distal end of the bougie is bent
into a curve of about 60 [49]. If clicks are present,
proceed with intubation by passing (‘railroading’) the
tube over the bougie (vide infra). Clicks will not be
present if the bougie goes down the centre of the
678
difficult tracheal intubation – during
routine induction of anaesthesia in an
adult patient.
tracheal lumen or is in the oesophagus. If clicks are not
elicited, the bougie should be advanced gently to a
maximum distance of 45 cm. If distal hold-up is sensed
as slight resistance to further advancement, indicating
that the bougie is held up in the bronchial tree, proceed
with intubation [47]. If the patient is not fully paralysed,
coughing may indicate the presence of the bougie in the
trachea [46]. If neither clicks, hold-up nor coughing are
elicited, the bougie is probably in the oesophagus.
Remove the bougie and consider another attempt at
passing the bougie blindly into the trachea – if the
laryngeal view is 3a [47].
Once the bougie is in the trachea, the tracheal tube is
railroaded over the bougie. Railroading is facilitated if the
laryngoscope is kept in the mouth [50] and the tube is
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rotated 90 anticlockwise [50, 51]. Use of a small tube
[52–54], reinforced tube [55, 56], the tube (Euromedical
ILM) supplied with the Intubating Laryngeal Mask [57,
58] and the Parker tube [59] have all facilitated railroading
in flexible fibreoptic intubation. By analogy, it is probable
that these tube factors will facilitate railroading with the
Eschmann introducer.
Success rates with the original reusable Eschmann
introducer in prospective studies have varied between
94.3% [24], 99.5% [48] and 100% [49]. Optimum results
depend on regular use and experience [48]. However, the
technique is of limited value when it is not possible to
elevate (grade 3b) [24] or visualise (grade 4) [25] the
epiglottis. There are concerns that some recently introduced single-use disposable introducers are not as effective as and may cause more trauma than the original
multiple-use bougie [60–62].
Alternative techniques of laryngoscopy, of proven
value, may be used by those experienced in these
techniques. In particular there is considerable evidence
of the value of the following techniques in experienced
hands:
direct use of the flexible fibreoptic laryngoscope
[63, 64];
Bullard-type laryngoscope [65–75].
There are situations in which these techniques can offer
unique advantages. The lighted stylet is not a visual technique, but may be successful in experienced hands [76].
Multiple and prolonged attempts at laryngoscopy and
tracheal intubation are associated with morbidity [77–81]
and mortality [3, 77, 78, 82]. The extent of laryngeal
oedema may not become apparent until fibreoptic
examination [83] or extubation [84]. An essential component of Plan A is therefore to limit the number and
duration of attempts at laryngoscopy in order to prevent
trauma and development of a ‘can’t ventilate’ situation. It
is difficult to justify use of the same direct laryngoscope
more than twice and the maximum number of laryngoscope insertions should be limited to four. However,
tracheal intubation may be successful when it is performed by a more experienced anaesthetist and one such
additional attempt is worthwhile [85, 86].
When these attempts at tracheal intubation have been
unsuccessful, Plan B should be implemented.
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Plan B: Secondary tracheal intubation plan
A different approach is required when direct laryngoscopy
has failed. Alternative techniques can allow continuous
ventilation and oxygenation both during and between
intubation attempts. This is best achieved by using a
‘dedicated airway device’, defined as ‘an upper airway
device which maintains airway patency while facilitating
tracheal intubation’ [87]. Although the classic laryngeal
2004 Blackwell Publishing Ltd
mask airway (LMATM) has been recommended as a
ventilation and intubation device in patients with a
difficult airway [88], it was not designed as a conduit for
tracheal intubation and has clear limitations when used for
this purpose (vide infra). Any other supraglottic airway
device could be used, but the intubating laryngeal mask
(ILMATM) [89, 90] was designed specifically to facilitate
tracheal intubation while maintaining ventilation. Each of
these devices has advantages and disadvantages.
ILMATM for secondary tracheal intubation: Numerous
reports have confirmed the effectiveness of the ILMATM
for both ventilation and blind intubation in patients
without airway difficulties [89, 91–98]. The overall
intubation success rate in 1100 patients in these studies
was 95.7% [90]. Further studies have confirmed its value
in management of patients with known or anticipated
difficult tracheal intubation [99–107]. The ILMATM has
also proved to be a useful device in the management of
unanticipated difficult intubation. In one study, blind
intubation was performed in 20 out of 23 patients with a
75% success rate at the first attempt (10% required two or
three attempts and 5% required four attempts) and 100%
overall success rate [104]. Fibreoptic guided intubation
was successful at the first attempt in the remaining three
patients.
Although high success rates can be achieved with a
blind technique, several attempts may be required and the
incidence of oesophageal intubation can be up to 5%
[108, 109]. Transillumination techniques may improve
first-attempt success rates [110] and certainly reduce the
number of manoeuvres required, the incidence of
oesophageal intubation and the time required to achieve
intubation [111, 112]. However, intubation under vision
through the ILMATM using a flexible fibreoptic laryngoscope has real advantages. The first-attempt [104] and
overall [113] success rates are higher than blind techniques, and it nearly always succeeds when blind
intubation fails [103].
The techniques of insertion and intubation through the
ILMATM differ in many respects from the classic LMATM,
and training and practice are essential if it is to be used to
achieve a high success rate and minimise trauma in the
unanticipated difficult tracheal intubation. A learning
curve of about 20 insertions has been described [95, 114].
The manufacturer’s instruction manual describes the
insertion and intubation techniques, the adjustments
necessary for ideal positioning of the device and an
approach to problem-solving [115]. The ‘Chandy manoeuvre’ (alignment of the internal aperture of ILMATM
and the glottic opening by finding the degree of sagittal
rotation which produces optimal ventilation, and then
applying a slight anterior lift with the ILMATM handle)
facilitates correct positioning and blind intubation
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through the ILMATM and has been shown to reduce the
number of intubation attempts [104]. Use of the dedicated silicone tracheal tube is strongly recommended [115].
The fibrescope can be used to visualise the ‘Epiglottic
Elevator Bar’ lifting the epiglottis and observe passage of
the tracheal tube through the glottis [90, 116] or it can be
passed into the trachea after glottic visualisation and then
used to railroad the tube [104]. We prefer the latter
technique. The lubricated silicone tracheal tube is first
inserted into the shaft of the ILMATM until its tip reaches
the mask aperture (indicated by the transverse line on the
tube). The fibrescope is then inserted through the tracheal
tube so that its tip is just within the tip of the tube. The
tube and fibrescope are then advanced together for about
1.5 cm so that the ‘Epiglottic Elevator Bar’ is seen to
elevate the epiglottis. Once the tip of the tube is in the
larynx, the fibrescope is advanced into the trachea and
the tube is then railroaded over it [90, 104]. Finally, the
position of the tube is checked with the fibrescope during
withdrawal. Oxygen and anaesthetic gases can be delivered continuously if a self-sealing bronchoscope connector is attached between the 15-mm tracheal tube
connector and the anaesthetic breathing system [104].
Ventilation is maximised by using a wide tracheal tube
with a narrow fibrescope [117]. The ILMATM should be
removed when tracheal intubation has been verified and
the tracheal tube secured [118, 119].
Classic LMATM for secondary tracheal intubation: Fibreoptic tracheal intubation through the classic LMATM (the
role of the single-use LMATM in management of the
difficult airway patient has not been established) should be
considered when an ILMATM is not available. Although
Heath [120] reported a 93% success rate for blind
intubation through the LMATM (in the absence of cricoid
pressure), others have achieved much lower success rates
[121, 122] and blind intubation cannot be recommended.
Success rates of 90–100% (depending on technique,
equipment, number of attempts allowed and experience
of user) can be achieved with fibreoptic intubation
through the classic LMATM [113, 123, 124]. The
limitations of the classic LMATM as a conduit for
intubation are well known [125, 126] and include the
following:
The LMATM tube connector is narrow and will
only allow a 6 mm (ID) tracheal tube through a size 3
or 4 LMATM and 7 mm (ID) through a size 5
LMATM;
The LMATM tube is so long that the cuff of an uncut
normal tracheal tube (26–27 cm) may lie between the
vocal cords so that it is ineffective and potentially
traumatic. A long flexometallic tube [127], nasal
RAE [128] or a microlaryngeal tube [129–131] is
recommended.
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The mask aperture bars may obstruct the passage of the
tracheal tube;
Manipulation requires head and neck movement
and ⁄ or finger insertion, both of which may worsen
difficulties.
Difficulties may be encountered during subsequent
removal of the LMATM. The LMATM may be left in situ if
its presence does not interfere with surgical access.
Techniques of LMATM removal without dislodging the
tracheal tube have been described, but they may fail and
expose the patient to avoidable danger [132].
The problems mentioned above can be avoided
by using a two-stage technique with a flexible fibreoptic
laryngoscope and an Aintree Intubation Catheter
[87, 133, 134].
Whatever technique of tracheal intubation through a
‘dedicated airway’ is used, the vocal cords should be open
and non-reactive before attempting to advance the
fibrescope or tracheal tube into the trachea. If two
attempts at the secondary tracheal intubation technique
fail, surgery should be postponed and the patient
awakened, i.e. Plan C should be implemented.
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Plan C: Maintenance of oxygenation and ventilation,
postponement of surgery and awakening the patient –
if Plans A and B have failed
If Plan B (secondary tracheal intubation technique) fails,
it remains important to avoid trauma to the airway and
to maintain ventilation and oxygenation with the
dedicated airway device. Elective surgery should be
cancelled and the airway device should be removed
only after muscle relaxation has been reversed, spontaneous ventilation is adequate, and the patient is awake.
An alternative plan for anaesthesia can then be made.
Although it may be possible to perform surgery under
regional anaesthesia, the safest plan is to secure the
airway with the patient awake [135]. If adequate
ventilation and oxygenation cannot be achieved with
the dedicated airway device, ventilation should be
performed using a face mask with or without an oral
or nasal airway.
If ventilation is impossible and serious hypoxaemia is
developing, then Plan D (Rescue techniques for ‘can’t
intubate, can’t ventilate’ situation) should be implemented without delay (vide infra).
Scenario 2: Unanticipated difficult tracheal
intubation – during rapid sequence induction
of anaesthesia (with succinylcholine) in a
non-obstetric patient (Fig. 3)
Plan A: Initial tracheal intubation plan
In scenario 2, in contrast to scenario 1, there is an
increased likelihood of regurgitation or vomiting, with a
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Unanticipated difficult tracheal intubation - during rapid sequence
induction of anaestheia in non-obstetric adult patient
Direct
laryngoscopy
Any
problems
Call
for help
Plan A: Initial tracheal intubation plan
Pre-oxygenate
succeed
Cricoid force: 10N awake
30N anaesthetised
Direct laryngoscopy - check:
Neck flexion and head extension
Laryngoscopy technique and vector
External laryngeal manipulation by laryngoscopist
Vocal cords open and immobile
If poor view:
Reduce cricoid force
Introducer (bougie) - seek clicks or hold-up
and/or Alternative laryngoscope
Not more than 3
attempts, maintaining:
(1) oxygenation with
face mask
(2) cricoid pressure and
(3) anaesthesia
Tracheal intubation
Verify tracheal intubation
(1) Visual, if possible
(2) Capnograph
(3) Oesophageal detector
"If in doubt, take it out"
failed intubation
Plan C: Maintenance of
oxygenation, ventilation,
postponement of
surgery and awakening
Maintain
30N cricoid
force
Plan B not appropriate for this scenario
Use face mask, oxygenate and ventilate
1 or 2 person mask technique
(with oral – nasal airway)
Consider reducing cricoid force if
ventilation difficult
succeed
failed oxygenation
(e.g. SpO2 < 90% with FiO2 1.0) via face mask
Postpone surgery
LMATM
Reduce cricoid force during insertion
Oxygenate and ventilate
failed ventilation and oxygenation
Figure 3 Management of unanticipated
difficult tracheal intubation – during
rapid sequence induction of anaesthesia
(with succinylcholine) in a non-obstetric
patient.
and awaken patient if possible
or continue anaesthesia with
LMATM or ProSeal LMATM if condition immediately
life-threatening
Plan D: Rescue techniques for
"can’t intubate, can’t ventilate" situation
consequent risk of pulmonary aspiration. The change in
management involves the use of pre-oxygenation and the
application of cricoid pressure. It is particularly important
to use a pre-oxygenation technique which maximises
oxygen stores [136].
Cricoid pressure has played an important role in the
prevention of pulmonary aspiration since its introduction by Sellick [137]. It is an integral part of the flowchart for the patient having rapid sequence induction.
However, it can impair insertion of the laryngoscope
[138], passage of an introducer [139] and can cause
airway obstruction [140–146]. A force of 30 N provides
good airway protection, while minimising the risk of
airway obstruction [147], but is not well tolerated by
2004 Blackwell Publishing Ltd
succeed
Difficult Airway Society Guidelines Flow-chart 2004 (use with DAS guidelines paper)
the conscious patient. Cricoid pressure should be
applied with an initial force of 10 N when the patient
is awake, increasing to 30 N as consciousness is lost
[139]. The force should be reduced, with suction at
hand, if it impedes laryngoscopy or causes airway
obstruction.
The principles of optimising the initial tracheal intubation technique, and use of the Eschmann introducer
and alternative direct laryngoscopes, are the same as in
Plan A in the elective patient. If intubation fails despite a
maximum of three attempts, a failed intubation plan with
the aim of maintaining oxygenation and awakening the
patient (Plan C) is initiated immediately. Further doses of
succinylcholine should not be given.
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Plan C: Maintenance of oxygenation and ventilation
and postponement of surgery, if possible
Plan B is omitted from airway management of the patient
having rapid sequence induction for two reasons. The risk
of regurgitation or vomiting is greater than in the elective
patient, so that the risk of aspiration during further
attempts at tracheal intubation is higher. The short
duration of succinylcholine increases the risk of laryngospasm and difficulty with laryngoscopy during recovery of
neuromuscular function, so that further tracheal intubation attempts increase the risk to the patient. When initial
attempts at tracheal intubation in this scenario fail, the
safest plan in most patients is to postpone surgery and
awaken the patient.
Plan C of this scenario contains two subsidiary
scenarios, in which the urgency of proceeding with
surgery differs. A risk-benefit assessment balances the risks
of delaying surgery against the risk of proceeding with a
suboptimal airway. If it is essential to proceed with
surgery, the traditional technique has been to continue
with a face mask and oral airway, maintaining cricoid
pressure [148, 149]. Continuation of anaesthesia with a
classic LMATM is now an established technique [150,
151], although not always effective [152] or accepted
[149, 153] (effect of cricoid pressure on LMATM
insertion – vide infra). If it proves difficult to ventilate the
lungs as a consequence of gas leakage past the cuff of the
classic LMATM, use of the ProSeal LMATM should be
considered. The ProSeal LMATM forms a better seal [154–
160] than the classic LMATM and provides improved
protection against aspiration [161–164]. The potential
advantages of the ProSeal LMATM have to be offset against
increased complexity of insertion [157, 160, 165, 166] (not
a problem when a precise technique [166] and the
insertion tool are used [156, 167]). The risk (about 5%)
of airway obstruction [168] may be lower than that with
the classic LMATM [158]. Airway obstruction may be
overcome by reinsertion [169], use of a smaller size [170],
withdrawal of air from the cuff [167, 170] and ⁄ or moving
the head and neck into the sniffing position [167].
However, poor seal and airway obstruction may be
significant problems in some obese patients [171].
Wherever possible the aim should be to postpone
surgery and awaken the patient. Maintenance of ventilation and oxygenation with a face mask is a conventional
technique. This may include the one- or two-person
technique and the use of an oral or nasal airway. A
narrow, soft, lubricated nasopharyngeal airway may be
inserted gently [172, 173] if this can be done without
trauma [174, 175]. It may be necessary to reduce cricoid
force in order to achieve satisfactory ventilation. If
satisfactory oxygenation (e.g. SpO2 > 90% with FiO2
1.0) cannot be achieved with a face mask, the LMATM
682
should be used. Cricoid force impedes positioning of
[176–180] and ventilation through [180–183] the
LMATM. It may be necessary to reduce cricoid force
during LMATM insertion when it is used in an emergency
[177, 178].
If ventilation is impossible and serious hypoxaemia is
developing, then Plan D (Rescue techniques for ‘can’t
intubate, can’t ventilate’ situation) should be implemented without delay.
Scenario 3: Failed intubation, increasing hypoxaemia
and difficult ventilation in the paralysed
anaesthetised patient
Plan D: Rescue techniques for ‘can’t intubate, can’t ventilate’
situation (Fig. 4)
This scenario may develop rapidly, but often occurs after
repeated unsuccessful attempts at intubation in scenarios 1
and 2, where a ‘can ventilate’ situation develops into a
‘can’t intubate, can’t ventilate’ (CICV) situation [77, 78,
81, 82]. It is probable that most patients who suffer
hypoxic damage pass through a CICV stage [77, 184]. In
situations where mask ventilation fails to oxygenate the
patient, the upper airway is normally sufficiently patent
to allow gas to escape upwards [185–189]. This has an
important bearing on the efficacy of different airway
rescue techniques (vide infra).
Before resorting to invasive rescue techniques, it is
essential that a maximum effort has been made to achieve
ventilation and oxygenation with non-invasive techniques, such as optimum mask ventilation and the
LMATM.
Other supraglottic airway devices, particularly the
CombitubeTM, have been used in the CICV situation.
Satisfactory placement of the Combitube is not always
possible, even when inserted with a laryngoscope [190].
When properly positioned, it allows ventilation with a
higher seal pressure than the classic LMATM, protects
against regurgitation [191], and allows subsequent
attempts [192] at intubation while the inflated oesophageal cuff maintains airway protection. Although
there have been failures [193, 194], the Combitube
has been used successfully in the difficult intubation
[191, 195] and the CICV situation [196–199], including
failure with the LMATM [200]. Adjustment of cuff
pressure may be necessary [201]. The Combitube is a
large and bulky device, and there have been some
reports of oesophageal damage with the original product
[202–205], but the risk should be lower with the SA
(Small Adult) size [192, 206]. The decision to use the
Combitube will depend on availability, experience and
the clinical situation.
The risks of an invasive rescue technique must be
constantly weighed against the risks of hypoxic brain
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Failed intubation, increasing hypoxaemia and difficult ventilation in the paralysed
anaesthetised patient: Rescue techniques for the "can’t intubate, can’t ventilate" situation
failed intubation and difficult ventilation (other than laryngospasm)
Face mask
Oxygenate and Ventilate patient
Maximum head extension
Maximum jaw thrust
Assistance with mask seal
Oral – 6mm nasal airway
Reduce cricoid force - if necessary
failed oxygenation with face mask (e.g. SpO2 < 90% with FiO2 1.0)
call for help
LMATM Oxygenate and ventilate patient
Maximum 2 attempts at insertion
Reduce any cricoid force during insertion
succeed
Oxygenation satisfactory
and stable: Maintain
oxygenation and
awaken patient
"can’t intubate, can’t ventilate" situation with increasing hypoxaemia
Plan D: Rescue techniques for
"can’t intubate, can’t ventilate" situation
or
Cannula cricothyroidotomy
Surgical cricothyroidotomy
Equipment: Kink-resistant cannula, e.g.
Patil (Cook) or Ravussin (VBM)
High-pressure ventilation system, e.g. Manujet III (VBM)
Equipment: Scalpel - short and rounded
(no. 20 or Minitrach scalpel)
Small (e.g. 6 or 7 mm) cuffed tracheal
or tracheostomy tube
Technique:
1.
2.
3.
4.
5.
6.
7.
Figure 4 Management of failed intubation, increasing hypoxaemia and difficult
ventilation in the paralysed anaesthetised
patient.
Insert cannula through cricothyroid membrane
Maintain position of cannula - assistant’s hand
Confirm tracheal position by air aspiration 20ml syringe
Attach ventilation system to cannula
Commence cautious ventilation
Confirm ventilation of lungs, and exhalation
through upper airway
If ventilation fails, or surgical emphysema or any
other complication develops - convert immediately
to surgical cricothyroidotomy
4-step Technique:
1.
2.
Identify cricothyroid membrane
Stab incision through skin and membrane
Enlarge incision with blunt dissection
(e.g. scalpel handle, forceps or dilator)
3. Caudal traction on cricoid cartilage with
tracheal hook
4. Insert tube and inflate cuff
Ventilate with low-pressure source
Verify tube position and pulmonary ventilation
Notes:
1. These techniques can have serious complications - use only in life-threatening situations
2. Convert to definitive airway as soon as possible
3. Postoperative management - see other difficult airway guidelines and flow-charts
4. 4mm cannula with low-pressure ventilation may be successful in patient breathing spontaneously
Difficult Airway Society guidelines Flow-chart 2004 (use with DAS guidelines paper)
damage or death [207]. Rapid development of severe
hypoxaemia, particularly associated with bradycardia, is an
indication for imminent intervention with an invasive
technique. Once the decision to perform an invasive
technique is made, it is essential to use an effective
technique. Rapid reoxygenation is now necessary, and
this is best achieved with a combination of an invasive
airway device and a ventilation technique which is
capable of reliably delivering a large minute volume with
an FiO2 of 1.0. Many cricothyroidotomy techniques have
been criticised because they are not capable of providing
effective ventilation [4, 208–213].
Classical emergency surgical tracheostomy involves
incision through skin and platysma, division of the isthmus
of the thyroid gland, haemostasis, incision of tracheal
2004 Blackwell Publishing Ltd
fail
cartilage, and insertion of a cuffed tracheostomy tube
[214]. Emergency tracheostomy can be very difficult and
have serious complications [215–217]. A few surgeons
may succeed in 3 min [85, 218], but most will take longer
[217, 219]. Delay in completion of tracheostomy in this
situation results in death of the patient [77, 219–224].
There are a few case reports of successful use of
percutaneous tracheostomy techniques in the failed
intubation [225–227] and CICV situation [228]. However, percutaneous tracheostomy techniques include a
number of steps and can take time.
The anaesthetist must be prepared to use invasive
techniques to secure the airway via the cricothyroid
membrane. Success depends on understanding the anatomy of the cricothyroid membrane [229–231] and of the
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factors which determine efficacy of ventilation with
different airway devices.
Invasive airway devices which are frequently recommended include:
cuffed tracheal or tracheostomy tubes;
narrow (4–6 mm ID) uncuffed tubes;
cannulae.
These must be matched to the ventilation technique in
order to provide a system which can deliver a large
minute volume. When a cuffed tube is used, a lowpressure ventilation system is satisfactory. When a 4-mm
(ID) uncuffed tube is used, successful ventilation is less
certain [232–235]. The ‘inflated’ gas may enter the lungs
or flow out through the upper airway. Factors which
promote entry of gas into the lungs include high
resistance in the upper airway, high lung compliance,
high flow rate and long inflation time. The limitations of
uncuffed tubes in the CICV situation are well summarised
by Walls [236]. When a cannula is used, a high-pressure
ventilation source is necessary. This system is discussed
clearly by Dworkin [237].
All current airway guidelines [5–8,12] recommend
management of the CICV situation using:
cannula cricothyroidotomy with percutaneous transtracheal jet ventilation (TTJV) or;
surgical cricothyroidotomy.
They remain the standard techniques.
Cannula cricothyroidotomy: Cannula cricothyroidotomy
involves the combination of insertion of a cannula
through the cricothyroid membrane with high-pressure
ventilation. It can provide effective ventilation [4, 209,
238–241], although low success rates have been reported [242]. We recommend use of kink-resistant
cannulae because standard intravenous cannulae are
easily kinked [243–245]. The technique is summarised
in the flow-chart and is described in detail by Benumof
[246] and Stewart [247]. Verification of correct cannula
placement by aspiration of air into a large syringe,
before the use of high-pressure ventilation, is essential.
Subsequent dislodgement of the cannula must be
prevented.
A high-pressure source is needed to achieve effective
ventilation through a cannula. The oxygen flush systems
of most modern anaesthesia machines do not provide
sufficient pressure [211, 248, 249] and an adjustable
high-pressure device (driven by gas pipeline pressure)
with a Luer Lock connection is recommended. Barotrauma [188, 238, 250, 251] is less likely if an initial
inflation pressure of less than 4 kPa (55 psi) is used
[213, 251, 252]. Some have recommended insertion of
a second cannula to facilitate exhalation [185, 186, 253].
However, the driving pressure for exhalation is relatively low and use of a second cannula is not a reliable
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means of relieving high airway pressure [254, 255].
Initial high-pressure ventilation should be performed
particularly cautiously. It is important to keep the upper
airway as open as possible and to verify deflation of the
lungs and exhalation through the upper airway. If an
LMA has been used, it should be kept in place to
facilitate exhalation.
Surgical cricothyroidotomy: Surgical (‘stab’) cricothyroidotomy can allow rapid restoration of ventilation and
oxygenation in the CICV situation [77, 242, 256–260]
and is included in ATLS and military [261] training.
Anaesthetic deaths could be prevented by appropriate use
of surgical cricothyroidotomy [207]. Emergency cricothyroidotomy can result in serious complications [216,
262], although these are infrequent when staff are well
trained [263–267]. The technique uses low-pressure
ventilation through a cuffed tube in the trachea.
A simplified cricothyroidotomy technique can be
performed in 30 s [268–270]. This 4-step technique
consists of:
Step 1 Identification of the cricothyroid membrane.
Step 2 Horizontal stab incision (No. 20 scalpel)
through skin and membrane.
Step 3 Caudal traction on the cricoid membrane with
a tracheal hook.
Step 4 Intubation of the trachea.
The ATLS cricothyroidotomy technique includes
blunt dilation of the incision made in step 2. It is
important to avoid endobronchial intubation [271] when
a tracheal tube is used.
Cricothyroidotomy is sometimes particularly difficult
in the obese patient. Insertion of the tube can be
facilitated by passage of an introducer (bougie) through
the incision [272] or use of a tracheal retractor [270, 273–
277].
Guidewire techniques of cricothyroidotomy have been
developed. Some claim that these can restore the airway
as quickly as the standard surgical technique [278], while
others have found the guidewire technique to take longer
[279], and to be less satisfactory, as a consequence of
kinking of the wires [280]. It has recently been shown
that the technique can be performed in 40 s after practice
in a manikin [281]. The MelkerTM guidewire intubation
set is now available with a cuffed tube. This technique
seems promising but further reports are needed before it
can be considered a core rescue technique.
Cannula and surgical cricothyroidotomy each have
advantages and disadvantages. Cannula cricothyroidotomy involves a smaller incision with less risk of bleeding. It
may be the technique of choice when dedicated equipment is immediately available and staff are trained in its
use. If it cannot be performed rapidly, is ineffective [242,
245, 258] or causes complications [258, 282], surgical
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Management of unanticipated difficult intubation guidelines
. ....................................................................................................................................................................................................................
cricothyroidotomy should be performed immediately
[242, 245, 258, 282]. Surgical cricothyroidotomy is more
invasive. It can be performed very rapidly and will allow
effective ventilation with low-pressure sources.
Invasive airway access is a temporary measure to
restore oxygenation. Definitive airway management will
follow. This may be a formal tracheostomy, but
tracheal intubation will be possible in some patients
[257, 283].
Discussion
A major impetus for the development of clinical guidelines was the finding of marked variations in medical
practice and the belief that guidelines could be used to
improve standards [284–286]. Guidelines have much to
offer in the management of infrequent, life-threatening
situations [287, 288]. In particular, following the resuscitation guidelines improves outcome [12, 289, 290].
There is evidence that use of airway guidelines has
improved airway management in France [291].
Unanticipated difficult intubation will continue to
occur. A new approach is needed to ensure optimal
management of infrequent airway problems. Medicine
has lagged behind the military [292–297] and the airline
industry [298–300], which use guidelines and regular
practice of drills to train staff to deal with infrequent
emergencies. Allnutt states that ‘there is no excuse for
poorly designed procedures when human life is at risk’
[301].
Tunstall first described a failed intubation drill [148] for
use in obstetric anaesthesia. Although of proven value
[302, 303], some components such as the lateral position
are no longer widely supported [146, 304–306] and new
devices such as the LMATM have changed management
[307]. There are now new failed intubation drills in
obstetrics [308].
There is a need for definitive national airway guidelines
for management of unanticipated difficult intubation in
the non-obstetric adult patient [309]. They should be easy
to learn and to implement as simple drills [310]. They
should include a minimum number of techniques of
proven value. They should be based on a practical
approach to airway management, using skills which are
widely available. The DAS guidelines are designed to
fulfil these requirements. Simple, clear and definitive
flow-charts have been produced to cover three important
clinical scenarios. They do not proscribe the use of
other techniques by those experienced in their use,
provided oxygenation is maintained and airway trauma is
prevented.
The DAS guidelines have been developed by consensus
and are based on experience and evidence. The principles
2004 Blackwell Publishing Ltd
applied are maintenance of oxygenation and prevention
of trauma. Maintenance of oxygenation is achieved
primarily by using the face mask and LMATM. Prevention
of trauma is achieved by limiting the number of attempts
at intubation and by using the ILMATM as a dedicated
airway to allow oxygenation, while tracheal intubation is
achieved under vision with the fibrescope.
Controlled studies cannot be performed in unanticipated
difficult intubation. The evidence basis of these guidelines
best fits the description of expert committee reports,
opinions and experience, and is defined as category IV
evidence [311]. The DAS recommendations are therefore
officially strength D. All DAS recommendations are
supported by at least two case reports or series, the strongest
evidence available for infrequent emergency situations.
We hope that implementation of these guidelines will
reduce the incidence of airway trauma and hypoxaemic
damage associated with unanticipated difficult intubation
and result in better outcomes for our patients.
The techniques which have been recommended in
these plans should be an integral part of initial and
continuing airway training. This can be achieved by
acquisition of knowledge in classroom teaching, learning
practical skills using manikins in workshops [281], and use
in clinical practice, when appropriate [312, 313].
There are equipment implications in these guidelines.
All the equipment described should be available for
regular practice. A cart containing the equipment should
be located no more than a couple of minutes from every
location where anaesthesia is administered. Recommended equipment lists will be published on the DAS
Web Site (http://www.das.uk.com).
We hope that these guidelines will be tested in a
clinical environment [314] and further modifications will
certainly follow. We seek constructive suggestions.
Notes on figures: Figures 2–4 in this paper contain a
considerable amount of detail in order to maximise their
value for training. Both these and simpler versions will be
available from the DAS Web Site (http://www.das.uk.
com) in the future. Others may wish to produce different
versions for their own purposes.
Acknowledgements
We gratefully acknowledge the suggestions and constructive criticism from many members of the Difficult Airway
Society and other colleagues. This paper would not have
been possible without the help of many librarians.
Conflict of interest: Various companies manufacturing ⁄
distributing equipment mentioned in the guidelines have
contributed to meetings and workshops held by DAS or
by the authors. Neither DAS or any of the authors have
any commercial links with any of these companies.
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