Bacillus anthracis Infection

Anthrax

Bacteremia, Primary of UnknownOrigin

tomatic is based on multiple factors, including history

of the patient, physical examination, body temperature,

peripheral leukocyte count and differential, clinical

outpatients or that are first identified within 48 h of

admission are now generally classified as healthcare-

associated if there is a significant history of healthcare

exposure as evidenced by recent admissions to hospital,

residence in a nursing homes or long-term care facility,

hemodialysis, recent intravenous therapy, or specialized

medical care in the home. Community-acquired bacter-

emias are diagnosed when these factors are not present [2].course, results of cultures from other sites, and percentage

of blood cultures positive [1]. The term bacteremia may

be considered synonymous with bloodstream infection.

An important aspect in defining bacteremia is thatDefinitionWhile many definitions for bacteremia exist, it may be

defined by the growth of a microbe from an aseptically

obtained blood culture specimen associated with symp-

tomatic infection. Determining if an infection is symp-VIKAS P. CHAUBEY, KEVIN B. LAUPLAND

Department of Critical Care Medicine, University

of Calgary and Calgary Health Region, Calgary,

AB, CanadaBacillus anthracis

Biological Terrorism, AnthraxB

B2M

Serum and Urinary Low Molecular Weight ProteinsJean-Louis Vincent & Jesse B. Hall (eds.), Encyclopedia of Intensive Care Med# Springer-Verlag Berlin Heidelberg 2012contamination of blood culture specimens must be ruled

out. Common skin contaminants including diphtheroids,

Bacillus spp., Propionibacterium sp., coagulase-negative

staphylococci, and micrococci generally require isolation

from two different blood cultures drawn from separate

sites to be considered as significant. A positive blood

culture is requisite for bacteremia; if the test is not

performed the diagnosis cannot be made. In addition,

prior administration of systemic antimicrobials may ster-

ilize blood culture specimens and result in the under

recognition of bacteremia.

Bacteremia may be classified as being either primary or

secondary. In the former, the origin of the bacteremia is

either associated with an intravascular catheter or is of

unknown origin. In the latter, the bacteremia is associated

with infection concurrently diagnosed at another body site,

such as with pneumonia, meningitis, or bone and joint

infection. Catheter-related bacteremia is a special case of

primary bacteremia that occurs in a patient with an intra-

vascular catheter. Such bacteremia is still considered primary

even if localized signs of infection are present at the access

site. A primary bacteremia that is not catheter-related is also

referred to as a bacteremia of unknown origin.

Traditionally, bacteremias that were present or incubat-

ing at the time of hospital admission were classified as

community-acquired and those that developed as a compli-

cation of hospitalization as nosocomial (usually first identi-

fied more than 48 h after admission). However, over the

recent years, there has been a shift in delivery of healthcare

with an increasing number of sicker patients with multiple

comorbidities managed in the community setting. When

community onset bacteremia occurs in patients that have

had extensive healthcare exposure, it tends to be associated

with higher rates of antimicrobial resistance and mortality

[2]. Bacteremias that occur in either community-basedicine, DOI 10.1007/978-3-642-00418-6,

282 B Bacteremia, Primary of Unknown Origin

EpidemiologyWhile a number of large observational and surveillance

studies have reported on the epidemiology of bacteremia

among critically ill patients, most have focused on noso-

comial infections and have not separated ICU patients

from the general inpatient population. Furthermore, it

must be emphasized that considerable differences exist at

the national, regional, and local levels with respect to the

epidemiology of bacteremia. In most cases, ICU-acquired

primary bacteremias are similar to nosocomial primary

bacteremias in the hospital population at large, with the

exception of an increased risk for antimicrobial resistance.

Gram-positive organisms including coagulase-negative

staphylococci and Staphylococcus aureus are themost com-

mon etiologies of ICU-acquired bacteremia. Community

onset primary bacteremic disease (including healthcare-

associated and community-acquired disease) is less well

defined among patients admitted to ICU, but Escherichia

coli, S. aureus, and Streptococcus pneumoniae are predom-

inant pathogens inmost studies. While coagulase-negative

staphylococci are regularly listed as a major etiology of

bacteremia in critically ill patients, these bacteremias are

almost exclusively healthcare or nosocomially associated

and are invariably related to intravascular catheters or

other implanted prosthetic materials.

The diagnosis of bacteremia of unknown origin is

made by exclusion of a secondary infected source. There-

fore, its identification will depend in part on the degree of

effort made to localize a source by clinical, laboratory, and

radiological means. As a result, there is considerable var-

iability in reported rates of bacteremia of unknown origin

among critically ill patients and ranges from 10% to 50%

of all bacteremias.

Risk factors specifically for primary bacteremia in criti-

cally ill patients have not been studied extensively. However,

even if not recognized as a focal source, intravascular cathe-

ters likely represent the main risk factor for development of

healthcare-associated, nosocomial, and ICU-acquired bac-

teremias. Factors associated with development of catheter-

related bacteremia include inexperience of the operator, high

patient-to-nurse ratios, catheter insertion with less than

maximal sterile barriers, placement in the internal jugular

or femoral vein rather than subclavian vein, placement in an

old site by guidewire exchange, heavy colonization of the

insertion site or contamination of a catheter hub, and

prolonged duration of use.

It is well documented that ICU-acquired bacteremia

increases cost, length of ICUand hospital stay, andmortality.

However, few studies have looked specifically at the effect of

primary bacteremia on outcomes. Generally speaking,primary bacteremia is associated with a significantly lower

mortality rate than with secondary bacteremia. This may in

part be due to a lower mortality attributable to catheter-

related bacteremias where the infectious source is easily

removed. In one case-control study of 111 episodes of bac-

teremia in 15 French ICUs, the authors found that the excess

mortality was 20% in patients with primary bacteremia and

was 55% for secondary bacteremia. The excess mortality for

those with catheter-related bacteremia was considerably

lower at 12% [3].

DiagnosisAt least two cultures of blood should be taken from separate

blood draws at different sites in patients suspected of having

bacteremia. Increasing the number of culture sets will

improve the detection rate for pathogens. While the sensi-

tivity of two sets of blood cultures has been reported to be

8090%, three and four setsmay be required to detect>95%

and >99% of bacteremias, respectively. At least one culture

should be drawn by peripheral venipuncture. Cultures may

be obtained through intravascular devices but should not be

taken throughmultiple ports of the same intravascular cath-

eter. Another advantage of multiple blood culture draws is

that it can aid in the assessment of the potential significance

of common contaminants. Isolating common contaminants

from multiple samples increased the probability that true

bacteremia is present [4]. Markers such as procalcitonin

may also help distinguish blood culture contaminants

from true positive blood cultures. However, the current

clinical standard involves integration of all available clin-

ical and microbiological data.

In patients where bacteremia is documented,

a thorough evaluation must be undertaken to determine

the source of infection as this can considerably influence

management. Common secondary sources for bacteremia

in critically ill patients include pneumonia, vascular cath-

eters, intra-abdominal and surgical site infections, and to

a much lesser degree sinusitis and urinary tract infections.

Catheter-associated bacteriuria is not commonly symp-

tomatic and rarely causes bacteremia. A detailed clinical

examination should be performed, and basic investiga-

tions should include a chest roentgenogram and cultures

of suspected body sites (i.e., urine, wounds, cerebrospinal

fluid, synovial fluid) as appropriate. Depending on the

suspected clinical source and the pathogen, further spe-

cific radiologic investigations may be indicated [4].

Endocarditis is an important diagnosis to consider in

any patient with bacteremia. While classical clinical signs

such as Janeway lesions, Osler nodes, and splinter hemor-

rhages are important when present, they are insensitive

Bacteremia, Primary of Unknown Origin B 283

Band their absence does not rule out this diagnosis with any

certainty. Other clues that may suggest a diagnosis of

endocarditis include persistently positive blood cultures

(particularly while on adequate therapy), persistent fever

after 72 h of appropriate therapy, and long-term intravas-

cular and hemodialysis catheter use. The specific etiology

of bacteremia is also important. This is especially so with

Staphylococcus aureus as approximately 1020% patients

with bacteremia due to this organism may have occult

endocarditis, with the rate highest in those with commu-

nity acquired disease. All patients with Staphylococcus

aureus bacteremia and those with other organisms and

clinical concern should undergo echocardiography.

Increased sensitivity of transesophageal echocardiography

makes it the diagnostic modality of choice to reliably rule

out endocardial complications of S. aureus bacteremia [5].

Upon suspicion of catheter-related bacteremia, the

catheter should be promptly removed under usual cir-

cumstances. A confirmation of line-sepsis can be done by

one of several methods including sonication, vortexing,

and the semiquantitative Maki roll-plate method.

Although there is concern about the sensitivity of the

Maki-method in detecting endoluminal infection, this

method performs well. Each of these methods has

a sensitivity of 90%. The specificity of both sonicationand the Maki-method are similar at approximately 80%,

while vortexing has a higher specificity of 90%. How-ever, the simplicity of the Maki-method frequently makes

it the procedure of choice in many laboratories. Briefly,

the Maki-method involves rolling the catheter tip across

a blood agar plate and uses a cut-off of 15 colony forming

units (CFUs) to diagnose true infection versus coloniza-

tion [5].

Controversy exists as to whether all central line tips

that are removed should be cultured or only those that are

removed after identifying bacteremia. On one hand, cul-

turing all removed lines may lead to over treatment of

many patients with uncomplicated line colonization. On

the other hand, such an approach may lead to preemptive

treatment of bacteremia with a reduction in associated

complications. It is prudent to at least culture those central

line tips that are suspected of being infected or removed

following an associated positive blood culture.

In most critically ill adults, removal of a catheter

suspected of being the source of infection is a low-

morbidity procedure. However, an approach where

a catheter could be classified as infected or not while in

situ with removal of only those infected catheters would be

preferred. Several methods have been developed in an

attempt to define whether a line may be infected prior toremoval and include differential quantitative blood cul-

tures and the differential time to positivity. Differential

quantitative blood cultures with a ratio 5:1 (comparingcolony counts from peripheral blood samples with colony

counts of blood samples from catheter hubs) has

a sensitivity of 70% and specificity of 95% relative to the

Maki-method. Differential time to positivity (comparing

time to positivity between cultures of blood samples

obtained from peripheral veins and from catheter hubs)

has a sensitivity of 95% and a specificity of 90% relative to

the Maki-method. It must be recognized that these

approaches require maintaining potentially infected cath-

eters in situ while cultures are incubated. While this may

be done safely in selected stable patients, suspected

infected catheters should be promptly removed in hemo-

dynamically unstable patients or in those where compli-

cations are suspected prior to the availability of blood

culture results.

Diagnostic imaging procedures frequently play an

important role in evaluating potential sources for bacter-

emia. Roentgenograms of the chest may identify pneumo-

nia. Free air due to a perforated viscus is readily identified

by typical views of the abdomen. Plain radiographs may

also be useful to identify bone and joint sources. While

often a reasonable first investigation, plain radiographs

suffer from limited sensitivity, and other modalities may

be indicated. Computed tomography has generally good

sensitivity and specificity to detect infective foci at most

body sites. Ultrasound is readily available at the bedside

and is particularly valuable for assessing the liver and

biliary tree, and can potentially identify infected large

vessel thrombi using Doppler mode. Magnetic resonance

imaging has markedly improved resolution as compared

to computed tomography and is particularly valuable in

defining infections of the head, neck, and spine. A main

limitation of these mentioned modalities is that they

require the clinician to select the body site to be imaged.

In many cases, clinical clues may suggest a potential focus

of infection, but in many cases, the site of infection is

clinically unapparent.

Nuclear medicine scans have been employed in

evaluation of bacteremia of unknown origin, and it may

allow a full body assessment. Traditionally, 67Gallium,111Indium, and 99mTechnetium radiotracers have been

employed but are limited in their specificity for localizing

bacterial infection. Scans using autologous leukocytes

labeled with either 111Indium or 99mTechnitium, while

specific for leukocyte infiltration, do not detect infection

per se. Several newer nuclear technologies are now being

evaluated in the diagnosis of bacterial infections.

delays in providing adequate antifungal therapy are asso-

patients who do not have implanted prosthetic material.

284 B Bacteremia, Primary of Unknown Originciated with adverse outcome. Once the etiology of bacter-

emia has been established, antimicrobial therapy should

be revised to provide optimum coverage. Generally speak-

ing, high doses of bactericidal/fungicidal agents are pre-

ferred and, with few exceptions, should be administered at

least initially through the intravenous route.

Catheter-related bacteremias may be classified as

uncomplicated or as complicated being associated with

one or more metastatic foci of infection. Complicated

catheter-related infections are secondary bacteremias

that require treatment directed at both the catheter source

and the complicated focus, and are discussed elsewhere in

the Encyclopedia. Of note, a negative transesophageal18-Fluorodeoxyglucose positron emission tomography

(18-FDG PET) scans have been investigated with consid-

erable success in identifying metastatic foci of infection.

However, 18-FDG is poorly taken up into the brain, heart,

kidneys, and bladder and therefore is complementary to

other imaging modalities. In addition, 18-FDG PETmay

have similar specificity issues as the radiotracers men-

tioned above. Another new imaging technology using99mTechnitium-ciprofloxacin has also been developed.

This tracer has the advantage of being specific to bacterial

enzymes. Performance in defining sources of bacteremia

as compared to other techniques is limited.

TreatmentThe treatment of primary bacteremia depends on

a number of factors not limited to patient factors includ-

ing severity of disease and comorbid illness, microbiolog-

ical factors including infecting species and in vitro

antimicrobial susceptibilities, evidence of metastatic foci

of infection, and whether the primary bacteremia is

catheter-related or is of unknown origin.

In patients suspected of having primary bacteremia, or

among those where preliminary blood culture results indi-

cate a presumptive infection, empiric therapy should be

initiated pending confirmation of true bacteremia.

Numerous observational studies have emphasized the

importance of early administration of effective antimicro-

bial therapies on the mortality outcome of serious infec-

tions including bacteremia. The selection of empiric

therapy involves an evaluation of the most likely agent(s)

causing disease and expected antimicrobial susceptibili-

ties. While generally one or more agents may be required

to cover a broad spectrum of potential bacterial patho-

gens, it should be recognized that evidence is emerging

that Candida species are frequent causes of primary

bloodstream infection in critically ill patients and thatOn the other hand, 4 or more weeks of treatment is

considered standard in primary catheter-related bacter-

emia due to most multidrug resistant organisms, includ-

ing methicillin-resistant Staphylococcus aureus [5]. The

treatment duration for primary bacteremia of unknown

origin is less well defined, but because a possible deep body

site focus has potentially not been recognized, treatment

durations are frequently prolonged as a precaution, par-

ticularly with Gram-positive and antimicrobial resistant

pathogens. Primary bacteremia of unknown origin caused

by susceptible Gram-negative organisms can generally be

treated for shorter courses (1014 days).

References1. Weinstein MP, Reller LB, Murphy JR, Lichtenstein KA (1983) The

clinical significance of positive blood cultures: a comprehensive anal-

ysis of 500 episodes of bacteremia and fungemia in adults. I. Labo-

ratory and epidemiologic observations. Rev Infect Dis 5:3553

2. Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP

et al (2002) Health careassociated bloodstream infections in adults:

a reason to change the accepted definition of community-acquired

infections. Ann Intern Med 137:791797

3. Renaud B, Brun-Buisson C (2001) Outcomes of primary and

catheter-related bacteremia cohort case control study critically ill

patients. Am J Respir Crit Care Med 163:15841590

4. OGrady NP, Barie PS, Bartlett JG, Bleck T, Carroll K, Kalil AC et al

(2008) Guidelines for evaluation of new fever in critically ill adult

patients: 2008 update from the American college of critical care

medicine and the infectious diseases society of America. Crit Care

Med 36:13301349

5. Mermel LA, AllonM, Bouza E, Craven DE, Flynn P, OGrady NP et al

(2009) Clinical practice guidelines for the diagnosis and manage-

ment of intravascular catheter-related infection: 2009 update by the

infectious diseases society of America. Clin Infect Dis 49:145echocardiogram is required to define an uncomplicated

episode of S. aureus bacteremia. The approach to manage-

ment of primary (uncomplicated) catheter-related bacter-

emia involves prompt removal of the infected catheter

source in addition to providing optimal antimicrobial

therapy [5].

The duration of antimicrobial therapy for primary

bacteremia has not been well defined in clinical trials and

is largely based on anecdotal experience. In uncomplicated

primary catheter-related bacteremia, the duration of ther-

apy will depend on clinical response and the infecting

organism. A typical therapy duration for a primary

uncomplicated catheter-related bacteremia is 2 weeks

following catheter removal as long as there is good clinical

response. However, it is common practice to prescribe

either no antimicrobials or only a brief course of therapy

in primary catheter-related bacteremias specifically due to

coagulase-negative staphylococci after catheter removal in

Some of these procedures can be lifesaving and are often

important to implement early. Specifically in the case of

cardiopulmonary resuscitation (CPR) and defibrillation

with automatic external defibrillators (AEDs), BLS pro-

medical technician (EMT)-basics.

Characteristics

Basic Life Support B 285

BBangs Disease

BrucellosisBAL

Bronchoalveolar Lavage (BAL).Bailout Surgery

Damage Control SurgeryBag-Valve-Mask Ventilation

Airway ManagementBacteriuria

Urinary Tract InfectionsBacterial Pneumonia

Burns, PneumoniaBacterial Meningitis

MeningitisBacterial Endocarditis

Cardiac and Endovascular InfectionsBLS can be provided by first responders or EMTs. EMTs

are classified as EMT-basic (EMT-b), EMT-advanced,or EMT-paramedic (please see Prehospital Care fora more detailed description of each level of provider).cedures can have a significant impact on survival, and are

typically delivered by initial responders (sometimes

referred to as first-responders) until more advanced and

definitive medical care can be implemented. BLS is typi-

cally provided by either first responders or emergencyDefinitionBasic life support (BLS) is defined as a variety of nonin-

vasive emergency procedures performed to assist in the

immediate survival of a patient, including cardiopulmo-

nary resuscitation, hemorrhage control, stabilization of

fractures, spinal immobilization, and basic first aid.SynonymsEMT-basic; Field medicine; First responder; Out-of-

hospital careBarlows Disease

Mitral Valvular Disease

Barotrauma

Diving SicknessPleural Disease and Pneumothorax

Basic Life Support

CHRISTOPHER B. COLWELL, GINA SORIYA

Department of Emergency Medicine, Denver Health

Medical Center, Denver, CO, USA

tila

wh

the

and

pat

sug

ma

not

a p

thr

2.

286 B Basic Life Supportshock is indicated, and deliver that electric shock. It can

detect pulseless ventricular tachycardia (VT) and ventric-

ular fibrillation (VF), which then stimulates the machine

to indicate to the provider that a shock is advised. The

AED is also able to recognize a non-shockable rhythm,

such as asystole and pulseless electrical activity (PEA), and

will not designate a shock advisory. The AED is designed

for use by first responders or laypeople that have ideally

been trained in the use of the machine although the use of

AEDs by members of the public that have not been previ-

ously trained in its use has been increasing. Lack of train-

ing on AEDs should never discourage a member of the

public from using thesemachines. Early use of AEDs in the

appropriate setting by trained or untrained responders

can have a significant impact on mortality [2].

Pre-existing Condition1. Unconsciousness/apnea/pulselessness

2. Foreign body obstruction/choking

3. Drowning

4. Hypothermia

5. Stabilization of basic injuries

Application1. Adult BLS/CPR sequence for the unconscious/apneic/

pulseless patient:

Establish scene safety. Assess victims level of consciousness: (1) ask are

you okay? (2) stimulate the patient physically to

check responsiveness.

Activate local emergency system: instructa bystander to call 911.

Apply an AED if available, and shock if advised. If no suspected spinal injury, open the airway

via head-tilt/chin-lift (image). If spinal injury is

suspected, open the airway via jaw-thrust (image).

Look, listen, and feel for 10 s: (1) Look forforeign body; if any are visible, remove with

finger-sweep technique. Blind finger sweep is notCardiopulmonary resuscitation (CPR) integrates ven-

tions and chest compressions in the setting of a patient

o is pulseless and/or apneic. The purpose of performing

se maneuvers in sequence is to provide oxygenation

circulation in an attempt to prevent brain injury in

ients whose heart has stopped. Recent research has

gested the early access to quality CPR and defibrillation

y be the most significant determinants of whether or

someone survives and recovers from cardiac arrest [1].

An automatic external defibrillator (AED) is

ortable computerized device that can diagnose a life-

eatening arrhythmia, direct the provider if an electric If no chest rise occurs, reposition the airway uti-lizing the appropriate technique and attempt arti-

ficial ventilations again. If ventilations continue to

be unsuccessful, and the patient is unresponsive,

consider an airway foreign body. Begin chest com-

pressions. Check airway after each set of 30 com-

pressions, removing any foreign body found, and

reattempting ventilations.

If ventilations are successful, check for a carotidpulse. If a pulse is found, continue with appropri-

ate ventilations and await immediate transport. If

there is no pulse, begin CPR with 30 compressions

followed by two ventilations at 100 compressions

per minute for five cycles.

After five cycles of CPR have been completed, thecycle should be repeated, starting with reassessing

the patients airway, breathing, and circulation.

The BLS sequence should be continued until oneof the following conditions has been met: (1) the

patient regains a pulse, (2) the initial provider is

relieved by another rescuer of equal or higher

medical training, (3) the rescuer is physically

unable to continue with CPR, or (4) the patient

is pronounced dead by a physician.

Foreign body obstruction/choking:

Airway obstruction from a foreign body may pre-

sent in a variety of ways, ranging from minimal symp-

toms to respiratory compromise and death. The death

rate nears 2,000 annually in the USA, with children

aged 13 as the primary victims. Mortality rates are up

to 3.3% [3].

Assess severity of obstruction. If the patient is ableto cough effectively, the patient should be encour-

aged to cough and monitored for deterioration.

If the patient is unable to speak or breathe, iscyanotic, or has a silent cough, abdominal thrusts

should be administered in rapid progression until

the obstruction is relieved. If the patient isforming a seal. Ensure chest rise with ventilations.recommended. Look for chest rise. (2) Listen

for breath sounds. (3) Feel for breath; feel for

chest rise.

If the patient is breathing normally, place patientin the lateral recumbent (recovery) position and

await transport. Continue to check for breathing.

If the patient is not breathing, administer two artifi-cial ventilations using mouth-to-mouth technique,

mouth-to-mask technique, or bag-valve-mask. If

usingmouth-to-mouth technique, close the patients

nostrils between the thumb and forefinger on one

hand, covering the mouth with that of the rescuers,

3.

4.

5. Sta

(a)

(b)

Basic Life Support B 287

BFor hypothermia patients with no perfusing

rhythm:

Assess the ABCs, keeping in mind it may takelonger to detect a pulse or respiratory rate.

If no respirations are detected, begin rescuebreathing. If there is no detectable pulse, or if

there is any doubt that a pulse may be present,

begin compressions. Compression-to-ventilation

ratio is 30:2.ister warm, humidified oxygen.obstruct the trachea.

There is no need to perform the Heimlich maneu-ver or abdominal thrusts in an attempt to clear

water from the lungs, as these moves are ineffective

and can be dangerous for the patient.

Patient emesis is not uncommon during resuscita-tion of the drowning victim. If this occurs, vomitus

from the airway should be removed via finger

sweep with the patients head turned laterally. If

the patient has a suspected cervical spine injury,

the patient should be logrolled to the side, and

vomitus swept from the airway.

Hypothermia:

For hypothermic patients with a perfusing rhythm:

Assess airway, breathing, and circulation. Thepulse and respiratory rate may be difficult to

detect, therefore it may take longer to adequately

assess, such as 4560 s.

Remove wet garments and prevent any furtherexposure to the cold environment.

Apply warm dry blankets, hot packs, or othermodality to warm the patient. If available, admin-airway, as the amount is minimal and does notpregnant or obese, chest thrusts should be deliv-

ered as an alternative to abdominal thrusts. In

infants under 1 year of age, the rescuer should

alternate between back blows and chest thrusts.

If the patient subsequently becomes unresponsive,the patient should be lowered to the ground, EMS

activated, and CPR initiated. The airway should be

assessed for foreign body and removed if visualized.

Drowning:

Death from drowning reaches over 8,000 annually

in the USA, almost 25% of those being children.

Remove the patient from the body of water,maintaining cervical spine immobilization if

trauma is suspected.

Assess airway, breathing, and circulation asoutlined under Sect. I. Proceed with CPR. Com-

pression-to-ventilation ratio is 30:2.

There is no need to clear aspirated water from theseek immediate help.

If there is an open wound at the site of thefracture, cover the wound and apply direct

pressure for bleeding control. Splint as above

and elevate.

If there is a suspected spinal injury, do notmove the patient unless assisted by trained

medical personnel.

(c) Burn care

Extinguish the burn with a large amount ofwater.recheck circulation. If there continues to be

lack of circulation, splint in alignment andplace.

Do not remove debris from the wound. If thereis a protruding foreign object, such as a knife,

leave in place and bandage securely so the

object is immobilized.

For chest wounds, seal open sucking woundswith hand or an air-tight dressing.

For abdominal wounds, cover with clean ban-dage. Do not replace protruding intestines into

the wound.

Fracture splinting

Immobilize the joints above and below thefracture site with a splint.

Check distal circulation, motion, and sensa-tion (CMS) before and after immobilization.

If the fracture is angulated and there is nonoted distal circulation, attempt to straighten

the fracture into anatomical alignment and Apply a clean dressing and bandage firmly inshould be delivered one time, then CPR imme-

diately resumed. The number of defibrillation

attempts in the hypothermic cardiac arrest is

controversial; however, further defibrillation

attempts should be postponed until the patients

core body temperature warms, in order to

improve the chance of conversion to a normal

rhythm.

bilization of basic injuries

Bleeding control

Check airway, breathing, and circulation.Resuscitate as indicated.

Expose area by removing or cutting clothing. Apply direct pressure to the bleeding wound. Check for circulation distal to the wound by

assessing pulse or capillary refill.

Elevate the wound if possible.the machine advises a defibrillation, the shockIf an AED is available, it should be applied. If

2. Bobrow BT et al (2008) Minimally interrupted cardiac resuscitation

by emergency Medical services for out-of-hospital cardiac arrest.

Cardiopulmonary Resuscitation

Pressure Ulcer Evaluation, Prevention and Treatment

Monitoring

DefinBedside

of phys

technol

vital sig

rate, te

logicall

288 B Basic Life Support (BLS)itionmonitoring refers to the systematic recording

iological data over time. This extends from the

ogically very simple and noninvasive collection of

ns such as heart rate, blood pressure, respiratory

mperature, and urine output, to the more techno-

y demanding noninvasive techniques such pulseSHELDEN MAGDER

Critical Care Division, McGill University Health Centre,

Royal Victoria Hospital, Montreal, QC, Canada

SynonymsHemodynamic monitoring; Pressure monitoring; Vital

signsBedside HemodynamicBed SoreJAMA 299:11581165

3. Soroudi A et al (2007) Adult foreign airway obstruction in the

prehospital setting. Prehosp Emerg Care 11(1):2529

Basic Life Support (BLS) Check airway, breathing, circulation, andresuscitate as indicated.

Remove smoldering clothing, as well as jew-elry, belts, and shoes.

Cover with sterile burn dressing if available;otherwise use any clean dry dressing.

Do not open or drain blisters.

References1. Eisenberg MS, Psaty BM (2009) Defining and improving survival

rates from cardiac arrest in US communities. JAMA 301:860862oximetry, end-tidal CO2, and techniques for the assess-

ment of cardiac output, and to invasive intravascular

measurements of pressures such as the central venous

pressure (CVP), arterial pressure, pulmonary artery pres-

sure, measurements of cardiac output, airway pressures

and flows, and cerebrospinal pressure. Measurement of

variables over times allows trend analysis so that changes

in the patients underlying condition or changes in

response to therapy can be assessed. In this entry, I will

concentrate on the hemodynamic components of bedside

monitoring. (I assume that respiratory and neuro

monitoring are covered elsewhere). For the purpose of this

discussion, a central assumption is that for an individual

patient there is a range of parameters such as heart rate,

blood pressure, cardiac output, and markers of metabolic

stability (e.g., arterial oxygen, lactate, base excess,

central venous oxygen content) that have been identified

by the treating team and there is a desire to maintain the

patients values in a given range. When a patients

values are in the desired range, the patient is defined as

hemodynamic stabile.

Pre-existing Condition

IndicationsHemodynamic monitoring has the following roles. (1) It

alerts the medical team to deterioration in a patients

hemodynamic status and the requirement for urgent

interventions. This includes the development of an inad-

equate heart rate response or rhythm disturbance, exces-

sively high or low blood pressure or inadequate cardiac

output for tissue needs. (2) It can be used to predict

potential responses to therapeutic interventions. (3) It

allows assessment of the response to therapeutic interven-

tions. (4) The pattern of hemodynamic wave patterns

themselves can have diagnostic information for the under-

lying condition.

In choosing a monitoring tool one must consider

potential benefits, costs, and risks. Costs and risks gener-

ally are more readily available but the benefits are much

harder to define. Although there is no rigorous evidence

that supports the utility of any hemodynamic tools

including vital signs, it is important to appreciate that

a monitoring tool is only as good as the algorithm

that makes use of the information. This is well illustrated

by studies in which investigators have tried to assess the

roles of the pulmonary artery catheters for the manage-

ment of critically ill patients [1, 2]. No benefit has been

observed in these studies, but in reality they have only

tested the presence of a catheter and not an algorithm and

there is no reason to expect that the catheter itself should

Bedside Hemodynamic Monitoring B 289

Bhave a benefit. Even a stethoscope has no value if the

clinician does not know how to interpret the sounds that

are heard and to put them into the context of the patients

overall condition.

Perhaps the most significant use of hemodynamic

monitoring is that it allows physicians to continuously

assess responses to therapeutic interventions and to cor-

relate these responses with the patients overall condition.

The important phrase here is overall condition. When

the predefined targets have been met as assessed by the

monitoring tool, the physician can limit further interven-

tions and potentially prevent harm from excess use of the

interventions. Physicians deal with individual patients,

not populations and hemodynamic monitoring allows

the physician to determine the response to a therapy in

an individual patient. If the expected response does not

occur, it does not make sense to continue the therapy

in that patient even if it is recommended as a standard

treatment from large population studies.

Conditions in which there is a greater potential for

hemodynamic instability to occur and close monitoring is

warranted include: (1) patients with known cardiovascu-

lar disease who have either developed new cardiac

dysfunction or who are under increased risk of hemody-

namic or rhythmic instability because of surgery or a new

medical condition; (2) patients undergoing high-risk

surgical procedures and who are expected to have major

fluid losses as well as large fluctuations in blood pressure

and cardiac output and in whom the subsequent use of

careful volume resuscitation and vasoactive drugs are

likely to be required to maintain hemodynamic stability;

(3) Patients with recent large blood losses from trauma,

gastrointestinal sources, or large surgical losses;

(4) patients with severe sepsis or septic shock, (5) patients

with major burns and who will have challenging volume

management; (6) patients requiring ongoing analysis

of their respiratory status. In all these conditions

the changing pattern of the measurements are more

important than the actual values.

Applications

TechniquesMeasurements can be categorized as those related to

(1) rhythm and rate, (2) pressure, (3) flow measurements,

and (4) metabolic consequences of flow and oxygen

delivery.

Rhythm and RateHeart rate and rhythm are easily assessed with surface elec-

trodes and the amplified signal of the electrocardiogram. Theidentification of rapid or bradycardic rhythms is a subject by

itself and will not be dealt with here. However, a cautionary

note is worthwhile related to the significance of rapid sinus

rhythm. A rapid heart rate is always abnormal and should

alert the physician to look for causes. However, it does not

necessarily indicate that the rate should be slowed pharma-

cologically and I would suggest that unless the patient man-

ifests evidence of myocardial ischemia or is known to be at

high risk of myocardial ischemia, there currently is no evi-

dence that slowing the rate pharmacologically is beneficial.

Tachycardia also is not a reliable indicator of a patients

intravascular volume status. Patients with inflammation in

the area of the celiac axis (e.g., pancreatitis, post-surgery, or

who has abdominal abscesses), can often be tachycardic but

volume replete. This likely occurs from activation of sympa-

thetic afferents from local sympathetic ganglia, which

increase central sympathetic output. On the other side,

a normal heart rate does not rule out hypovolemia.

Pressures

General PrinciplesPressures that we measure are primarily due to the elastic

force that stretches the walls of vessels and the heart [3].

A key principle is that measured pressures are relative to

a reference value. Since we are normally surrounded by

atmospheric pressure, we are interested in deviations from

atmospheric pressure and atmospheric pressure actually is

the reasonable starting value or zero for our measure-

ments. A pressure of zero is actually not zero but around

760 mmHg and an arterial systolic pressure of 120 mmHg

is really about 880 mmHg. The commonly used units of

pressure as millimeters of mercury (mmHg) or centime-

ters of water (cmH2O) are based on the force produced by

the height of a column of fluid and the density of that

fluid. The density of mercury is 13.6 times greater than

that of water and this value can be used to interconvert the

values in cmH20 and mmHg.

The use of fluid-filled tubes to connect the patient to

a transducer introduces an additional gravitational com-

ponent to the pressure measurement. The difference in

height of the column of fluid between the reference level

on the patient and the transducer produces an addition

pressure of around 8 mmHg for every 10 cm height.

Standard and consistent leveling of the transducer to the

patient is thus essential for the comparison of values in

a particular patient to other patients and for trending

measurement over time in the same patient. The generally

accepted (although arbitrary) physiological reference

level is the midpoint of the right atrium for that is where

the blood comes back to the heart before it is pumped out

this level gives values of vascular pressures that are approx-

290 B Bedside Hemodynamic Monitoringimately 3mmHg higher than the value obtained by using 5

cm below the sternal angle. The appropriate level on the

transducer is the level of the stopcock that is used to open

the system to atmospheric pressure for zeroing.

It is the pressure across the wall of elastic structures

that determines the stretch of the wall; this is called

transmural pressure. The pressure outside the heart is

pleural pressure and not atmospheric pressure and

pleural pressure changes relative to atmospheric pressure

during the ventilator cycle. However, transducers that are

used to measure intrathoracic pressure are outside the

chest and referenced to atmospheric pressure and it is

not possible to easily obtain the pleural pressure to

calculate the transmural pressure. To minimize the error

produced by of changes in pleural pressure during the

ventilatory cycle, pressures are measured at the end of

expiration (which is also the point just before inspiration)

whether ventilation occurs with negative or positive

pressure ventilation. However, this does not account for

positive end-expiratory pressure and there is no simple

solution for this error. Although expiration is normally

passive, critically ill patients often have active expiratory

efforts and if these increase during the expiratory

phase, they increase the end-expiratory pressure that is

measured relative to atmosphere. In these situations,

the valid pressure is likely at the beginning of the

expiratory phase, before the patient begins to recruit

expiratory muscles.

Arterial PressureArterial pressure is themost commonly measured vascular

pressure and can be measured invasively with intravascu-

lar catheters or noninvasively by the classic auscultation

method or by devices that use oscillometry. These latter

devices are frequently used for repeated automatic mea-

surements, but it is important to appreciate that the values

obtained with these devices need to be validated with

occasional auscultatory measured pressures for they can

sometimes produce artifactual values of pressure.again. That level is approximately 5 cm vertical distance

below the sternal angle which is where the second rib

meets the sternum and is valid when the patient is flat or

sitting at up to 60. Accurate measurement of this levelrequires a carpenters leveling device and a marker of 5 cm

below the device so that it is more popular to reference

transducers to the midpoint of the thorax at the fourth rib.

This position, though, should only be used in the supine

position for it will vary relative to themidpoint of the right

atrium when the upper body is elevated. Referencing atIn patients in the ICU following surgical procedures

upper limits for pressure are often set to reduce the risk of

bleeding. Identification of high pressure is also important

in patients with hypertensive crisis, aortic dissection, or an

unstable aneurysm, but not as important in the short run

in most other patients. In the majority of cases, decreased

arterial pressure is the primary concern. Despite the fre-

quency of the hypotension and its aggressive treatment, it

is amazing how little empiric knowledge there is for

acceptable limits of low pressures and whether the impor-

tant pressure is the systolic, mean, or diastolic pressure. It

is important to remember that flow to the tissues, or even

more precisely delivery of oxygen and nutrients and

clearance of waste is what counts and not pressure.

The pressure is used as a surrogate for potential

flow. The patients clinical status provides an important

guide. A low pressure in patient who is awake with normal

sensorium, who has stable renal function, and no acidosis,

is likely of no consequence. However, in many patients

some or all of these are abnormal. The pressure may or

may not be a contributor and empiric values must be

chosen to guide therapy.

There are advantages and disadvantages for the

choices of any one of systolic, diastolic, or mean pressure.

When the pressure is measured by auscultation, it is gen-

erally a low systolic pressure that triggers clinical responses

and provides a convenient signal. When arterial catheters

and transducers are used to measure pressure, the charac-

teristics of the measuring device can affect the observed

systolic pressure and one must be careful to make sure that

the waveform of the signal is appropriate and not over- or

under-damped. The mean pressure should be related to

overall flow to organs with higher flows, but does not give

a good guide to regions that receive more of their flow in

systole. There are some patients who also have a low

diastolic pressure but high systolic pressure and targeting

the mean can result in high doses of vasopressor. Finally,

diastolic pressure is important for coronary flow, but

excess use of vasopressors to raise the diastolic pressure

could end up increasing myocardial oxygen demand by

increasing systolic pressures and cardiac ionotropy

and also decrease coronary flow by constricting the

coronary arteries.

Ideal pressures really need to be established empiri-

cally, but there are few rigorous studies to provide guid-

ance. Optimal arterial pressures have been studied best for

the kidney and it is suggested that a minimal mean pres-

sure of 80 mmHg is required for normal renal function.

However, this value is primarily derived from animal

studies over short periods of time and without underlying

vascular or intrinsic renal disease. Septic patients are an

It is also the change in CVP in relation to other hemody-

pulmonary vascular changes, obstructive processes, or

Bedside Hemodynamic Monitoring B 291

Bobliterative processes.

Inflation of a balloon at the end of a pulmonary cath-

eter or advancing a pulmonary catheter until the end-hole

occludes the vessel gives the pressure distal to the end-hole

which after equilibration is equal to the left atrial pressure.

This wedged pressure provides diagnostic information

about the behavior of the left side of the heart. It also gives

an indication of the minimal pressures in the pulmonary

capillaries and thus the hydrostatic force that drives pul-

monary capillary filtration. On the other hand it does not

give an indication of the preload status of the heart as

a whole for that is related to the CVP for the left heart can

only put out what the right heart gives it. An important

use of these catheters is that they provide a simple tool for

measuring cardiac output which is discussed below.namic events that is helpful. Importantly, CVP by itself is

not an indicator of blood volume.

Pulmonary Arterial and Pulmonary ArterialOcclusion PressurePulmonary artery pressure is an important indicator of

the load on the right ventricle. It is also an indicator of

pathology in the pulmonary vasculature. The pulmonary

artery pressure can be elevated passively because of high

left heart pressures, high pulmonary flow and reactiveinteresting example where monitoring pressure and urine

output can allow individualization of pressure targets.

Elevation of arterial pressure with vasopressors can restore

renal blood flow and function and this individualized

pressure thus provides a useful pressure target for the use

of vasopressors in these patients.

One must be careful of some potential measurement

problems that can occur. Patients with a stenosis proximal

to the measuring device will appear to have low arterial

pressures, when in fact central pressure is normal.

In patients who have a distal arterial catheter and who

are receiving high doses of vasopressors, constriction of

the vessel can lead to underestimates of the central

pressure.

Central Venous PressureCentral venous pressure (CVP) is a commonly used mea-

sure and can even be estimated without a catheter by

examining the level of jugular venous distension [4].

A fuller discussion of the use of CVP with changes in

cardiac output will be given below for the CVP is only

useful in conjunction with an estimate of cardiac output.Cardiac OutputThe cardiac output, liter per minute, is a major compo-

nent of the ultimate clinical end-point which is the deliv-

ery of nutrients to the tissues and removal of waist and

thus a very desirable value to measure [5, 6]. Unfortu-

nately, flow is not as easy to measure as pressure. One of

the most reliable methods but a cumbersome one is based

on the dilution of an indicator that is injected at

a proximal site such as a major vessel and detected by

a sensor at a downstream site. Indocyannine green was

one of earliest indicators, but the development of thermal

sensing catheters allowed the use of temperature which is

a much simpler indicator to use although it has more

potential errors. Small doses of lithium can also be used

as an indicator. Placement of the thermistor in the pul-

monary artery allows injection of a solution that is cooler

than blood into the right atrium and sensing the change in

temperature in the pulmonary artery but this requires

passing a catheter through the right heart and the risks

of arrhythmias and perforation. The alternative is to place

the sensor in an artery which generally needs to be bigger

than a radial artery so that it also has an invasive compo-

nent and is not without risks. Two key requirements for

the use of an indicator dilution technique are that there

must be immediate complete mixing and no loss of indi-

cator. This can be a problem when the injection is made

in the right atrium and the patient has tricuspid insuffi-

ciency for some of the indicator (temperature) is poten-

tially lost when the blood goes back and forth and mixing

may not be complete because of the regurgitant flow.

Pulmonary catheters can also be equipped with a sensor

for oxygen saturation and these catheters allow the

measurement of cardiac output continuously.

Flow can also be measured with Doppler techniques

which detect the velocity of blood by the phase shift of the

Doppler wave when it hits the flow pulse and gives

a measure of the stroke volume which is then converted

to cardiac output by multiplying by the heart rate.

The calculation of flow from velocity requires a measure

of the cross-sectional area of the vessel for flow is equal to

the product of velocity and the cross-sectional area of the

vessel. The latter is not always easy to obtain and is often

assumed, which is reasonable under basal conditions but

not when a patient is in shock. Continuous assessment of

flow by Doppler probes can be made with a probe placed

in the esophagus but this is really only tolerable in

a heavily sedated or unconscious patient. Appropriate

positioning of the catheter must also be made.

Devices have also been developed to measure the elec-

trical impedance related to blood volume and the changes

during the cardiac cycle give a measure of stroke volume.

ascending part of its function curve. If the cardiac output

increases, more volume can be given to try to maintain the

desired values, but importantly a positive response only

means that the patient is volume responsive but it does not

indicate that the patient actually needs volume. That is

a clinical decision. If the cardiac output does not increase

with a bolus that increased the CVP by 2 mmHg or more,

the patient should be considered volume unresponsive

and further volume loading will not help and may be

harmful no matter what the starting CVP value. This

situation indicates limitation of right ventricular output

and even if the left heart is deemed to be underfilled based

on the pulmonary artery occlusion pressure or by

292 B Bedside Hemodynamic Monitoring

This too is multiplied by heart rate to give cardiac output.

These devises give reasonable estimates in normal subjects

but there are potential problems in critically ill patients

who have increased chest wall edema, pleural or pericar-

dial effusions, or hyperinflated chests

A number of techniques have been developed to try to

estimate stroke volume from the pulse pressure. This

requires knowledge of the elastic properties of the patients

vessels which is hard to predict in individual patients. It

will also vary with disease and likely be very sensitive to the

volume in the vessel for elastance is curvilinear against

the radius of vessels. These techniques can give trends in

patients who do not have major pathology but likely will

not be useful in patients who are hemodyanmically unsta-

ble which is when you really need them.

All techniques that attempt to measure stroke volume

and calculate cardiac output by multiplying stroke

volume by heart rate will always show at least a moderate

relationship to direct measurements of cardiac output for

populations but one must be cautious about extrapolating

this to individual patients. This is because the heart rate,

which provides a very reliable measure, is a large percent-

age of the product and therefore drives a large part of the

correlation. However, it is often the smaller changes in

stroke volume that are important for that it identifies

changes in cardiac muscle function.

Therapeutic ApplicationAs discussed above, the values of pressures and flow that

are adequate for a patients metabolic need are not well

empirically established and need to be customized to the

individual patient. However, hemodynamic monitoring

that includes a measure of cardiac output can be useful

for detecting a decrease from the values that the patient

had when deemed stable or becomes stable and also to

identify the dominant hemodynamic process. Clinical

responses are most often triggered by decreases in arterial

blood pressure. Arterial pressure is approximately equal to

the product of cardiac output and systemic vascular resis-

tance (SVR) (Fig. 1). The two measured values are arterial

pressure and cardiac output (or a surrogate) so that SVR is

a derived variable. This means that it is changes in cardiac

output that are key. If the blood pressure is low and cardiac

output is normal or elevated, the primary problem is

a decrease in SVR and the differential diagnosis for the

problem is specific. If the cardiac output is depressed, then

the next question is why is it decreased? The steady-state

cardiac output is determined by the interaction of cardiac

function (based on the FrankStarling relationship) and

the function that determines venous return. These twofunctions intersect at the working cardiac output and the

working right atrial pressure which is approximately the

same as the CVP. A low cardiac output with a high CVP

indicates that the cardiac function is the primary limiting

factor, whereas a low cardiac output with a low CVP

indicates that the return function is the primary limiting

factor and the most common cause is inadequate vascular

volume. The specific values are not as useful as the change

in values. A fall in cardiac output with a rise in

CVP indicates a decrease in cardiac function and a fall in

cardiac output with a fall in CVP indicates a return

problem, which is most commonly insufficient vascular

volume (Fig. 2).

If inadequate volume is thought to be the primary

problem then the best test is to do a volume challenge

[4]. In this procedure, a small bolus is given quickly with

the aim of raising CVP. The faster the fluid is given the less

fluid that is needed. The hemodynamic variable that one is

trying to correct needs to be reassessed as soon as the CVP

is increased. A reasonable value for the increase in CVP is

2 mmHg because that is a value that can be detected with

certainty on a monitor. It also should produce an obvious

increase in cardiac output if the heart is functioning on the

Part = Q x SVR (+K)

CircuitStressed volumecomplianceresistancePra

SepsisDrugsSpinal

HeartHeart rateAfterloadContractilityPreload

Dobutaminemilrinone

VolumeNE NE

Bedside Hemodynamic Monitoring. Figure 1 Predictions of

changes of cardiac output and changes in CVP

Implications of changes in cardiac output and CVP

se

em

up

ed

ou

Bedside Hemodynamic Monitoring B 293

Bechocardiography, volume will not solve the problem for

the left heart can put out what the right heart gives it. This

raises an important limitation of the use of echocardiog-

raphy for hemodynamic monitoring as is sometimes

advocated [7]. Besides not being able to provide easy and

rapid assessment of serial values, it mainly assesses left

heart function, but the output of the left heart is totally

dependent upon right heart function which often does not

functioning well in critically ill even though left ventricu-

lar function is intact. In that situation, the volume status

of the left ventricle is no help for fluid management.

There have been many attempts to use the respiratory

variations in arterial pressure or pulse with positive

pressure ventilation to predict volume responsiveness

[8]. These techniques can be effective but are only valid

if there are no spontaneous inspiratory or expiratory ven-

tilatory efforts by the patients. The various values given for

these variations also are only valid when the patient is

ventilated with the same ventilator parameters as in the

original study and when the rhythm is regular. Their use is

thus limited.

An inspiratory fall in CVP with a spontaneous

(negative pressure swing) breath, whether the patient is

on a ventilator or not, has also been shown to predict

volume responsiveness [4]. The test works best in the

Cardiac Output CVPDecreased Decreased Decreased Increased Increased Increased Increased Decreased

Bedside Hemodynamic Monitoring. Figure 2 Approach to as

management. Part arterial pressure, Q cardiac output, SVR syst

downstream value of pressure because the true equation is

pressure (= CVP), NE norepinephrine. Cardiac output is determin

the preload of the cardiac function is the Pra which is also thenegative. Absence of an inspiratory fall in CVP in

a patient with an adequate effort indicates that the patient

will not have an increase in cardiac output in response to

an infusion of volume. When using this technique, one

must be careful to make sure that the inspiratory fall in

CVP is not in fact the release of a forced expiration that

looks like an inspiratory fall and produces an apparent

false positive.

Information can also be gathered by examining wave-

forms. As some examples, a wide arterial pulse pressure is

suggestive of a low SVR. Prominent y descents in the

CVP tracing suggest that the right heart is volume limitedand will not respond to further volume loading. A large

C-V wave in the CVP tracing is indicative of tricuspid

regurgitation. A prominent v in the pulmonary artery

occlusion pressure is indicative of mitral regurgitation but

is seen when there is excessive filling of the left heart.

A loss of a y descent in the CVP can be a sign of the

development of cardiac tamponade.

ConclusionThe important part of bedside monitoring is not the

actual values but the changes in the values as they related

to changes in the patients condition. In a sense, the

meaning of a patients values should be calibrated to

the clinicians impression of the patients overall status.

This is especially important when trying to gauge the

impact of therapeutic interventions. The value of

the information obtained by bedside monitoring can

only be as good as the skill of the clinicians and nurses

receiving them.

References1. Vincent JL, Pinsky MR, Sprung CL, Levy M, Marini JJ, Payen D,

Rhodes A, Takala J (2008) The pulmonary artery catheter: in medio

virtus. Crit Care Med 36:30933096

2. HadianM, PinskyMR (2006) Evidence-based review of the use of the

pulmonary artery catheter: impact data and complications. Crit Care

IndicatesDecreased return (most often volume )Decreased Pump functionIncreased return (likely volume ) Increased pump function

ssment of cause of hypotension and simplified approach to

ic vascular resistance, K a constant representing the

stream minus downstream pressure Q x SVR, Praright atrial

by the interaction of the cardiac function and return function;

tflow pressure for the venous return (circuit)10(Suppl 3):S8

3. Magder S (2007) Invasive intravascular hemodynamic monitoring:

technical issues. Crit Care Clin 23:401414

4. Magder S (2006) Central venous pressure: a useful but not so simple

measurement. Crit Care Med 34:22242227

5. Magder S (1997) Cardiac output measurement. In: Tobin MJ (ed)

Principles and practice of intensive care monitoring. McGraw-Hill,

Chicago, pp 797810

6. de Waal EE, Wappler F, Buhre WF (2009) Cardiac output monitor-

ing. Curr Opin Anaesthesiol 22:7177

7. Vignon P (2005) Hemodynamic assessment of critically ill patients

using echocardiography doppler. Curr Opin Crit Care 11:227234

8. Magder S (2004) Clinical usefulness of respiratory variations in

arterial pressure. Am J Resp Crit Care Med 169:151155

Being the Active Part of Fish Oil

Serum and Urinary Low Molecular Weight Proteins

JONATHAN BALL

General Intensive Care Unit, St. Georges Hospital &

Beta-adrenoceptor blocking drugs (b-blockers) have beena mainstay of therapy for hypertension, myocardial ische-

mia, and, more recently, cardiac failure. The current Brit-

b-blockers involves marked differences in their pharma-codynamics as well as differences in their pharmacokinet-

ics. Our understanding of adrenergic receptors and the

294 B Bedside Ultrasonographymyriad roles the sympathetic nervous system plays, in

both health and disease, continues to increase. Coupled

with the extensive body of trial data examining, the role ofish National Formulary [1] lists 15 b-blockers while themedical literature contains at least as many agents again,

either in development or consigned to history. Unlike

most other classes of drugs, the heterogeneity betweenMedical School, University of London, London, UK

IntroductionBeta-BlockersOmega-3 Fatty Acids

Beta-2-MicroglobulinBedside Ultrasonography

Ultrasound: Uses in ICU

Bedside Ultrasound

Shock, Ultrasound Assessmentb-blockers in a diverse group of settings has resulted inmuch ongoing controversy. In critical care, not only do we

need a clear understanding of the risks and benefits of

acute therapy with b-blockers, but we must also be awareof the consequences of chronic therapy in our patients.

Basic ScienceThe sympathetic nervous system has two principal trans-

mitters, noradrenaline (norepinephrine) and adrenaline

(epinephrine). The receptors for these endogenous ago-

nists have been classified into alpha and beta with more

recent identification of a number of subtypes. Beta-

adrenoceptors are found in nearly every human organ

and tissue. There are three subtypes: b1, b2, and b3. A b4subtype was believed to exist but has been proven to be the

b1-receptor in a different conformational state with dis-tinct agonist/antagonist binding [2]. Their tissue location

and agonist binding responses are detailed in Table 1.

Pathophysiologically and therapeutically cardiac beta-

adrenoceptors have been studied in the greatest detail

[3, 4]. A review of beta-adrenoceptor physiology, patho-

physiology, and polymorphisms can be found here [12].

Despite this body of research many questions remain

unanswered.

An important property of beta-adrenoceptors is the

autoregulatory process of receptor desensitization. This

process operates to prevent overstimulation of receptors

in the face of excessive beta-agonist exposure. Desensiti-

zation occurs in response to the association of receptor

with the agonist molecule, and is prevented by the inter-

action of the receptor with an antagonist. The mecha-

nisms by which desensitization can occur consist of three

main processes: (1) uncoupling of the receptors from

adenylate cyclase, (2) internalization of uncoupled recep-

tors, and (3) phosphorylation of internalized receptors.

The extent of desensitization depends on the degree and

duration of the receptor agonist or antagonist response

[13]. From the perspective of b-blockade, the physiologi-cal process of desensitization results in an increase in

sensitivity in subjects exposed to chronic blockade.

Indicationsb-blockers have been used for multiple indications formany decades. Perhaps surprisingly therefore, many gaps

remain in our knowledge with regard to the optimal use of

currently available agents. Commonly used b-blockersexhibit variable degrees of relative affinity to b1-, b2-,and b3-receptors [14]. The effect of drug receptor bindingalso produces variable effects with some agents producing

universal antagonism, while others produce partial

te

oat

ty

sti

Beta-Blockers B 295

BBeta-Blockers. Table 1 Subtypes of beta-adrenoceptors. Adap

Receptor Tissue Response to agonist

b1 Heart (b1:b2 70:30 atria,80:20 ventricles)

Increases heart rate (sin

node, cardiac contractili

Ubiquitous coupling toagonism or inverse agonism [15, 16]. Table 2 summarizes

the pharmacology of the most commonly used b-blockers.It should be stressed that b-blockers are a very heteroge-neous group of drugs. Indeed, much of the controversy

surrounding their optimal use results from the wide-

Pro-apoptotic

Chronic stimulation results

Lung (20%) [8] Bronchodilatation [9]?Juxtaglomerular cells Increases rennin secretion

Innate and adaptive

immune cells

Pro-inflammatory

Coagulation system May increase platelet aggr

Brain Poorly characterised [10]

b2 Heart (b1:b2 70:30 atria,80:20 ventricles)

Increases heart rate (sinoat

node, cardiac contractility

Coupled to both stimulato

Anti-apoptotic

Chronic stimulation results

Lung (180%) [8] Bronchodilatation and alveSmooth muscle Relaxation of smooth mus

tract

Skeletal muscle Glycogenolysis; uptake of

Liver Glycogenolysis; gluconeog

Pancreas Insulin and glucagon secre

Thyroid T4 to T3 conversion

Innate and adaptive

immune cells

Downregulate the synthes

anti-inflammatory cytokine

Coagulation system Reduces platelet aggregab

concentration; increases fib

Brain Poorly characterized [10]

b3 Heart Inactive during normal phyStimulation seems to prod

b1- and b2-receptors [11]

Smooth muscle Relaxation of smooth mus

genitourinary tract

Brain Present in discrete regions

cerebral cortex areas know

responsible for the negativ

disorder

Adipose tissue Lipolysis; thermogenesisd from [37]

rial firing), impulse conduction through the atrioventricular

(>b2), and rate of relaxationmulatory G-proteinsranging pharmacodynamic and pharmacokinetic proper-

ties of available agents and the lack of comparative studies

in patients. Thus, for each indication, the choice of b-blocker significantly influences the balance of risks and

benefits.

in endocytosis and reduction in functional density

egability; may decrease fibrinolytic activity

rial firing), impulse conduction through the atrioventricular

(

Beta-Blockers.Table

2Commonlyusedb-blockers

andtheirpharmacology[17,1

8]

Drug

Relativereceptoraffinity

Lipo*

PB(%

)Enteral

IVT1/2

Metabolism

andelimination

Notes

b1:b

2b

2:b

3b1:b

3

Atenolol

4.7:1

76:1

355:1

+10

50%

absorption

68h

100%

GF

Remove

dbyhemodialysis

Bisoprolol

13.5:1

10.7:1

145:1

++

30

100%

absorption10%

FPM

912h

50%

GF.RemainderCYP450

toinactive

metabolites

Carve

dilo

l1:4.5

12.6:1

2.8:1

+++

98

100%

absorption75%

FPM

610h

98%

CYP450to

active

metabolites,mostlyexcreted

inbile

Racemicmixture,o

nlyS(-)

enan

tiomerhas

b-blocking

activity.B

oth

enan

tiomers

areselectivea 1-adrenergic

antagonists.C

a2+entry

blockad

e.A

ntioxidan

t.

Antiproliferative

.

Vasodilating.W

eak

membranestab

ilizer

Esmolol

32:1

+55

9min

Rap

idlyan

dextensive

ly

metabolizedviaRBC

esterases.Inactive

metobilte

100%

GF

Moderatelyb 1

selective

Labetalol

1:2.5

71:1

28:1

+50

100%

absorption75%

FPM

48h

95%

conve

rtedto

inactive

glucu

ronideofwhich60%

GF

andremainderin

bile

Racemicmixture

withtw

o

opticalcenters.Selectivea 1-

adrenergican

tagonist.b 2

partial

agonist.Vasodilating

Metoprolol

2.3:1

54:1

126:1

++

12

100%

absorption50%

FPM

34h

510%

GF.Remainder

CYP450to

inactive

metabolites

Crossesnorm

alBBB(CSF

leve

ls78%

ofserum).Despite

minim

alprotein

bindingnot

significan

tlyremove

dby

hae

modialysis

296 B Beta-Blockers

Nevibolol

47:1

+++

98

100%

absorptionExtensive

FPM

827h

CYP450to

3metabolites,one

ofwhichisactive

.Subject

to

polymorphismshence

wide

spectrum

ofT1/2.A

ctive

metaboliteisdependan

t

uponGFforelim

ination

Racemicmixture.H

ighlyb 1

selectivean

tagonistan

db 3

agonist.Vasodilating

propertiesbydirect

actionon

endotheliu

m,p

ossiblybyNO

production/release

Propranolol

1:8.3

141:1

17:1

+++

90

100%

absorption

Extensive

FPM

34h

Eightmetabolites,at

least1

active

.Elim

ination

independentofGF

Racemicmixture,o

nly

l-isomeractive

.Moderate

membranestab

ilizingeffect.

DecreasesHbO2affinity.

Decreasesplatelet

aggregab

ility.C

rossesnorm

al

BBB

Sotalol

1:12

63:1

5.2:1

+10

100%

absorption

1020h

100%

GF

Racemicmixture.C

lass

IIan

d

IIIan

ti-arrhythmicactivity.

Potentiallypro-arhythmicin

thepresence

of

hyp

okalaemia.P

artially

remove

dbyhae

modialysis

Tim

olol

1:26

758:1

2.1:1

++

1030

90%

absorption50%

FPM

45h

80%

CYP450to

inactive

metabolites.20%

+

metabolitesviaGF

Commonlyusedin

ophthalmicpreparationsbut

associatedwithsignifican

t

systemiceffects

Notes:Relative

receptoraffinitydatatakenfrom

[14].Lipo*=lip

ophilicity.Lipophilicity

isassociatedwithCNSpenetrationan

dbetterCVSoutcomes[19].PB(%

)=percentageprotein

bound.

IV=intravenouspreparationavailable

intheUK.T

1/2=elim

inationhalflife.G

F=glomerularfiltration/renal

clearan

ce

Beta-Blockers B 297

B

298 B Beta-Blockers

HypertensionThe optimal role of b-blockers as a class, and specificagents in particular, in the management of chronic hyper-

tension, remains controversial [20]. However, in patients

with hypertensive crises (malignant hypertension and pre-

eclampsia) or those in whom rapid reduction/control is

indicated (aortic dissection and spontaneous Intracerebral

hemorrhage) b-blockers have an established role. In thesesetting, intravenous (IV) labetolol, usually as an infusion

(15160 mg/h titrated to response), is commonly

employed as a first-line agent. Of the commonly available

b-blockers, labetolol has several pharmacodynamic andpharmacokinetic properties that make it the optimal

choice. In addition to its b1 antagonism, it is also a b2partial agonist and a1-adrenergic antagonist thus pro-duces a significant vasodilating effect. It is available as an

intravenous preparation and has a relatively short elimi-

nation half-life.

Ischemic Heart Disease (IHD)b-blockers have an established role in the management ofacute and chronic angina, acute coronary syndromes,

myocardial infarction [20], and during percutaneous cor-

onary intervention (PCI) [21]. Most of these effects are

mediated through b1 antagonism, which results in [20]:

1. A reduction of myocardial oxygen requirements by

a decrease in heart rate, systolic pressure, and ventric-

ular contractility

2. Bradycardia, which prolongs the coronary diastolic

filling period

3. A reduction in arrhythmogenic free fatty acids

4. A redistribution of coronary flow to vulnerable

subendocardial regions

5. A reduction of platelet stickiness

6. An increase in the threshold to ventricular fibrillation

7. A reduction in infarct size

8. A reduction in risk of cardiac rupture

9. A reduction in the rate of reinfarction

However, the evidence of efficacy of the use of b-blockers,especially in the acute setting, has been questioned by

some authors [22, 23]. Atenolol, metoprolol, and

bisoprolol are the most widely investigated and utilized

b-blockers in the management of IHD. Each agent has itsstrengths and weaknesses and no comparative trials exist.

Optimal dosing remains controversial; however, up-

titration to maximal tolerated doses is widely advocated.

Adequate dosing can be judged by both resting heart rate

(target

Beta-Blockers B 299

B(New York Heart Association class II, III and IV), regard-

less of etiology [36, 37]. b-blockers improve myocardialperformance (increase in ejection fraction of 510%) and

prevent complications of cardiac failure by the following

means [20]:

1. Bradycardia, leading to increased diastolic coronary

filling time (particularly relevant to ischemic heart

failure)

2. Reduction in myocardial oxygen requirements

3. Antiarrhythmic activity

4. Upregulation of b1 receptors5. Inhibition of the rennin/angiotensin system

6. Increasing atrial and brain naturetic peptide secretion

7. Inhibition of catecholamine-induced necrosis. This is

an effect of both b1 antagonism and b2 agonism

There have been positive outcome trials for carvedilol,

metoprolol, bisoprolol, and nevibolol and even a trial

comparing carvedilol and metoprolol. Whether b1 selec-tivity is an advantage or disadvantage remains controver-

sial, however, carvedilol may be the optimal agent [32]. Of

note, nevibolol, in addition to its marked b1 selectivity, isa b3 agonist. Whether b3 agonism is a good or bad thing inchronic cardiac failure remains unclear [11].

b-blocker therapy should not be initiated in patientswith acute decompensation of cardiac failure, until their

condition has been stabilized, however, long-term therapy

should not be stopped unless shock is evident. Therapy

should be started/restarted at the earliest opportunity.

Therapy should commence at a low dose and be up-

titrated to the maximal tolerated dose. Again, controversy

exists as to the best determinant of effective dose in an

individual.

Portal Hypertension and VaricealHemorrhageNonselective b-blockers have an established role both inthe primary and secondary prevention of variceal hemor-

rhage [38]. Propranolol is the most widely used agent. The

recommended starting dose is 40 mg twice daily, increased

as tolerated up to 160 mg twice daily. Carvedilol [39] and

nadolol [40] have also been investigated but their place in

therapy remains undefined.

To prevent bleeding/re-bleeding, nonselective

b-blockers must reduce the hepatic venous pressure gra-dient (HVPG) to

300 B Beta-Blockers

harm than good. The effects of selective or nonselective b-blockade on the innate and adaptive immuno-

inflammatory systems, remains speculative, but b1-blockade coupled with b2 stimulation is a potentiallyattractive therapeutic target.

Thyroid Storm [46]b-blockers relieve the symptoms of thyrotoxicosis but donot modify the underlying disease. Their use is advocated

in the acute management of a thyrotoxic crisis (storm) as

part of package of endocrine care. Nonselective b-blockersare usually recommended though this is predominantly

based on historical president.

Useful Neuropsychiatric effects?Agitation and aggressive behavior, following acquired

brain injury is a common and complex problem for

which numerous pharmacological and therapeutic strate-

gies have been trialled. There is some evidence from small-

scale trials to suggest propranolol and possibly pindolol

may form part of a useful strategy in reducing agitation

and aggression following moderate to severe brain injury

[47]. Early studies also suggest a potential role for pro-

pranolol in both the prevention and treatment of post-

traumatic stress disorder [48].

b-blockers appear to causemeasurable neuropyschiatriceffects including sleep disturbance, vivid dreams, anxiolysis,

and subtle effects on memory. When administered during

general anesthesia, they appear to exhit antinociceptive

and anesthetic-sparing effects [49, 50]. Whether this is

a synergistic effect or merely a result of b-blockers alteringthe pharmacokinetics of opiates and anesthetic agents

remains unclear.

Contraindications [1] Second- and third-degree heart block Cardiogenic shock Peripheral arterial insufficiency (relative contraindica-

tion as vasodilating agents may be well tolerated)

Asthma (relative contraindication as highly b1 selec-tive agents may be tolerated)

Recurrent hypoglycemia

Adverse Reactions [1]b-blocker therapy may be associated with the followingadverse reactions:

Generalized fatigue. Cardiovascular hypotension, bradycardia, asystole,

cardiogenic shock. A deterioration in symptoms of

peripheral arterial insufficiency. Respiratory bronchospasm, due to b2-blockade,which may be averted by using highly b1 selectiveagents. b-blockers are generally well tolerated inchronic obstructive pulmonary disease. The respira-

tory effects of b-blockers in chronic cardiac failure arecomplex and reviewed here [51]. In short, the overall

effect is beneficial but some drug-specific effects may

have detrimental effects in some individuals. Monitor-

ing of pulmonary function is advised.

Brain sleep disturbances with nightmares, believedto be less common with the less lipophilic agents.

Metabolic a small deterioration of glucose toleranceand interference with the metabolic and autonomic

responses to hypoglycemia. They may also cause an

increase in serum triglycerides, low density and very

low density lipoprotein cholesterol, and a decrease in

high density lipoprotein cholesterol.

b-Blocker Toxicity and Overdose [52]In addition to supportive care beta-adrenoceptor agonists,

phosphodiesterase inhibitors (e.g., milrinone), glucagon,

and hyperinsulinemic euglycemia have been investigated

as antidotes. Individually, none are reliably effective and

only anecdotal reports support combination therapy.

Atenolol and sotalol may be significantly cleared by

hemodialysis.

Drug Interactions Class Effects [1]Synergistic effects with other antihypertensives can lead to

symptomatic hypotension. Synergistic effects with other

negative chronotropes can lead to symptomatic bradycar-

dia and even asystole. Synergistic effects with other nega-

tive inotropes can lead to cardiogenic shock. Use with a1agonists can result in severe hypertension.

Drug Interactions Specific Agents [1]Propranolol decreases the threshold for lidocaine and

bupivacaine toxicity. Sotalol increases the risk of ventric-

ular arrhythmias when coadministered with any drug that

causes QT prolongation.

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