Transcript Emergency

TASHKENT MEDICAL ACADEMY
Infectious and children infectious
diseases department
Emerging and Re-emerging
Situation of Infectious
Diseases
Lecturer:
• Emerging infectious diseases:
• Infectious diseases that have newly appeared
in a population.
• Global :
• Regional:
• Re-emerging Diseases: Diseases’ incidence in
human has increased during the last 20 years
or threatens to increase in the near future.
• Global:
• Regional:
Emerging Infections in the World
since 1973
1973
1976
1977
1977
1977
1977
1980
1981
1982
1982
1982
Rotavirus
Cryptosporidium
Ebola virus
Legionella
Hantaan virus
Campylobacter
HTLV-1
Toxin prod. S.aureus
E.coli 0157:H7
HTLV-II
Borrelia burgdorferi
Enteritis/Diarrhea
Enteritis/Diarrhea
VHF
Legionnaire’s dz
VHF w/ renal flr
Enteritis/Diarrhea
Lymphoma
Toxic Shock Synd.
HUS
Leukemia
Lyme disease
1983
1983
1988
1989
1990
1991
1992
1992
HIV
AIDS
Helicobacter pylori Peptic ulcer dz
Hepatitis E
Hepatitis
Hepatitis C
Hepatitis
Guanarito virus
VHF
Encephalitozoon
Disseminated dz
Vibrio cholerae O139 Cholera
Bartonella henselae Cat scratch dz
1993
1994
1994
1995
1995
1996
1997
1999
1999
2001
2003
2003
2004
2005
Sin Nombre virus
Hanta Pulm. Synd.
Sabia virus
VHF
Hendra virus
Respiratory dz
Hepatitis G
Hepatitis
H Herpesvirus-8
Kaposi sarcoma
vCJD prion
Variant CJD
Avian influenza (H5N1)
Influenza
Nipah virus
Encephalitis
West Nile virus
Encephalitis
BT Bacillus anthracis Anthrax
Monkeypox
Pox
SARS-CoV
SARS
H5N1
Avian Influenza
GLOBAL EXAMPLES OF EMERGING AND
RE-EMERGING INFECTIOUS DISEASES
AS Fauci
Economic Impact of Selected Infectious
Diseases
$50bn
SARS
China, Hong Kong,
Singapore, Canada
$30-50bn
Estimated Cost
$40bn
$30bn
Foot & Mouth
UK
$25–30bn
$20bn
BSE UK,
$10-13bn
$10bn
Foot & Mouth
Taiwan, $5-8bn
Classical Swine
Fever,
Netherlands
$2.3bn
BSE Japan
$1.5bn
HPAI, Italy
$400m
Nipah, Malaysia
$350-400m
1994
1995
1996
Figures are estimates and are presented as relative size.
1997
1998
1999
2000
Avian Flu Asia,
$5–10bn
BSE Canada
$1.5bn
Avian Flu, NL
$500m
2001
2002
BSE U.S.,
$3.5bn
2003
2004
2005
2006
Factors responsible for emerging of
infections.
I-Ecological changes and Agricultural
development.
Placing the people in contact with a natural
reserviour or host of a hitherto unfamiliar, but
usually already present,
Toxic Shock Syndrome
• Severe life threatening syndrome
characterized by:
– High fevers
– Severe hypotension
– Diffuse erythroderma
– Mucous membrane hyperemia
– Pharyngitis
– Diarrhea
Toxic Shock Syndrome
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May progress rapidly
Multisystem disfunction
Severe electrolyte disturbances
Renal failure
Shock
Toxic Shock Syndrome
• Discovered in 1978 in apparently healthy
children – Staph aureus isolated
• TSS epidemic – 1981 associated with
increased tampon use
• Incidence has dropped significantly,
• Currently most cases are unrelated to menses
• Case Definition of Toxic Shock Syndrome, table
142-1
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Case Definition of Toxic
Shock Syndrome, Table 142-1
Fever – temp >102.0 F (>38.9 C)
Rash: diffuse macular erythroderma
Hypotension
Multisystem envolvement (three or more)
– GI: vomiting or diarrhea at onset of illness
– Muscular: sever myalgia or creatine
phosphokinase level at least twice the upper limit
of normal
– Mucous membrane: vaginal, oropharyngeal, or
conjunctival hyperemia
• Renal: blood urea nitrogen or creatinine at
least twice the upper limit of normal for
laboratory or urinary sediment with pyuria
(greater than or equal to 5 leukocytes per
highpower field) in the absence of urinary
tract infection
• Hepatic: total bilirubin, alanine
aminotransferase enzyme, or asparate
aminotransferase enzyme levels at least twice
the upper limit of normal for laboratory
• Hematologic: platelets less than 100,000/ml
• CNS: disorientation or alterations in
consciousness without focal neurologic signs
when fever and hypotension are absent
• Lab criteria: negative results on the following
tests, if obtained:
– Blood, throat, or cerebrospinal fliud cultures
(blood culture may be positive for Staphlococcus
aureus
– Rise in titer to Rocky Mountain Spotted fever,
leptospirosis, or measles
Case Definition of TSS
• Case classification
– Probable: five of six clinical findings are present
– Confirmed: all six clinical findings are present,
including desquamation, unless patient dies
before desquamation occurs
Epidemiology
• TSS – initially a disease of young healthy
menstruating women, comprised fifty percent
of cases reported in 1986-87
• Tampon use increased risk up to 33%
• In 2000, 135 reported cases, 3 were in men,
and 2 fatalities were from menstrual-related
TSS (MRTSS)
• FDA - Tampons now made of cotton and
rayon, should be changed every 4-8 hrs
Epidemiology
• Non-menstrual related cases of Toxic Shock
Syndrome (NMTSS)
– Increasing since 1980
– 41% NMTSS
– Men comprise one-tenth of population
• Mortality rate 3.3 x that of MRTSS in women
• S. aureus isolated from 98% of women with TSS
• Women with MRTSS most likely colonized with
Staph aureus before the onset of menstruation
Epidemiology
• TSS associated with influenza or influenza-like
illnesses – mortality rate (43%)
• Nasal packing (nasal tampons) also associated
with TSS
Pathophysiology
• Most TSS associated with S. aureus
• TSST-1: toxic shock syndrome toxin, exotoxin
– Induce fever via the hypothalamus or via IL-1 and
TNF
– T-lymphocyte “superantigenation” and
overstimulation
– Induce interferon production
– Enhance delayed hypersensitivity
– Supress neutrophil migration and IG secretion
– Enhance host suseptibility to exotoxins
Pathophysiology
• Enterotoxins B and C
– Similar chemical structure to TSST-1
– Seen primarily in NMTSS
– Elicit similar clinical manifestations as TSST-1
Pathophysiology
• Vaginal conditions favorable to TSST-1
– Temp 39-40 C
– Neutral pH
– PO2 > 5%
– Supplemental CO2
– Menstruation – neutralizes vaginal pH
– Tampon use may increase O2 and CO2
– Synthetic fibers in tampon composition
– Synergistic relationship between S. aureus and E.
coli
Pathophysiology
• Vasodilation – rapid and massive onset
• Hypotension
– Decreased vasomotor tone, blood pooling,
decreased vascular return
– Nonhydrostatic leakage of fluid into the
interstitium, contributing to hypotension and
nonpitting edema of the head and neck
– Depressed cardiac function
– Total body water deficits from vomiting and
diarrhea and fever
Pathophysiology
• IL-1
– Hypoalbuminemia, hypoferrinemia, and
proteolysis manifest as peripheral edema, anemia,
and rhabdomyolysis seen in TSS
• TNF
– Acidosis, shock, and multisystem organ failure
– Multisystem organ failure
• Direct result from toxin
• Rapid onset of hypotension and decreased perfusion
– Small amts of TSST-1 and enterotoxins B and C can
be detected in pts with TSS up to 1 year
Clinical Features
• TSS must be considered when
– Unexplained febrile illness with erythroderma,
hypotension, and diffuse organ pathology
• Pts with NMTSS present 3rd to 5th days of
menses
• Postoperative NMTSS – approx 2 days
Clinical Features
• Mild TSS:
– Fever
– Chills
– myalgias
– Abdominal pain
– Sore throat
– Nausea
– Vomiting
– Diarrhea
– Self-limiting
Clinical Features
• Severe
– Acute onset
– Early multiorgan envolvement
– Prodrome
• Headache, malaise, myalgias, nausea, vomiting, and
diarrhea
• Sudden onset of fevers and chills 1-4 days prior to
presentation
– Orthostatic lightheadedness, profuse watery
diarrhea, sore throat, paresthesias, photophobia,
abdominal pain, and cough
Clinical Presentation
• PE
– Hypotension
– Pt appears acutely ill
– Change in mental status
– Oliguria
– Nonpitting edema of face and extremities
– Watery diarrhea
– Pharygitis strawberry red tongue
– Tender erythematous external genitalia diffuse
vaginal hyperemia, strawberry cervix, scant
purulent cervical discharge, bilat adenexal
tenderness
Clinical Features
• Rash – diffuse painless blanching
erythroderma, fades in three days
• Followed by full-thickness desquamation
particularly of palms and soles of feet
• Severely affected patients may have hair and
nail loss 2-3 months later
Clinical Features
• Focal neuro findings are rare
• Varying degrees of altered consciousness
• Toxic encephalopathy - confusion,
disorientation, agitation, hysteria,
somnolence, and seizures
• CT and LP will help deliniate
Clinical Features
• Lab findings
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Leukocytosis
lymphocytopenia
Anemia
ARF: azotemia, myoglobinuria, sterile pyuria, RBC casts
Liver abnormalities
Metabolic acidosis 2nd to hypotension
Electrolyte abnormalities
Arrhythmias
ARDS
Differential Diagnosis
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Acute pyelonephritis
Septic shock
Acute rheumatic fever
Scarlet fever: strep or staph etiologies
Leigionare’s disease
PID
HUS
Differential Diagnosis
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Acute viral syndrome
Leptospirosis
SLE
Rocky Mountain Spotted fever
Tick typhus
Gastroenteritis
Kawasaki disease
Reye syndrome
Toxic epidermal necrolysis
Erythema multiforme
Treatment
• Aggressive shock management
• Continuous monitoring: central
• Aggressive fluid replacement – 4-20 L of
crystalloid and FFP
• Ventilatory management if ARDS develops
• Complete blood work and cultures
• Removal of foreign bodies, i.e. tampon or
nasal packing
• Antistaphlococcal penicillin or cephalosporin
Treatment
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Antistaphlococcal penicillin or cephalosporin
Nafcillin or oxacillin 2g IV every 4hrs
Cefazolin 2g IV every 6hrs
Oral anti-staphlococcal ABx for the next 10 -14
days
Treatment
• Pt not treated with β-lactamase-stable abx can
have recurrence
• MRTSS – recurrence occurs in second month
after the initial disease, recurring on the same
day of the menstrual cycle
• Initial episode is the most severe
Streptococcocal Toxic Shock Syndrome
• Group A Strep
– Soft tissue infection, early shock, multisystem
organ failure, higher mortality than TSS, “Flesh
eating bacteria”
– Most serious – Strep necrotizing fasciitis and
myositis
• STSS
– Most commonly affects 20 – 50 yr olds without
prior illness
STSS
• Risk factors
– Extremes of age
– Diabetes
– EtOH
– Drug abuse
– NSAIDS
– Immunodeficiency
– Rarely develops from symptomatic pharyngitis
STSS
• 2000-3000 cases annually; with 500 to 1500
cases of necrotizing fasciitis
– Mortality rate of 30 – 80%
– 70% of cases progress to necrotizing fasciitis
• Surgical intervention
• Mortality
– Strep fasciitis – 60%
– Strep Myositis – 85-100%
Case Definition of Streptococcocal Toxic
Shock Syndrome
• An illness with
– Hypotension
– Multiorgan involvement with two or more of the following:
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Renal impairment
Coagulopathy
Liver involvement
ARDS
Generalized erythematous macular rash that may desquamate
Soft tissue necrosis
Case Definition of Streptococcal Toxic Shock
Syndrome
• Laboratory Criteria
– Isolation of group A streptococcus
• Case Classification
– Probable – clinical case definition in the absence
of another identified etiology with isolation of
group A strep from a nonsterile site
– Confirmed – clinical case definition with isolation
of group A streptococcus from an otherwise
sterile site
STSS
• Epidemiology
– Incidence – 1-5 per 100,000
– STSS associated Necrotizing Fasciitis 13-46%
• Pathophysiology
– GAS invasive infections – more virulent exotoxins
than TSS
• SPE – Streptococcal pyogenic exotoxins
– SPE A – Scarlet fever toxin – most potent and commonly
isolated SPE in STSS cases
– SPE A and B – pyrogenicity, superactivation of T-cells,
synthesis of TNF, IL-1 and IL-6, leading to acidosis, shock,
organ failure
STSS
• Patients without immunity to M-type SPE A
and B producing strains of GAS are most
susceptible to STSS
• Portal of entry
– Vagina, pharynx, mucosa, and skin, most are
unidentifiable
– Commonly begins at site of minor skin trauma
STSS
• Clinical Features
– Pain most common with preceding local tenderness
– May present as
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Peritonitis
PID
Pneumonia
Pericarditis
Fever
Severe pain
Swelling
Redness
Compartment syndrome
STSS
• PE
– Fever
– Shock on admission or within 4-8hrs
– Vesicles and/or bullae at infection site
– ARDS
– Less commonly erythematous rash
• Labs
– Mild increase in WBC
– LFT 2x normal
STSS
• Labs
– Decreased platelets
– Disseminated intravascular coagulopathy
– Renal dysfunction – requiring dyalysis
– Blood cultures - +GAS 60%
– Tissue cultures – 90%
STSS
• Diagnosis
– Differential is the same as for TSS with the
addition of invasive and noninvasive GAS
infections, necrotizing fasciitis, myositis, serious
infections caused by C. perforingens and C.
septicum, and mixed aneorbic and aerobic
organisms
• Treatment
– Aggressive shock management with early use of
vasopressors
STSS
• IV ABx should be started in the ED once
cultures have been taken. Inability to obtain
Cx should not delay administration of IV ABx
– Pen G 24 million U/d divided
– Clindamycin 900mg IV q 8hr
– Erythromycin 1g IV q 6 hr in PCN allergic pts
– Ceftriaxone 2g IV q 24 hr with Clindamycin 900mg
IV q 8hr
– IVIG 2g/kg q 48 hr in patients without IGA
deficiency improve 30 day mortality
STSS
• Surgery
– Prompt consultation in addition to IV ABx
• Exploration
• Debridement
• 70% of cases require debridement, fasciotomy, or
amputation
TSS and STSS
• 1.) Toxic Shock Syndrome is only a disease of
young healthy menstruating women. T/F
• 2.) The rash of TSS is a diffuse, blanching,
erythroderma, classically described as a
“painless sunburn”, that fades within 3-4 days
of its appearance and is followed by fullthickness desquamation of the palms and
soles during convalescence. T/F
TSS and STSS
• 3.) STSS is defined as any group A
streptococcocal (GAS) infection with invasive
soft tissue infection, early onset of shock, and
organ failure. T/F
• 4.) STSS associated with GAS invasive
infections most commonly affects individual
between the ages of 20 – 50 with a
predisposing illness. T/F
• Answers: 1.) F, 2.) T, 3.) T, 4.) F
Sepsis and Septic Shock
• Definitions
• Epidemiology
• Pathogenesis
• Principles of management
Definitions
• Infection: microbial phenomenon
characterised by an inflammatory response to
the presence of micro organisms or the
invasion of normally sterile host tissue by
these organisms
• Bacteraemia: the presence of bacteria in the
bloodstream
• Septicaemia: no longer used
ACCP/SCCM Consensus Conference: Bone et al, Chest 1992 101:1644
Definitions
• Sepsis: systemic response to infection manifested by
≥ 2 of:
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Temp > 38oC or < 36oC
HR > 90 bpm
RR > 20 bpm or PaCO2 < 32 mmHg
WBC > 12 x 109/L, < 4 x 109/L or >10% band form
• Septic shock: sepsis with hypotension despite
adequate fluid resuscitation, with perfusion
abnormalities that could include, but are not
limited to, lactic acidosis, oliguria, and/or acute
mental status.
ACCP/SCCM Consensus Conference: Bone et al, Chest 1992 101:1644
Organ dysfunction at time of severe
sepsis recognition
80
Percent of Patients
70
60
50
40
30
20
10
0
Bernard NEJM 344:699, 2001
Shock
Respiratory
Renal
Metabolic
Coag
DIC
Pathogenesis of Sepsis
Pathogenesis of Sepsis
Pathogenesis of Sepsis
Clinical Spectrum of Infection
Infection
Bacteremia
Sepsis
Severe Sepsis
Septic Shock
ACCP / SCCM Consensus Definitions of
SIRS and Allied Disorders
(Critial Care Med 1992 (20):864-874)
SIRS
The systemic inflammatory response to a variety of severe clinical insults.
Manifested by 2 or more of the following conditions:
Temperature
HR
Respiratory Rate
WBC
>38 deg C or <36 deg C
>90 beats/min
>20 breaths/min or PaCO2 <32 torr (<4.3 kPa)
>12,000 or <4,000 cells/mm3 or >10% bands
SEPSIS
The systemic response to infection. Manifested by the same criteria as
SIRS.
ACCP / SCCM Consensus Definitions of SIRS and
Allied Disorders
(Critial Care Med 1992 (20):864-874)
SEVERE SEPSIS
Sepsis associated with organ dysfunction, hypoperfusion, or hypotension.
Perfusion abnormalities include but are not limited to:
lactic acidosis
oliguria
mental status
SEPTIC SHOCK
Sepsis with hypotension (SBP<90), despite adequate fluid resuscitation and
perfusion abnormalities as listed for severe sepsis. Patients on inotropic/
vasopressor agents may not be hypotensive.
Incidence / Magnitude of Problem
•
300,000 to 500,000 cases of bacteremia each year in the US with
associated 20-30% mortality.
•
200,000 bouts of septic shock.
•
Sepsis is the leading cause of death in noncoronary intensive care
units.
•
Mortality has changed little over the last 20 years.
•
Incidence of sepsis appears to be increasing.
Reasons Underlying Rising Incidence of Sepsis
and Continued High Mortality
(Chest 1991 (99): 1000-09).
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Increased patient age
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Increased use of cytotoxic/immunosuppresive drug therapy
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Increased incidence of concomittent medical illness
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Increased use of invasive devices for diagnosis and therapy
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Rising incidence of infections due to organisms other than Gram
negative bacteria (Gram + bacteria, fungi, and possibly viruses)
Perhabs, the emergence of antibiotic resistant organisms
Individual Host Risk Factors
Bone, RC. The Pathogenesis of Sepsis. Ann Int Med 1991(115): 457-69.
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Extremes of age
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Chronic disease
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Substance abuse
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Immunosuppressive therapy
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Vascular catheterization
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Prosthetic devices and urinary catheters
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Tracheal intubation
Changes in Cardiac Performance During Acute &
Recovery Phases of Septic Shock
Parillo, JE. Pathogenetic Mechanisms of Septic Shock NEJM 328(20):1471-1477.
Acute Phase (Hypotension and Reduced SVR)
LVEDV 225 ml
LVESV 150 ml
MAP
CVP
Cardiac Output
Heart Rate
SVR
EF
40 mm Hg
2 mm Hg
11.25 L/min
150 beats/min
270 dyn*sec*cm-5
225ml-50ml =33%
225ml
Recovery Phase (Normotension)
LVEDV 125 ml
LVESV 50 ml
MAP
CVP
Cardiac Output
HR
Stroke Volume
SVR
EF
75 mm Hg
5 mm Hg
5.25 L/min
70 beats/min
75 ml
1067 dyn*sec*cm-5
125 ml- 50 ml =60%
125 ml
Hemodynamic Patterns with Prognostic Value
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A lower heart rate at the onset of disease is predictive of survival.
Normalization within 24 hours of either tachycardia or elevated
cardiac index is associated with survival. Persistence of hyperdynamic
state increases likelihood of death.
Parker et al. Serial Cardiovascular Variables in Survivors and Nonsurvivors; HR as an Early Predictor of Prognosis
Crit Care Med 1987(15): 927-9.
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A low ejection fraction and ventricular dilatation are also associated
with survival. This perhabs reflects Frank-Starling compensation of
sepsis induced myocardial depression.
Parrilo, JE. Pathogenetic Mechanisms of Septic Shock, NEJM 1993; 328(20): 1471-77.
Jardin et al. (University of Vienna) prospectively studied 27 surgical
ICU patients in early septic shock.
MAP <60 mmHg.
Age range (21-76), mean 46 years old.
A-line + PAC monitoring.
11 patients (41%) had RV ejection fraction <45 %.
This group required vasoactive/inotropic drugs to achieve &
maintain an adequate perfusion pressure (MAP >60 mm Hg.
Fluid replacement alone, (average 2850 +/- 210 ml crystalloid)
was unsuccessful in keeping MAP >60 mmm Hg at the end of 2
hours in these patients.
Critical Care Med 1990; 18: 1055-1062.
Why Is Ventricular Function Impaired ?
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Initial hypothesis of coronary hypoperfusion leading to
ischemic myocardial dysfunction was disproven by Cunnion et
al., Circulation 1986; 73: 637-44. They showed septic patients
had coronary blood flows controls, and similar myocardial
lactate levels to patients with sepsis but no obvious
myocardial depression.
The presence in the bloodstream of one or more myocardial
depressant substances (MDS) has been supported by in vitro
myocyte preparations.
Myocardial Depressant Substance
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affect myocyte contractility in a dose dependent manner
water soluble
not diffuse through dialysis membrane
moderate size molecule at least 10,000 daltons
Purified endotoxin, IL-1, Il-2 produced no depression of
myocyte contraction.
Endotoxin and IL-2 have produced hemodynamic alterations
similar to septic shock in some human studies.
TNF, based on animal models & in vitro myocyte preparation
studies appears to be one of the major mediators of
cardiovascular insufficiency in septic shock.
Chest 1991; 99: 1000-09.
Role of TNF-a in Septic Shock
(Clinical Infectious Diseases 1995(20):143-58.)
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TNF-a has been proposed as the principal cytokine mediating
septic-shock and sepsis related organ damage. Evidence to this
effect includes:
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High circulating TNF-a levels correlate with mortality in endotoxemia.
Passive immunization of some animal models with monoclonal Abs
against TNF-a is protective against mortality/critical organ injury from
lethal bacteremia.
Injection of recombinant TNF-a without LPS leads to pathophysiologic
changes similar to those of bacteremia & MODS.
Biologic Actions of TNF-a (Cachectin)
(Hall, Schmidt, & Wood, Principles of Critical Care, McGrawHill, Inc., New York, 1992.)
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Hemodynamic
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Hyperdynamic circulatory shock
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Capillary leak syndrome
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Microvascular thrombosis
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Inhibition of cardiac myocyte B-adrenergic responsiveness.
Microbiologic
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PMN activation, degranulation, enhanced O2 radical release.
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Neutrophilia, lymphopenia.
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Increased vascular permeability of the gut.
Immunologic
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Induction of hepatic acute phase synthesis
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Fever
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Promotion of IL-1, IL-2, PAF, IL-6, and eicosanoid production.
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Stimulation of B & T lymphocyte proliferation
Pathogenesis of Septic Shock
Journal of Infection 1995; 30: 201-206.
MONOCYTE
CD 14
Bacteria
LPS
LBP
TNF-A
ENDOTHELIAL CELL
LPS
soluble CD 14
LPS
LBP
LPS
Pathogenesis of Sepsis Mediated Hemodynamic
Dysfunction
NIDUS OF INFECTION
ORGANISMS
Pneumonia
Peritonitis
Cellulitis
Abscess
Other Infection Sites
EXOGENEOUS TOXINS
Organism
Structural Component
Exotoxin (TSST-1, Toxin A)
Endotoxin
ENDOGENOUS
MEDIATORS
CYTOKINES
*Interleukin 1,2,….6
*Tumor Necrosis Factor
PLATELET ACT FACTOR
ARACHID ACID METAB
HUMORAL CASCADES
*Complement
*Kinins
*Coagulation
Severe Decrease SVR
HYPOTENSION
Depressed CO
CARDIOVASCULAR
INSUFFICIENCY
DEATH
MOSF
Multiple Organ System
Failure
RECOVERY
MYOCARDIUM
*Depression
*Dilatation
VASCULATURE
*Vasodilation
*Vasoconstriction
*Endothelial Damage
*Maldistribution of flow
SIRS and Sepsis
• SIRS: Systemic Inflammatory Response
Syndrome
• Fever, leucocytosis, organ failure
• Recognises difficulty of always identifying
infection, but…
• As a result, high sensitivity but low specificity
Stages of Sepsis
Consensus Conference Definition
• Systemic Inflammatory Response Syndrome (SIRS)
Two or more of the following:
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Temperature of >38oC or <360C
Heart rate of >90
Respiratory rate of >20
WBC count >12 x 109/L or <4 x 109/L or 10% immature forms (bands)
• Sepsis
SIRS plus a culture-documented infection
• Severe Sepsis
Sepsis plus organ dysfunction, hypotension, or hypoperfusion
(including but not limited to lactic acidosis, oliguria, or acute mental
status changes)
• Septic Shock
Hypotension (despite fluid resuscitation) plus hypoperfusion
Multiple Organ Dysfunction
Syndrome
• Dysfunction of 2 or more systems
• Four or more systems - mortality near
to 100 percent
Factors Associated with Highest
Mortality
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Respiratory > abdominal > urinary
Nosocomial infection
Hypotension, anuria
Isolation of enterococci or fungi
Gram-negative bacteremia, polymicrobial
Body temperature lower than 38°C
Age greater than 40
Underlying illness: cirrhosis or malignancy
Predisposing Underlying Diseases
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Heart disease-rheumatic or congenital
Splenectomy
Intraabdominal sepsis
Septic abortion or pelvic infection
Intravenous drug abuse
Immunocompromised
Organisms Responsible for Septic Shock in
Relation to Host Factors
Asplenia
Cirrhosis
Alcoholism
Encapsulated organisms
Pneumococcus spp.,
Haemophilus influenzae,
Neisseria meningtidis,
Capnocytophagia
canimorsus Babesiosis
Vibrio, Yersinia, and
Salmonella spp., other
Gram-negative rods (GNRs),
encapsulated organisms
Klebsiella spp.,
pnemococcus
Diabetes
Steroids
Mucormycosis and Pseudomonas ssp.
(malignant external otitis), Escherichia
coli
Tuberculosis, fungi, herpes virus
Neutropenia
Enteric GNR, Pseudomonas,
Aspergillus, Candida, and Mucor spp.,
Staphylococcus aureus
T-cell
abnortmalities
Listeria, Salmonella, and Mycobacteria
spp., herpes virus group (herpes simplex
virus, cytomegalovirus, varicella zoster
virus)
Bacteremia in the Preantibiotic Era
•
•
•
•
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Streptococcus pneumoniae
Group A streptococcus
Staphylococcus aureus
Haemophilus influenzae
Neisseria mennigitidis
Salmonella spp.
Emergence of
Gram-Negative Organisms
• Antibiotic pressure on normal flora
• Use of invasive devices
• Immune suppression
Differential Diagnosis
of Fever and Shock
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•
•
•
•
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Purulent bacterial pericardial effusion
Peritonitis
Pneumonia with severe hypoxia
Mediastinitis
Anaphylaxsis
Staphylococcal toxic shock syndrome
Streptococcal toxic shock syndrome
Clinical Manifestations
•
•
•
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Fever, chills, hypotension
Hypothermia, especially in the elderly
Hyperventilation - respiratory alkalosis
Diaphoresis, apprehension, change in mental
status
History
•
•
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•
•
Community versus hospital-acquired
Prior or current medications
Recent manipulations or surgery
Underlying diseases
Travel history
Approach to Septic Patient
• Seek primary site of infection
• Direct therapy to primary site
• Repeated examination
Skin
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Furuncles, cellulitis, bullous lesions
Intravenous sites, phlebitis
Erythema multiforme
Ecchymotic or purpuric lesions
DIC, petechiae
Ecthyma gangrenosum
Purpura fulminans
Cardiovascular Signs
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•
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“Warm shock” -  CO,  SVR
“Cold shock” -  CO,  SVR
Anaerobic metabolism - lactic acidemia
Myocardial depressant factor - ??
Pulmonary Signs
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•
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Tachypnea
Hyperventilation, respiratory alkalosis
ARDS, respiratory failure
Ventilation-perfusion mismatch
Widened alveolar-arterial oxygen gradient
Reduced lung compliance
Hematologic Findings
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Neutrophilic leukocytosis
Leukemoid reaction
Neutropenia
Thrombocytopenia
Toxic granulations
DIC
Renal and
Gastrointestinal Signs
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Acute tubular necrosis, oliguria, anuria
Upper GI bleeding
Cholestatic jaundice
Increased transaminase levels
Hypoglycemia
Acute Physiology and
Chronic Health Evaluation
APACHE II
Temp
Arterial pH
MAP
Serum Na; Serum Cr
Heart rate
Hematocrit
Resp. rate
WBC
Oxygenation
Glasgow Coma Score
Acute physiology score + Age + Chronic health points
Laboratory Studies
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Blood cultures
Infected secretions/body fluids
Stool for WBC, C. difficile
Aspirate advancing edge of cellulitis
Skin biopsy/scraping
Buffy coat
Therapy of Septic Shock
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Correct pathologic condition
Optimize intravascular volume
Administer empiric antimicrobial therapy
Administer vasoactive drugs
Failure of Fluid Replacement and
Vasopressors
•
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•
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acidosis - pH<7.3
hypocalcemia
adrenal insufficiency
hypoglycemia
Empiric Antimicrobial Regimens for
Sepsis Syndrome
• Community-acquired non-neutropenic
– Urinary tract: 3rd generation cepholosporin,
piperacillin, quinolone + AG
– Non-urinary tract: 3rd generation
cepholosporin + metronidazole, -lactam/ lactamase inhibitor + AG
• Hospital-acquired
– Nonneutropenic: 3rd generation cephalosporin +
metronidazole, -lactam / -lactamase inhibitor,
menopenem all + AG
– Neutropenic: Timentin + AG, meropenem + AG;
ceftazidime + metronidazole + AG
Septic Shock
Outcomes for Patients on
Hospital Wards versus ICU’s
• Ward patients: Delays in ICU transfer (67 mins.)
IV fluid boluses (27 vs 15 mins.)
Inotropic agents (310 vs 22.5
mins)
• Mortality:
Wards (70%) vs ICUs (39%)
Apache II scores (18.5 vs 24)
Candidemia
JS Lunberg, Crit. Care Med. 26:1020; 1998
Immunotherapies for
Septic Shock
• Corticosteroids
• Antiendotoxin monoclonal
antibodies E-5, HA-1A
• Anti-TNF antibodies
• IL-1 receptor antagonists
Other Treatment Modalities
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•
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Granulocyte transfusions
Recombinant colony-stimulating factors
Diuretics
Pentoxifylline, ibuprofen, naloxone
Oral nonabsorbable antimicrobial agents
Parasite
Virus
Infection
Fungus
Severe
Sepsis
shock
SIRS
Sepsis
Severe
SIRS Trauma
Bacteria
BSI
Burns
Where’s the infection ?
Abdomen
15%
Urine
10%
Lung
47%
Bernard & Wheeler NEJM 336:912, 1997
Other
8%
Culture
Negative
20%
What’s the infection?
Pure isolates, total n = 444 pts, 61% micro documented
80
70
60
50
Early
Late
40
30
20
10
0
Gram pos
Gram neg
Cohen et al, J Infect Dis 1999 180:116
Fungal
HOST
PRR
Pathogen recognition
receptor
PARASITE
PAMP
Pathogen associated
Molecular pattern
Sepsis and septic shock
Bacterial infection
Excessive host response
Host factors lead to cellular damage
Organ damage
Death
Molecular architecture of the IR to sepsis
Bacterial factors
Cell wall components
Extracellular products
Effector mechanisms
Lymphokine storm
Chemokine activation
Neutrophil migration
Vascular inflammation
Host factors
Acquired immunity
Innate immunity
Genetic susceptibility
Cohen, Nature: 2002 420:885
Management of Sepsis
• Recognition
• Supportive care
• Source control
• Antibiotics
• Specific (adjunctive) therapy
How likely is it that the diagnosis of sepsis is
being missed? Is it...
Total (n=497)
Extremely likely
3%
3%
Very likely
51%
51%
Not very likely
Not sure
29%
27%
Somewhat likely
Not likely at all
Intensive Care Physicians (n=237)
16%
17%
0%
2%
Ramsay, Crit Care 2004 8:R409.
1%
0%
Initial resuscitation of sepsis:
therapeutic goals
• Central venous pressure: 8 – 12 mmHg
• Mean arterial pressure: ≥ 65 mmHg
• Urine output: 0.5 mL/kg/h
• Central venous (SVC) or mixed venous
oxygen saturation: ≥ 70%
Dellinger, Crit Care Med, 2003 31:946
Dellinger, Crit Care Med, 2003 31:946
Issues in the rational choice of antibiotics
EFFICACY
• Spectrum of activity
• Pharmacokinetics & pharmacodynamics
• Patterns of resistance
TOXICITY
COST
Choosing antibiotics in sepsis
• There is no, single, “best” regimen
• Consider the site of the infection
• Consider which organisms most often cause
infection at that site
• Choose antibiotic(s) with the appropriate
spectrum
• After obtaining cultures, give antibiotics
quickly and empirically at appropriate dose
“Non-antibiotic” therapy for sepsis
• Low dose steroids
• Intensive insulin therapy
– tight glycaemic control
• Activated protein C
• Goal directed therapy
CORTICUS
• International, prospective double-blind
RCT of hydrocortisone in patients with
moderate – severe septic shock
• HC 50 mg q6h for 5 d then tapering to d
11. No fludrocortisone.
• Primary EP 28 d mortality in
nonresponders
Sprung et al, N Engl J Med 2008 358:111
CORTICUS - Results
• No effect on 28 day mortality in whole
population or pre-identified subgroups
• Did not reverse shock in whole
population or pre-identified subgroups
• Did reduce the time to shock reversal
• No significant problem with superinfection
Sprung et al, N Engl J Med 2008 358:111
PROWESS – Continuing debate
• Is there confidence in the baseline
comparability of the populations – especially
the subpopulations?
• There are variable outcomes depending on
the severity marker used (IL6, APII, SOFA)
• There is no confirmatory study
• ADDRESS severe subgroup did not show
benefit
Early goal directed therapy
• Purpose: to adjust cardiac preload, afterload
and contractility to balance oxygen delivery
with oxygen demand
• Entry criteria: patients in the emergency dept
with severe sepsis & shock
• Plan: randomise to 6h of EGDT before transfer
to ICU
Rivers et al, N Engl J Med 2001 345:1368
Treatment of Hypotension
• Volume Resuscitation:
– Hypotension in severe Sepsis and septic shock results from a loss of
plasma volume into the interstitial space, decreases in vascular tone, and
myocardial depression.
– An arterial catheter may be inserted if blood pressure is labile.
• Intravenous fluids : Crystalloids vs. Colloids.
– Goals for initial resuscitation include :
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•
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Central venous pressure 8 to 12 mmHg.
Mean arterial pressure 65 mmHg.
Urine output 0.5 mL per kg per hr.
Central venous or mixed venous oxygen saturation 70%.
Pulmonary capillary wedge pressure exceeds 18 mmHg.
Volume status, tissue perfusion, blood pressure, and the presence or absence
of pulmonary edema must be assessed before and after each bolus.
• Pressors, if above measures fail.
• PRBC’s.
Coticosteroids
• Anti-inflammatory actions such as inhibiting the production of
proinflammatory cytokines, enhancing the release of anti-inflammatory
mediators.
• Decreasing the function and migration of inflammatory cells.
• Maintains BP by upregulation of adrenergic receptors.
• Patients with Septic shock has relative adrenal insufficiency despite
elevated levels of cortisol.
• Cosyntropin stim test – Cortisol of < 9mcg/dl identifies patients with
relative adrenal insufficiency.
• In 2001, studies showed that physiologic doses of steroids are useful in
patients with refractory shock.
• Administration of replacement-dose corticosteroids(50mg of
Hydrocortisone IV q 6hrs with fludrocortisone 50mcg NGTfor 7 days)
improved refractory hypotension and (63% vs 73% mortality; P =
0.02),in patients with relative adrenal insufficiency.
• But only in patients with relative adrenal insufficiency (defined as an
increase of serum cortisol in response to the corticotropin stimulation
test of 9 mg/dL or less).
Role of Coticosteroids
• Unanswered questions :
– What defines adrenal dysfunction? High dose ACTH,
Low dose ACTH test?
– How long should treatment continue once shock has
resolved?
– Taper Steroids?
– Role of Fludrocortisone?
Treatment
Tight Glycemic control
• A decreased release of insulin, increased release of hormones with
effects countering insulin, and increased insulin resistance combine to
produce stress hyperglycemia in many critically ill patients.
• Hyperglycemia diminishes the ability of neutrophils and macrophages
to combat infections. Also insulin possesses antiapoptotic effects.
• A large, single-center, randomized trial of more than 1500 critically ill
patients demonstrated that, maintaining serum glucose levels between
80 and 110 mg/dL (mean morning glucose of 103 mg/dL) through the
use of a continuous insulin infusion decreased mortality (4.6% vs 8%;
P < 0.04), development of renal failure (P = 0.04), and episodes of
septicemia (P = 0.003), compared with conventional treatment (mean
morning glucose of 153 mg/dL.
• Physicians liberalize their insulin treatment to keep blood glucose
levels less than 150 mg/dL due to concerns of hypoglycemia.
• Studies are needed to determine whether less tight control of blood
glucose — for example, a blood glucose level of 120 to 160 mg per
deciliter (6.7 to 8.9 mmol per liter) — provides similar benefits.
Activated Protein C
Early Goal Directed Therapy
• A/E admissions with severe sepsis/shock
treated for 6 h before ICU transfer
• Protocol designed to achieve:
– CVP ≥ 8 – 12 mmHg
– MAP ≥ 65 mmHg
– ScvO2 ≥ 70%
– Urine output ≥ 0.5 ml/kg.hr
Rivers et al, N Engl J Med 2001 345:1368-77
Pharyngeal and Tonsillar Diphtheria
• Insidious onset of exudative pharyngitis
• Exudate spreads within 2-3 days and may form
adherent pseudo membrane
• Membrane may cause respiratory obstruction
• Fever usually not high but patient appears toxic
Thick Membrane
Pseudo membrane
‘Bull Neck’
Diphtheria Antitoxin (DAT)
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•
•
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Produced in horses
First used in the U.S. in 1891
Used only for treatment of diphtheria
Neutralizes only unbound toxin
Coma
Neural basis of consciousness
• Consciousness cannot be readily
defined in terms of anything else
• A state of awareness of self and
surrounding
• Mental Status =
Arousal + Content
Anatomy of Mental Status
• Ascending reticular activating system (ARAS)
– Activating systems of upper brainstem, hypothalamus, thalamus
– Determines the level of arousal
• Cerebral hemispheres and interaction between
functional areas in cerebral hemispheres
– Determines the intellectual and emotional functioning
• Interaction between cerebral hemispheres and
activating systems
The content of consciousness
• Sum of patient’s intellectual (cognitive)
functions and emotions (affect)
Sensations, emotions, memories, images, ideas
(SEMII)
• Depends upon the activities of the cerebral
cortex, the thalamus & their interrelationship
Lesions of these structures will diminish the content
of consciousness (without changing the state of
consciousness)
The state of consciousness (arousal)
• The ascending RAS, from the lower border of
the pons to the ventromedial thalamus
• The cells of origin of this system occupy a
paramedian area in the brainstem
Altered Mental Status
Abnormal change in level of arousal or altered content of
a patient's thought processes
• Change in the level of arousal or alertness
– inattentiveness, lethargy, stupor, and coma.
• Change in content
– “Relatively simple” changes: e.g. speech, calculations, spelling
– More complex changes: emotions, behavior or personality
– Examples: confusion, disorientation, hallucinations, poor
comprehension, or verbal expressive difficulty
Definitions of levels of arousal (conciousness)
• Alert (Conscious) - Appearance of wakefulness, awareness of the
self and environment
• Lethargy - mild reduction in alertness
• Obtundation - moderate reduction in alertness. Increased
response time to stimuli.
• Stupor - Deep sleep, patient can be aroused only by vigorous and
repetitive stimulation. Returns to deep sleep when not continually
stimulated.
• Coma (Unconscious) - Sleep like appearance and behaviorally
unresponsive to all external stimuli (Unarousable
unresponsiveness, eyes closed)
Semicoma was defined as
complete loss of consciousness
with a response only at the reflex
level (now obsolete)
Psychogenic unresponsiveness
• The patient, although apparently unconscious,
usually shows some response to external stimuli
• An attempt to elicit the corneal reflex may cause
a vigorous contraction of the orbicularis oculi
• Marked resistance to passive movement of the
limbs may be present, and signs of organic
disease are absent
Vegetative state (coma vigil, apallic syndrome)
• Patients who survive coma do not remain in this
state for > 2–3 weeks, but develop a persistent
unresponsive state in which sleep–wake cycles
return.
• After severe brain injury, the brainstem function
returns with sleep–wake cycles, eye opening in
response to verbal stimuli, and normal respiratory
control.
Locked in syndrome
• Patient is awake and alert, but unable to move or
speak.
• Pontine lesions affect lateral eye movement and
motor control
• Lesions often spare vertical eye movements and
blinking.
Vegetative
Locked-in
Confusional state
• Major defect: lack of attention
 Disorientation
 Patient
to time > place > person
thinks less clearly and more slowly
 Memory
faulty (difficulty in repeating numbers
(digit span)
• Misinterpretation of external stimuli
• Drowsiness may alternate with hyper -excitability
and irritability
Delirium
• Markedly abnormal mental state
– Severe confusional state
– PLUS Visual hallucinations &/or delusions
(complex systematized dream like state)
•
•
Marked: disorientation, fear, irritability,
misperception of sensory stimuli
Pt. out of true contact with environment and
other people
•
Common causes:
1.
2.
3.
4.
5.
Toxins
metabolic disorders
partial complex seizures
head trauma
acute febrile systemic illnesses
To cause coma, as defined as a state of
unconsciousness in which the eyes are
closed and sleep–wake cycles absent
• Lesion of the cerebral hemispheres
extensive and bilateral
• Lesions of the brainstem: above the lower
1/3 of the pons and destroy both sides of
the paramedian reticulum
The use of terms other than coma and
stupor to indicate the degree of
impairment of consciousness is beset
with difficulties and more important is
the use of coma scales (Glasgow Coma
Scale)
Glasgow Coma Scale (GCS)
Best eye
response (E)
4 Eyes opening
Best verbal
response (V)
Best motor
response (M)
5 Oriented
6 Obeys commands
4 Confused
5 Localizes to pain
3 Inappropriate words
4 Withdraws from pain
2 Incomprehensible
3 Flexion in response to
sounds
pain
1 None
2 Extension to pain
spontaneously
3 Eye opening to
speech
2 Eye opening in
response to pain
1 No eye opening
1 No motor response
• Individual elements as well as the sum of the
score are important.
• Hence, the score is expressed in the form "GCS 9
= E2 V4 M3 at 07:35
Generally, comas are classified as:
• Severe, with GCS ≤ 8
• Moderate, GCS 9 - 12
• Minor, GCS ≥ 13.
Approaches to DD
Unresponsive
ABCs
Glucose, ABG, Lytes, Mg, Ca,
Tox, ammonia
Y
IV D50, narcan,
flumazenil
Brainstem
or other
Focal signs
Y
CT
N
Unconscious
N
Diffuse brain dysfunction
metabolic/ infectious
Focal lesions
Tumor, ICH/SAH/ infarction
Pseudo-Coma
Psychogenic,
Looked-in, NM
paralysis
LP± CT
Approaches to DD
General examination:
On arrival to ER immediate attention to:
1. Airway
2. Circulation
3. establishing IV access
4. Blood should be withdrawn: estimation of
glucose # other biochemical parameters # drug
screening
• Attention is then directed towards:
1. Assessment of the patient
2. Severity of the coma
3. Diagnostic evaluation
• All possible information from:
1. Relatives
2. Paramedics
3. Ambulance personnel
4. Bystanders
particularly about the mode of onset
•
Previous medical history:
1. Epilepsy
2. DM, Drug history
•
Clues obtained from the patient's
1. Clothing or
2. Handbag
•
Careful examination for
1. Trauma requires complete exposure and ‘log roll’
to examine the back
2. Needle marks
• If head trauma is suspected, the
examination must await adequate
stabilization of the neck.
• Glasgow Coma Scale: the severity of coma
is essential for subsequent management.
• Following this, particular attention should
be paid to brainstem and motor function.
Temperature
Hypothermia
• Hypopituitarism, Hypothyroidism
• Chlorpromazine
• Exposure to low temperature
environments, cold-water immersion
Risk of hypothermia in the elderly with
inadequately heated rooms, exacerbated
by immobility.
•
C/P: generalized rigidity and muscle
fasciculation but true shivering may be
absent. (a low-reading rectal thermometer is
required).
• Hypoxia and hypercarbia are common.
• Treatment:
1. Gradual warming is necessary
2. May require peritoneal dialysis with warm
fluids.
Hyperthermia (febrile Coma)
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•
•
•
•
•
Infective: encephalitis, meningitis
Vascular: pontine, subarachnoid hge
Metabolic: thyrotoxic, Addisonian crisis
Toxic: belladonna, salicylate poisoning
Sun stroke, heat stroke
Coma with 2ry infection: UTI, pneumonia, bed
sores.
Hyperthermia or heat stroke
Loss of thermoregulation dt. prolonged exertion in
a hot environment
• Initial ↑ in body temperature with profuse
sweating followed by
• hyperpyrexia, an abrupt cessation of sweating,
and then
• rapid onset of coma, convulsions, and death
• This may be exacerbated by certain drugs,
‘Ecstasy’ abuse—involving a loss of the thirst
reaction in individuals engaged in prolonged
dancing.
Other causes
• Tetanus
• Pontine hge
• Lesions in the floor of the third ventricle
• Neuroleptic malignant syndrome
• Malignant hyperpyrexia with anaesthetics.
Heat stroke neurological sequelae
• Paraparesis.
• Cerebellar ataxia.
• Dementia (rare)
Pulse
• Bradycardia: brain tumors, opiates,
myxedema.
• Tachycardia: hyperthyroidism, uremia
Blood Pressure
• High: hypertensive encephalopathy
• Low: Addisonian crisis, alcohol, barbiturate
Skin
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•
•
•
•
•
Injuries, Bruises: traumatic causes
Dry Skin: DKA, Atropine
Moist skin: Hypoglycemic coma
Cherry-red: CO poisoning
Needle marks: drug addiction
Rashes: meningitis, endocarditis
Pupils
• Size, inequality, reaction to a bright light.
• An important general rule: most metabolic
encephalopathies give small pupils with
preserved light reflex.
• Atropine, and cerebral anoxia tend to dilate
the pupils, and opiates will constrict them.
Structural lesions are more commonly associated
with pupillary asymmetry and with loss of light
reflex.
• Midbrain tectal lesions : round, regular, mediumsized pupils, do not react to light
• Midbrain nuclear lesions: medium-sized pupils,
fixed to all stimuli, often irregular and unequal.
• Cranial n III distal to the nucleus: Ipsilateral fixed,
dilated pupil.
• Pons (Tegmental lesions) : bilaterally small pupils,
{in pontine hge, may be pinpoint, although
reactive} assess the light response using a
magnifying glass
• Lateral medullary lesion: ipsilateral Horner's
syndrome.
• Occluded carotid artery causing cerebral
infarction: Pupil on that side is often small
Diencephalons
Small, reactive
Midbrain
Medium-sized, fixed
Dilated, Fixed
Pons
Ipsilateral dilated, Fixed
.
small, pinpoint
In hge reactive
Ocular movements
• The position of the eyes at rest
• Presence of spontaneous eye movement
• The reflex responses to oculocephalic and
oculovestibular maneuvers
• In diffuse cerebral disturbance but intact
brainstem function, slow roving eye
movements can be observed
• Frontal lobe lesion may cause deviation of the
eyes towards the side of the lesion
• Lateral pontine lesion can cause conjugate
deviation to the opposite side
• Midbrain lesion Conjugate deviation
downwards
• Structural brainstem lesion disconjugate
ocular deviation
The oculocephalic (doll's head) response
rotating the head from side to side and
observing the position of the eyes.
• If the eyes move conjugately in the opposite
direction to that of head movement, the
response is positive and indicates an intact
pons mediating a normal vestibulo-ocular
reflex
Caloric oculovestibular responses These are
tested by the installation of ice-cold water into
the external auditory meatus, having
confirmed that there is no tympanic rupture.
• A normal response in a conscious patient is
the development of nystagmus with the quick
phase away from the stimulated side This
requires intact cerebropontine connections
Odour of breath
•
•
•
•
Acetone: DKA
Fetor Hepaticus: in hepatic coma
Urineferous odour: in uremic coma
Alcohol odour: in alcohol intoxication
Respiration
• Cheyne–Stokes respiration:
(hyperpnoea alternates with apneas) is
commonly found in comatose patients, often
with cerebral disease, but is relatively nonspecific.
Rapid, regular respiration is also common in
comatose patients and is often found with
pneumonia or acidosis.
• Central neurogenic hyperventilation
Brainstem tegmentum (mostly tumors):
↑ PO2, ↓ PCO2, and
Respiratory alkalosis in the absence of any
evidence of pulmonary disease
Sometimes complicates hepatic encephalopathy
• Apneustic breathing
Brainstem lesions Pons may also give
with a pause at full inspiration
• Ataxic:
Medullary lesions: irregular respiration
with random deep and shallow breaths
Cheyne-Stocks
Central Neurogenic Hyperventilation
Apneustic
Cluster
Ataxic
Abnormal breathing patterns in coma
Cheynes - Stokes
Central Neurogenic
Midbrain
Apneustic
Pons
Ataxic
Medulla
ARAS
Motor function
• Particular attention should be directed towards
asymmetry of tone or movement.
• The plantar responses are usually extensor, but
asymmetry is again important.
• The tendon reflexes are less useful.
• The motor response to painful stimuli should be
assessed carefully (part of GCS)
• Painful stimuli: supraorbital nerve pressure and
nail-bed pressure. Rubbing of the sternum
should be avoided (bruising and distress to the
relatives)
• Patients may localize or exhibit a variety of
responses, asymmetry is important
• Flexion of the upper
limb with extension
of the lower limb
(decorticate
response) and
extension of the
upper and lower limb
(decerebrate
response) indicate a
more severe
disturbance and
prognosis.
Signs of lateralization
•
•
•
•
•
•
•
•
Unequal pupils
Deviation of the eyes to one side
Facial asymmetry
Turning of the head to one side
Unilateral hypo-hypertonia
Asymmetric deep reflexes
Unilateral extensor plantar response (Babinski)
Unilateral focal or Jacksonian fits
Head and neck
• The head
1. Evidence of injury
2. Skull should be palpated for depressed
fractures.
• The ears and nose: haemorrhage and leakage
of CSF
• The fundi: papilloedema or subhyaloid or
retinal haemorrhages
•
Neck: In the presence of trauma to the head,
associated trauma to the neck should be
assumed until proven otherwise.
• Positive Kernig's sign : a meningitis or SAH. If
established as safe to do so, the cervical
spine should be gently flexed
• Neck stiffness may occur:
1. ↑ ICP
2. incipient tonsillar herniation
Causes of COMA
CNS causes of coma
Cerebrovascular disease is a frequent cause of
coma.
• Mechanism:
Impairment of perfusion of the RAS
• With hypotension
• Brainstem herniation ( parenchymal hge,
swelling from infarct, or more rarely, extensive
brainstem infarction)
Subarachnoid haemorrhage
Loss of consciousness is common with SAH
• only about 1/2 of patients recover from
the initial effects of the haemorrhage.
• Causes of coma:
1. Acute ↑ICP and
2. Later, vasospasms, hyponatraemia
Parenchymal haemorrhage
May cause a rapid decline in consciousness, from
1. Rupture into the ventricles
2. or subsequent herniation and brainstem
compression.
• Cerebellar haemorrhage or infarct with
1. Subsequent oedema
2. Direct brainstem compression, early
decompression can be lifesaving.
Hypotension
• The critical blood flow in humans
required to maintain effective cerebral
activity is about 20 ml/100 g/min and any
fall below this leads rapidly to cerebral
insufficiency.
• The causes:
1. syncope in younger patients
2. cardiac disease in older patients.
Hypertensive encephalopathy
• Now rare with better control of blood
pressure.
• C/P: impaired consciousness, grossly raised
blood pressure, papilloedema.
• Neuropathologically: fibrinoid necrosis,
arteriolar thrombosis, microinfarction, and
cerebral oedema (failure of autoregulation)
Raised intracranial pressure
• Mass effects: tumours, abscesses,
haemorrhage, subdural, extradural
haematoma, brainstem herniation→
distortion of the RAS.
• C/P: depends on normal variation in the
tentorial aperture, site of lesion, and the
speed of development.
• Herniation and loss of consciousness Lesions
located deeply, laterally, or in the temporal
lobes > located at a distance, such as the frontal
and occipital lobes.
• Rate of growth: slowly growing tumours may
achieve a substantial size and distortion of
cerebral structure without impairment of
consciousness, in contrast to small rapidly
expanding lesions
• Central herniation involves downward
displacement of the upper brainstem
• Uncal herniation in which the medial
temporal lobe herniates through the
tentorium
• Central herniation: small pupils are followed by
midpoint pupils, and irregular respiration gives
way to hyperventilation as coma deepens.
• Uncal herniation: a unilateral dilated pupil, due
to compression of the III nerve, and asymmetric
motor signs. As coma deepens, the opposite
pupil loses the light reflex and may constrict
briefly before enlarging.
• Rarely, Upward herniation can occur with
posterior fossa masses
Head injury
• The leading cause of death below the age of
45, head injury accounts for 1/2 of all trauma
deaths
• A major cause of patients presenting with
coma.
• A history is usually available and, if not, signs of
injury such as bruising of the scalp or skull
fracture lead one to the diagnosis
• Alcohol on the breath provides a direct
clue to a cause of coma, evidence of head
injury need not necessarily imply that this
is the cause.
• Epileptic seizure, may have resulted in a
subsequent head injury
• Damage can be diffuse or focal.
• Rotational forces of the brain cause
surface cortical contusions and even
lacerations, most obvious
frontotemporally because of the irregular
sphenoidal wing and orbital roof.
• Subdural bleeding due to tearing of veins
• Diffuse axonal injury is now seen as the major
consequence of head injury and associated
coma.
• Mild degrees of axonal injury also occur with
concussion and brief loss of consciousness
• Secondary damage can occur from parenchymal
haemorrhage, brain oedema, and vascular
dilatation, all of which will lead to ↑ICP→
↓perfusion pressure, which can be accentuated
by systemic hypoxia and blood loss.
• Subdural and extradural haematomata may
cause impairment of consciousness following
apparent recovery are important to diagnose, as
they are readily treatable surgically.
Infections
• Systemic infections may result in coma as an
event secondary to metabolic and vascular
disturbance or seizure activity.
• Direct infections of the CNS, as with meningitis
and encephalitis, can all be associated with
coma.
• Meningitis: the onset is usually subacute,
intense headache, associated with fever and
neck stiffness. meningococcal meningitis may be
rapid in onset
• Diagnosis is confirmed by identifying the
changes in the CSF, from which it may be
possible to isolate the causative organism.
• Prompt treatment of acute meningitis is,
however, imperative and may precede
diagnostic confirmation.
• Encephalitis: usually subacute, and often
associated with fever and/or seizures, herpes
simplex encephalitis may be explosive at
onset, leading to coma within a matter of
hours Treatment with aciclovir, precedes
definitive diagnosis.
Parasitic infections
Cerebral malaria
• 25 % mortality rate.
• Associated with 2–10 % of cases of infection
with Plasmodium falciparum.
• C/P: acute profound mental obtundation or
psychosis, leading to coma with extensor
plantar responses
• CSF: may show increased protein,
characteristically there is no pleocytosis
• Hypoglycaemia and lactic acidosis, which may
contribute to the coma.
• Treatment: intravenous quinine.
Steroids, which were at one time prescribed
widely for oedema, are now contraindicated as
they prolong the coma.
Septic patients
• Commonly develop an encephalopathy.
• In some patients this can be severe, with a
prolonged coma.
• Lumbar puncture in such patients is usually
normal or only associated with a mildly elevated
protein level.
• EEG is valuable and is abnormal, ranging from
diffuse theta through to triphasic waves and
suppression or burst-suppression
• Although there is a high mortality, there is
the potential for complete reversibility
• Presence of coma should not prevent an
aggressive approach to management of
such patients including, for example,
haemodialysis to deal with acute renal
failure
Metabolic causes of coma
Hepatic coma
The patient is known to be suffering from liver
failure
• May occur in patients with chronic liver failure
and portosystemic shunting (In these cases
jaundice may be absent)
• Precipitation: GIT hge, infection, certain diuretics,
sedatives, analgesics, general anaesthesia, highprotein food or ammonium compounds
• Subacute onset, although it can be sudden, with
an initial confusional state often bilateral asterixis
or flapping tremor.
• Asterixis, a -ve myoclonus jerk, results in sudden
loss of a maintained posture. elicited by asking
the subject to maintain extension at the wrist
• As coma supervenes, there is often decerebrate
and/or decorticate posturing with extensor plantar
responses
• Diagnosis: signs of liver disease hepatic fetor, and
biochemical evidence of disturbed liver function.
EEG with paroxysms of bilaterally synchronous
slow waves in the delta range or with occasional
triphasic waves
• The disturbance of consciousness due to
raised ammonia, and indeed treatments to
reduce ammonia
• endogenous benzodiazepine ligands may
contribute to the hepatic coma,
benzodiazepine antagonist, flumazenil, in
hepatic coma would support this view
Stage I
Personality Changes
Stage II
Lethergy
Flapping tremor
Muscle twitches
Stage III
Nagy
Abusive
Violent
Stage IV
Coma
Renal coma
• May occur in acute or chronic renal failure
• Raised blood urea alone cannot be responsible
for the loss of consciousness but the
• Metabolic acidosis, electrolyte disturbances and
Water intoxication due to fluid retention may be
responsible
• Early symptoms Headache, vomiting, dyspnoea,
mental confusion, drowsiness or restlessness,
and insomnia
• Later muscular twitchings, asterixis, myoclonus,
and generalized convulsions are likely to precede
the coma.
• ↑ blood urea or creatinine establishes the
diagnosis (DD hypertensive encephalopathy)
•
Dialysis may develop iatrogenic causes of
impaired consciousness.
Dialysis disequilibrium syndrome
1. Is a temporary, self-limiting disorder, but it can
be fatal
2. More common in children and during rapid
changes in blood solutes. Rapid osmotic shift of
water into the brain is the main problem
3. accompanied by headache, nausea, vomiting,
and restlessness before drowsiness and
marked somnolence.
4. It can occur during or just after dialysis
treatment, but resolves in 1 or 2 days
Dialysis encephalopathy dialysis dementia syndrome
1. Progressive dysarthria, mental changes,
2. progression to seizures, myoclonus, asterixis,
and focal neurological signs
3. terminally, there may be coma
4. EEG: paroxysmal bursts of irregular,
generalized spike and wave activity.
5. has been attributed to the neurotoxic effects
of aluminium: aluminium-containing antacids
and a high aluminium content in the water
6. Reached its peak prevalence in the mid 1970s,
before preventive action was taken.
Disturbance of glucose metabolism
Diabetic Ketoacidosis
• Subacute onset with late development of coma.
• Marked ketoacidosis, usually above 40 mmol/l,
together with ketonuria.
• Secondary lactic acidosis (DD severe anoxia or
methyl alcohol or paraldehyde poisoning)
• Patients are dehydrated, rapid, shallow breathing,
occasionally acetone on the breath.
• The plantar responses are usually flexor until coma
supervenes.
Hyperglycaemic non-ketotic diabetic coma
• More commonly seen in the elderly.
• Coma is more common than with ketoacidosis.
• Profound cellular dehydration, risk of developing
cerebral venous thrombosis, which may
contribute to the disturbance of consciousness.
• It may be induced by drugs, acute pancreatitis,
burns, and heat stroke
Hypoglycaemic coma
• Much more rapid onset.
• Symptoms appear with blood sugars of less than
2.5 mmol/l
• Initially autonomic: sweating and pallor, and then
inattention and irritability progressing to stupor,
coma, and frequent seizures.
• May present with a focal onset (hemiparesis)
• Plantar responses are frequently extensor.
• Patients may be hypothermic.
Diagnosis of Hypoglycemic Coma:
• The patient is known to be taking insulin.
• Spontaneous hypoglycaemia with insulinomas are
usually diagnosed late.
• There may be a long history of intermittent
symptoms and in relation to fasting or exercise.
• May also be precipitated by hepatic disease,
alcohol intake, hypopituitarism, and Addison's
disease
Treatment:
• Glucose, together with thiamine
• Unless treated promptly, hypoglycaemia results
in irreversible brain damage. Cerebellar Purkinje
cells, the cerebral cortex, and particularly the
hippocampus and basal ganglia are affected
• Dementia and a cerebellar ataxia are the clinical
sequelae of inadequately treated hypoglycaemia.
Other endocrine causes of coma
Pituitary failure
• Rare cause of coma and is the result of
hypoglycaemia, hypotension, hypothermia, and
impaired adrenocortical function
• History of fatigue, occasionally depression and
loss of libido
• Patients are very sensitive to infections and to
sedative drugs, which often precipitate
impaired consciousness.
• Pituitary apoplexy Acute onset of
hypopituitarism occurs with
haemorrhagic infarction in pre-existing
tumours, patients present with impaired
consciousness, meningism, and
opthalmoplegia
Hypothyroidism
• Mental symptoms are common, with headaches,
poor concentration, and apathy; this is frequently
diagnosed as depression.
• With progression there is increasing somnolence
and, patients become sensitive to drugs and
infections.
• These and cold weather, particularly in the
elderly, may precipitate myxoedemic coma.
• Myxoedemic coma has a high mortality and is
associated with hypoglycaemia and
hyponatraemia.
• low-reading thermometer to detect hypothermia
• Treatment: support of ventilation and blood
pressure and cautious correction of the thyroid
deficiency with tri-iodothyronine
Hyperthyroidism
• Mild mental symptoms: anxiety,
restlessness,reduced attention.
• ‘Thyroid storm’ with agitated delirium, which
can progress to coma, may have bulbar
paralysis
• Apathetic form of thyrotoxicosis: particularly
the elderly, with depression leading to apathy,
confusion, and coma without any signs of
hypermetabolism
Adrenocortical failure
• Mental changes are common in Addison's disease
and secondary hypoadrenalism.
• Undiagnosed Addison's disease is frequently
associated with behavioural changes and fatigue.
• Infection or trauma may precipitate coma and
associated hypotension, hypoglycaemia, and
dehydration
• Tendon reflexes are often absent
• ↑ ICP, papilloedema
• Friedrichsen–Waterhouse syndrome acute
adrenal failure due to meningococcal
septicaemia a cause of sudden coma in infants.
• Acute adrenal failure due to HIV infection can
occur
Disturbance of Ca and Mag metabolism
Hypercalcaemia
• Mental confusion, apathy, often with headache. If
severe, stupor and even coma.
• Causes: metastatic bone disease, including
multiple myeloma
Hypocalcaemia
• Primarily affects the peripheral nervous system,
with tetany and sensory disturbance
• It can be associated with ↑ICP and papilloedema
Hypomagnesaemia
• Inadequate intake and prolonged parenteral
feeding,
• Overshadowed by other metabolic
disturbances, including hypocalcaemia, but can
give rise to a similar clinical picture.
Hypermagnesaemia
• Renal insuf., overzealous replacement of mag
and its use (in eclampsia) can give rise to mag
intoxication, with major CNS depression.
Drugs
• Poisoning, drug abuse, and alcohol
intoxication accounting for up to 30 % of those
presenting through accident and emergency
departments.
• 80 % require only simple observation in their
management.
•
1.
2.
3.
•
1.
2.
3.
The most commonly drugs in suicide attempts
are :
Benzodiazepines
Paracetamol
antidepressants.
Narcotic overdoses (heroin)
Pinpoint pupils
Shallow respirations , needle marks.
The coma is easily reversible with naloxone
•
Solvent abuse and glue sniffing should be
considered in the undiagnosed patient with
coma.
• Drugs may also result in disturbed
consciousness due to
1. secondary metabolic derangement
2. the acidosis associated with ethylene glycol
and carbon monoxide poisoning
Alcohol intoxication
• Apparent from the history, flushed face, rapid
pulse, and low blood pressure. The smell of
alcohol on the breath.
• Intoxicated are at increased risk of hypothermia
and of head injury can be the cause of coma.
• At low plasma concentrations of alcohol, mental
changes, at higher levels, coma ensues, >350
mg/dl may prove fatal.
Miscellaneous causes of coma
Seizures
• Common cause of coma, with a period of
unconsciousness following a single generalized
seizure commonly lasting between 30 and 60
minutes.
• Following status epilepticus, there may be a
prolonged period of coma. History, trauma to the
tongue or inside of the mouth.
• Seizures secondary to metabolic disturbances
may have a longer period of coma.
Extensive neurological disease
• PMLE
• severe end-stage multiple sclerosis.
• Prion disease may lead to coma over a
short period of 6–8 weeks, but this is
following a progressive course of
widespread neurological disturbance.
Eclampsia
• In the second half of pregnancy and
represents a failure of autoregulation, with
raised blood pressure.
• Neuropathologically: there are ring
haemorrhages around occluded small
vessels with fibrinoid deposits.
• CP: seizures, cortical blindness, and coma.
• Management: control of convulsions and raised
blood pressure. Parental magnesium is
commonly employed, may give rise to
hypermagnesaemia.
Postpartum complications of pregnancy cerebral
angiitis and venous sinus thrombosis, may also
lead to coma
Investigation of coma
• At presentation blood will be taken for
determination of glucose, electrolytes, liver
function, calcium, osmolality, and blood gases.
• Blood should also be stored for a subsequent
drug screen if needed
• Following the clinical examination, a broad
distinction between a metabolic cause, with
preserved pupillary responses, or a structural
cause of coma is likely to have been
established
• Although most patients with coma will require
CT scanning, or indeed all with persisting
coma, clearly this is of greater urgency when a
structural lesion is suspected
• In the absence of focal signs, but with
evidence of meningitis, a lumbar puncture
may need to be performed before scanning, as
a matter of clinical urgency.
• In other situations, lumbar puncture should
be delayed until after the brain scan because
of the risk of precipitating a pressure cone
secondary to a cerebral mass lesion
• All patients will require chest radiography and
ECG, detailed investigations of systemic
disease will be directed by the clinical
examination.
• The EEG is of value in identifying the
occasional patient with subclinical status
epilepticus, and is clearly of value in assessing
the patient who has been admitted following
an unsuspected seizure
• Fast activity is commonly found with drug
overdose and slow wave abnormalities with
metabolic and anoxic coma.
• An isoelectric EEG may occur with druginduced comas, but otherwise indicates
severe cerebral damage.
Edema vasogénico
Edema citotóxico
Edema intersticial
Edema osmótico
Condiciones normales
Na+ :
K+ : 4
Na+
Na+
K+
Cl-
Célula
140
Cl- : 100
ATP
K+
Na+ :
138
K+ : 5
Cl- :
108
Capilar
Edema vasogénico
Na+ :
K+ : 4
Na+
Na+
K+
Cl-
Célula
140
Cl- : 100
ATP
BHE
K+
AGUA
Capilar
Edema citotóxico
Na+ :
140
K+ : 4
Na+
K+
Cl-
Cl- : 100
Célula
Na+
Capilar
Edema intersticial
Na+
Na+
K+
Cl-
Célula
Na+ :
ATP
140
K+ : 4
K+
Na+ :
138
Cl- : 100
K+ : 5
Cl- : 108
Capilar
Edema osmótico
Na+ :
140
K+ : 4
Na+
K+
Cl-
Célula
Disrupción de la
membrana
ATP
Cl- : 100
Capilar
Management of the unconscious patient
• Treatment of the underlying cause
• Maintenance of normal physiology: respiration,
circulation, and nutrition
• Patient should be nursed on his or her side without
a pillow
• Attention will clearly need to be paid to the airway,
requiring an oral airway as a minimum
• Intubation, if coma is prolonged, tracheostomy
• Retention or incontinence of urine will require
catheterization
• Intravenous fluid is necessary and, if coma
persists, adequate nutrition is required.
• Care of Skin, frequent changing of position, special
mattress, avoid urine and stool soiling and good
care of bed sores
Prognosis in coma
• In general, coma carries a serious prognosis.
• This is dependent to a large extent on the
underlying cause.
• Coma due to depressant drugs carries an excellent
prognosis provided that resuscitative and
supportive measures are available and no anoxia
has been sustained
• Metabolic causes, apart from anoxia, carry a
better prognosis than structural lesions and head
injury
• Length of coma and increasing age are of poor
prognostic significance.
• Brainstem reflexes early in the coma are an
important predictor of outcome
• in general, the absence of pupillary light and
corneal reflexes 6 hours after the onset of coma
is very unlikely to be associated with survival
• The chronic vegetative state usually carries a
uniformly poor prognosis, although a partial
return of cognition, or even restoration to partial
independence, has been reported very rarely.
• Although unassociated with coma, the ‘locked-in’
syndrome also carries a poor prognosis, with
only rare recoveries reported.
Intravenous Rehydration
• Used in patients who lost more than 10% of body
weight from dehydration or are unable to drink
due to vomiting
• Ringer’s Lactate used commercially in hospitals
with appropriate electrolyte concentrations
specified to patients needs
Intravenous Rehydration –
Additional Options
• Saline can be used, however, bicarbonate and
potassium losses are not being replaced
• Glucose in water; this does not replace the
sodium, bicarbonate, or potassium losses
Dosage =
Antimicrobial Therapy
• Seen as an adjunct to appropriate rehydration
• Reduce the volume of diarrhea by a half and the
duration of excretion to about 1 day, therefore, they
lower the expense of treatment and play a role in
cholera control.
• Due to short duration of illness, antibiotics not highly
recommended:
– High cost
-- Antibiotic Resistance
– Limited gain from usage
Dosage – Antibiotic Agents
• Given orally when vomiting
stops.
• Tetracycline is the standard
treatment
• Administered in single dose
primarily to prevent spread
of secondary infection
WHO guidelines
Prevention
• V. Cholerae is spread through contaminated food
and water, therefore, prevention depends upon
the interruption of fecal-oral transmission
• Anti-biotic prophylaxis, vaccines and surveillance
of new cases are the answer to preventing the
spread of disease.
Antibiotic prophylaxis
• The World Health Organization recommends
prophylaxis if 1 household member in a family
becomes ill.
• Mass administration of antibiotics to a whole
community is not effective nor recommended
Weaponization: Historical Perspective
• WWI
• allegations that Germany tried to spread cholera in Italy
• 1930s
• “Japan dropped bombs on Chinese that released cholera,
among other biological pathogens.”
• 1980-1993
• S. Africa Biological Weapons Program
• included Bacillus anthracis, Vibrio cholera, and
Clostridium species
•Urbanization-more people concentrated in citiesoften without adequate infrastructure
•Increases in the elderly populations
•Increases in children in daycare: working woman
with kids under 5 was 30% in 1970, is 75% in 2000.
•Fast paced Lifestyles- increase in convenience items
and more stress
•High-risk behavior- Drug use and unprotected sex
War and Famine
War refugees are a full 1% of the global population
War refuges are forced onto new areas where they are
exposed to new microbes from vectors and people.
War and famine are closely linked.
In 2001, tracking 16 countries with “food emergencies”,
showed that 9 were because of civil unrest.
Famine is also caused by social, economic, and political
forces. Weather and HIV/AIDS
• III-International travel and Commerce.
• 365 days to circumnavigate the globe…now it takes
36 hours
• -used to quarantine ships, but 36 h faster than
disease incubation
• 400 million people per year travel internationally
• increased incidence of both Tuberculosis and
Influenza transmission on long flights
• -Transportation of products is an increased
concern.
• -rapid transport of disease harboring fresh
products.
• -transport of livestock facilitates movements of
viruses and arthropods (especially ticks)
Travel and HIV/AIDS.
-Silk route and plague.
-Slaves trade and yellow fever.
-Migration to new world and smallpox.
Cholera and Hajj.
IV- Technology and industry
• Modern mass production increased the
chance of accidental contamination and
amplifies the effect of such contamination.
-Contamination of hamburger meat by E.coli
strains causing haemolytic uraemic syndrome.
-Feeding cattle by byproducts of sheep causing
bovine spongiform encephalitis.
• Concentrating effect of blood and nasocomial
infections e.g. Ebola fever by contaminated
hypodermic apparatus.
• New diagnostic technology lead to identification of
previously unknown microbes for known diseases
e.g. Helicobacter pylori and peptic ulcer, human
herpes virus 6 and roseola.
• Medical technology
People living longer, but have weaker immune
systems.
Blood & organ transplantation transmit infections.
V-Microbial Adaptation and Change
A number of microbes utilizing different genetic
mechanisms
-genome sequences show that lateral transfer
is common
-high mutation rates in RNA viruses-rapid
adaptation
-quick reproduction so rare mutations build up
rapidly
Antimicrobials for livestock growth enhancement and over
-prescription of antimicrobials by Drs. (convenience)
-evolve modifying enzymes and “drug pumps”
• Increased antibiotic resistance with increased use of
antibiotics in humans and food animals (VRE, VRSA,
penicillin- and macrolide-resistant Strep
pneumonia, multidrug-resistant Salmonella,….)
• Increase virulence (Group A Strep?)
• Jumping species from animals to humans (avian
influenza, HIV?, SARS?)
VI- Breakdown of public health measures.
• -Decrease in choline in water supplies lead to
rapid spread of cholera in South America.
• Non functioning water plant in Wisconsin, USA
lead to outbreak of waterborne
cryptosporidium.
• Inadequate vaccinations and Diphtheria in former
USSR independent countries.
• Discontinued mosquito control efforts and dengue
and malaria re-emergence.
Major Factors Contributing to the Emergence
of Infectious Diseases
1.
2.
3.
4.
5.
6.
Human demographics and behavior
Technology and industry
Economic development and land use
International travel and commerce
Microbial adaptation and change
Breakdown of public health measures
Institute of Medicine Report 1992
Weaponization: Means to Increase Virulence
amplify and insert virulent portion of the
genome into another pathogen for either
dispersion via aerosolization or water
contamination that is contagious
“V. cholerae is particularly well adapted to its
lifestyle in both the aquatic environment and
as an enteric pathogen.”
“On microbes”
Nor do I doubt if the most formidable armies
ever heere upon earth is a sort of soldiers who
for their smallness are not visible”
Sir William Petty, 1640
ry