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1
SEPSIS WHICH STRATEGY? from clinical medicine
to molecular biology or from molecular biology
to clinical medicine?
Critical points for Sepsis management at
the bedside
Giorgio Tulli M.D. Department of Anaesthesia and
Intensive Care Hospital San Giovanni di
Dio Florence
R
2003
2
Sepsis the systemic response to
infection Pathophysiology a continuum A
disorder due to uncontrolled inflammation or due
to failure of the immune system?
bacteria fungi, viruses parasites
GENETIC POLYMORPHISMS
D E A T H
Renal failure Liver failure CNS failure Heme
failure
SIRS altered organ perfusion
Lung failure
SIRS
LIR
Cardio vascular failure
When microorganisms invade, multiply in a sterile
site
focus
NODES
METASTASES
Death
D E A T H
TUMOR
D E A T H
Site of infection
ARDS
SEVERE SEPSIS
SEPSIS
Local infection
MOFS
SEPTIC SHOCK
Characteristics of the particular pathogen
Clinical presentation of sepsis A disorder due to
uncontrolled inflammation ? Or due to failure of
the immune system?
3
Comorbid disease and immunosuppression-chronologic
al vs biological age-population health


socio economic factors

cultural
influences

environmental influences


diet, exercise, employment


alcohol, smoking
Stressor Event Disease process Massive
hemorrhage Trauma Burns Major operations Infection
s
Physiologic Reserve genetic environmental factors
that contribute to
measured severity
RISK OF CRITICAL ILLNESS
OUTCOME
Proactive Adjunctive
Reactive Supportive

• Cell injury
• Dysoxia
• diagnosis

Inappropriate statistical methods, poor selection
of patients
THERAPY Errors Complications
Assessment of specific therapy antibiotics,
timely surgery, thrombolytics, insulin
Cardiovascular reserve Immune state Inflammatory
response Nutrition Potential links between
Cardiovascular reserve and Inflammatory response
Assessment of supportive management hemodynamics,
ventilation, dialysis Variability in supportive
management
OUTCOME Which? Inappropriate use of mortality End
point for both supportive and specific therapy
FAILURE TO SHOW CONVINCINGLYCOMPARABILITY
BETWEEN PATIENTS CRITICAL CARE STUDIES REDEFINING
THE RULES
4
THE EARLIEST , THE BETTER
5
INTENSIVE CARE UNIT INFECTIONS INTERNATIONALLY

• An international prospective study examined
  14,364 patients admitted to 28 ICUs in 8
  countries during a 12 month period.
• (Alberti et al . Intensive Care Med 2002 28
  108-121)
• A total of 3034 infectious episodes were
  documented at ICU admission (crude
  incidence21.1 ) , and another 1581 infectious
  episodes were recorded in ICU patients
  hospitalized gt 24 hours (crude incidence18.9)
• Over one half of infections were associated with
  severe sepsis or septic shock
• The crude hospital mortality rates ranged from
  16.9
• for non infected patients to 53.6 for
  patients who had infection at ICU admission and
  acquired additional nosocomial infections while
  in the ICU

6
CLINICAL PULMONARY INFECTION SCORE (CPIS)
CALCULATIONCPIS at baseline is assessed on the
basis of the first 5 variables . CPIS at 72
hours is calculated based on all 7 variablesAm
J Respir Crit Care Med 2000 162 505-511

Pathogenic bacteria cultured in moderate
or heavy quantity Same pathogenic bacteria seen
on Gram stain add 1 point
Pathogenic bacteria cultured in rare or light
quantity or no growth
Culture of tracheal aspirate
(semiquantitative)
7
HIGH RISK PATIENT
gt3 risk factors and symptoms
2 or more Candida positive foci
Peritoneal infection
Candida in the blood
Candida endophtalmitis
Urinary tract infection Candiduria with
leukocyturia gt105mL
Candida in peritoneal cavity drainage cultures
Pancreas pancreatitis
liver
spleen
gt104 BAL gt103 PBS abnormal chest radiograph
Cultures of Pleural fluid Pericardial fluid, BAL,
Tracheal aspirate
Tipical Ct scan findings
Signs and symptoms of infection and
organ dysfunction
Certain infection
Suspected infection
Prophylaxis therapy
Definite therapy
Early pre-emptive/empiric therapy
8
MORE IS MISSED BY NOT LOOKING THAN BY NOT
KNOWING Anonymous Patient examination in the
Intensive Care Unit
9

• STANDING AT THE END OF THE BED
• The handover
• in summary the problems are..and our direction
  is..
• Handover should always be at the patient bedside
  and not in a
• separate room , concentrating on results and
  numbers
• This emphasizes the importance of the physical
  examination and the fact that the patient is a
• person and not only a series of numbers

• THE HISTORY
• History taking in ICU is complex and not confined
  to subtle clues
• concerning the current diagnosis
• The history is essential to reconstructing the
  patients pre-
• admission health status , as well as details
  about the patients
• course in hospital, up to the point of the
  current examination

10
THE INITIAL EXAMINATION

• THE PHYSICAL EXAMINATION
• Neurological
• Airway
• Breathing
• Cardiovascular system
• Gastrointestinal system
• Renal system and fluids
• Limbs

Guidelines for daily recording of patients
clinical status

• A airway
  
• B breathing
• C circulation
• D disability GCS and focal neurology
• E electrolytes results
• F fluids are they appropriate?
• G gut- examine (IAP) and nutritional assessment
• H ematology
• I infection microbiology and WC count,
  procalcitonin , CRP
• L lines are the sites clean ? How long have
  they been in ?
• M medications- review and interactions
• R relatives what is the common message ?
• S skin

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MOST COMMON SIGNS OF SEPSIS

• Fever (sometimes hypothermia), chills
• Increased serum concentration of C reactive
  protein (CRP) and procalcitonin (PCT), altered
  white blood cell count, increased interleukin 6
  (IL-6), IL-8
• Increased heart rate, increased cardiac output,
  low systemic vascular resistance, increased
  oxygen consumption, low oxygen extraction ratio
  (OER)
• Tachypnea, low PaO2/FiO2
• Altered skin perfusion, reduced urine output
• Otherwise unexplained alterations in coagulation
  parameters, increases D-dimers, low protein C ,
  low antithrombin, increased prothrombin
  time/activated partial thromboplastin time
• Increased insulin requirements
• Otherwise unexplained alterations in mental
  status
• Increased urea and creatinine, low platelet count
  or other coagulation abnormalities,
  hyperbilirubinemia
• Vincent JL Sepsis definitions Lancet Infect
  Dis 2002, 2135

12
INFECTIOUS AND NONINFECTIOUS CAUSES OF FEVER IN
THE ICU

• Infected intravascular catheters
• Sinusitis or otitis media ( in patients with
  intranasal devices such as nasogastric tubes or
  nasal endotracheal tubes)
• Acalculous cholecystitis
• Drug fever
• Pulmonary emboli
• Deep venous thrombosis
• Central fever (in patients with head trauma)
• Clostridium difficile colitis
• Postcardiotomy syndrome
• Secondary infection by resistant organisms
• Fungal infection
• FUO (fever of unknown origin)

13
Organ specific clinical findings suggesting the
source of sepsis
14
STORIA CLINICA
ESAME OBIETTIVO ACCURATO
PROCALCITONINA(PCT) PROTEINA C REATTIVA(CRP) NEOPT
ERINA
Azioni diagnostiche e terapeutiche da compiere
nel giro di ore ( 6 ore,lt12ore, max 24 ore)
Leucocitosi, leucopenia, gt10band forms
Febbre Ipotermia Tachipnea Tachicardia
PIRO model
INFEZIONE diagnosi
SIRS diagnosi
NO
Intervento chirurgico urgente (ascesso etc.)
SI
INFEZIONE sospetta
TERAPIA DI SUPPORTO DEGLI ORGANI Protocollo di
Rivers Ventilazione protettiva
Monitoraggio microbiologico
NO
SI
Antibioticoterapia empirica
48 ore
Monitoraggio coagulazione
INFEZIONE CERTA
TERAPIA AGGIUNTIVA rh-Proteina C attivata (Xigris)
ATIII,APC, D-dimero,piastrine VWF,TAT,PAP,Fram
12 aPTT,PT
pneumonia
addominale
Tratto urinario altro
sistemica
STATO DI IMMUNO PARALISI
ANTIBIOTICOTERAPIA MIRATA
STATO PROINFIAMATORIO PROCOAGULATIVO
IMMUNO-MONITORAGGIO
IL-6,IL-8,IL-10,CD4/CD8,HLA-DR
TESTS DI GRAVITA E DI INSUFFICIENZA DORGANO
Apache2,Saps2, SOFA,MODscore
48 ore
Test con ACTH
SHOCK SETTICO
MOD/MOF
SEPSI
SEPSI GRAVE
G.Tulli R
15
IMMUNOLOGICAL MONITORING
Immunological competence HLA-DRmonocytes,
TNF/IL-12, IL-10,Th1/Th2
CD-13/CD14HLA-DR
Inflammation TNF,IL-6,IL-8 plasmatic, IL-8(BAL),
CRP
Infection Procalcitonin Neopterin
Tissue injury IL-6, E-Selectin (plasmatic) s-Throm
bomodulin,s-VWF
16
Cytokines Kinetics
17
Potential mechanisms of Immune Suppression in
Patients with Sepsis

• Shift from an inflammatory (Th1) to an
• anti-inflammatory (Th2) response
• Anergy
• Apoptosis induced loss of CD4T cells, B cells
  and dendritic cells
• Loss of macrophage expression of major
  histocompatibility-complex class II and
  costimulatory molecules
• Immunosuppressive effect of apoptotic cells

Th1 denotes type 1 helper T cell, and Th2
type 2 helper T cell
18
MONITORING OF COAGULATION PARAMETERSglobal and
dynamic
19
Healthy person with meningococcemia
IMMUNE STATUS Hypoimmune Normal
Hyperimmune
Elderly patient with malnutrition and
diverticulitis
Patient with diabetes, chronic renal failure and
pneumonia
recovery
death
days
1
2
3
4
5
7
8
6
The individual response is determined by many
factors, including the virulence of the organism
, the size of the inoculum, and the patients
coexisting conditions, age and polymorphisms in
genes for cytokines.The initial immune response
is hyperinflammatory, but the response rapidly
progresses to hypoinflammatory. A secondary bump
in the hyperimmune state can occur during the
hospital course with secondary infections. In
the hypotetical healthy person who has contracted
a serious meningococcal infection there is an
initial robust hyperinflammatory response. This
patient would have extremely high plasma
concentrations of TNFa and other inflammatory
cytokines. Death may occur due to a
hyperinflammatory state, and antiinflammatory
treatments may improve the likelihood of
survival. If infection resolves rapidly, there is
only a minimal hypoimmune state. In the
hypotetical elderly malnourished person with
diverticulitis, the initial response is limited
and , if infection persists, a prolonged
hypoinflammatory response develops, followed by
either recovery or death. In the hypotetical
patient with diabetes, chronic renal failure and
pneumonia, the initial response is blunted and
there is prolonged depression of immune
function, culminating in death
20
FOUR THERAPEUTIC GOALS FOR SEPSIS

• TO TREAT UNDERLYING INFECTION
• (elimination of the infecting microorganisms
  through control of the source of infection and
  effective antimicrobial therapy)
• TO PRESERVE ORGAN PERFUSION
• (aggressive and targeted shock resuscitation
  and cardiovascular support)
• TO MAINTAIN TISSUE OXYGENATION
• (supportive care of multiple organs at risk
  for dysfunction)
• TO AVOID COMPLICATIONS
• (selective modification of the hosts
  adaptive and maladaptive responses to infection)

21
TO TREAT UNDERLYING INFECTION

• ANTIBIOTIC CHEMOTHERAPY
• - FACTORS IN EMPIRIC ANTIBIOTIC CHOICE
• a) SITE OF INFECTION
• b) ENVIRONMENTAL EXPOSURE
• c) IMMUNOSUPPRESSION
• d) DRUG ALLERGY
• e) REVIEWING EMPIRIC THERAPY
• - ANTIBIOTIC INDUCED ENDOTOXIN RELEASE
• DETECTION AND REMOVAL
• OF INFECTED MATERIAL
• a) DRAIN ABSCESSES
• b) RESECT DEAD TISSUE
• c) REMOVE INFECTED FOREIGN MATERIAL
• LOCATING THE UNDERLYING FOCUS OFTEN
  REQUIRES CONSIDERABLE DETERMINATION AND PATIENCE
  AND SOMETIMES REPEATED DISCUSSIONS WITH SURGICAL
  COLLEAGUES

22
ANTIBIOTICS IN SEPSIS 1

• Retrospective studies have shown that early
  administration of appropriate antibiotics reduces
  the mortality in patients with bloodstream
  infections caused by Gram-negative bacteria
• By analogy with the observations made in patients
  with Gram-negative sepsis and despite the lack of
  substantial clinical data in the literature, it
  is likely that appropriate antibiotic therapy
  reduces the morbidity and the mortality of Gram
  positive sepsis
• Antifungal therapy is recommended for patients
  with candidemia. Whether early treatment is
  associated with better outcome is unknown, and
  additional studies are needed to evaluate this
  question

23
ANTIBIOTICS IN SEPSIS 2

• Monotherapy with carbapenem antibiotics and with
  third or fourth generation cephalosporins is as
  effective as combination therapy with a ß-lactam
  and an aminoglycoside for the empirical treatment
  of non-neutropenic patients with severe sepsis
• Extended spectrum carboxypenicillins or
  ureidopenicillins combined with beta lactamase
  inhibitors have been shown to be effective for
  the treatment of suspected infections in febrile
  , neutropenic cancer patients and in patients
  with peritonitis or nosocomial pneumonia. Similar
  studies have not yet been carried out in patients
  with severe sepsis or shock
• Monotherapy with aztreonam appears to be as
  effective as combination of a beta lactam and an
  aminoglycoside for the treatment of patients with
  documented Gram negative sepsis. The fact that
  aztreonam lacks any appreciable activity against
  Gram-positive or anaerobic bacteria precludes its
  use as empirical single agent therapy in patients
  with severe sepsis

24
ANTIBIOTICS IN SEPSIS 3

• Fluoroquinolones are highly effective for the
  treatment of documented Gram-negative bloodstream
  infections. Data are lacking to support their use
  as single agent treatment of severe sepsis,
  especially as first generation fluoroquinolones
  display suboptimal activities against Gram
  positive bacteria
• The indiscriminate use of glycopeptide
  antibiotics (i.e., vancomycin or teicoplanin) for
  presumed Gram positive infections in patients
  with severe sepsis and septic shock should be
  avoided. Glycopeptides are appropriate in
  severely ill patients with catheter related
  infections or in centers in which methicillin
  resistant staphylococci predominate. The possible
  clinical benefit associated with the empirical
  use of glycopeptides should be weighed against
  the risks of selecting resistant organisms and of
  increased toxicity. Most cases require additional
  Gram negative coverage , at least until
  microbiological results are available
• Antifungal agents , such as fluconazole, should
  not be used on a routine basis as empirical
  therapy in patients with severe sepsis and septic
  shock
• Fluconazole is as effective and less toxic than
  amphotericin B for the treatment of candidemia in
  nonneutropenic patients. However , if the patient
  is unstable or has been treated previously with
  fluconazole, it might be prudent to begin therapy
  with Ambisome or Caspofungin while waiting for
  the identification of the Candida species and for
  the results of susceptibility testing. Whether 5
  fluorocytosine should be combined with
  amphotericin B in unstable patients is debatable

25
Endotracheal tube
increasing costs and resource utilization
decreasing evidence or acceptance
CASS
Kinetic rx
Subglottic secretions
BIPAP/HME
Oral care/oral intubation
Endotracheal tube cuff
Avoid sedation/Infection control
Wean/semirecumbent/condensate removal/avoid
gastric overdistension
biofilm
Pooled secretions in airway
Dispersal of biofilm with ventilation

• Kinetic rx kinetic therapy
• CASS Coninuous aspiration subglottic space

26
TREATMENT OPTIONS FOR INFECTIONS DUE TOEXTENDED
SPECTRUM ß-LACTAMASE (ESBL)PRODUCING ORGANISMS
27
Possible empiric antibiotic choice in severe
sepsis
Nosocomial severe sepsis and septic shock
without a clear site of infection Beta
lactam vancomycin aminoglycoside or
quinolone
28
CONCENTRATION DEPENDENT vs INDEPENDENT BEHAVIOR
OF ANTIBIOTICS

• CONCENTRATION DEPENDENT (TIME INDEPENDENT)
• The rateand extent of bacterial kill and the PAE
  all increase as the antibiotic concentration
  increase
• A) aminoglycosides
• B) fluoroquinolones
• C) metronidazole
• CONCENTRATION INDEPENDENT (TIME DEPENDENT)
• Once a threshold concentration of these
  antibiotics is achieved , further increases in
  antibiotic concentration do not result in an
  appreciably increased rate or extent of bacterial
  kill or an extension of the PAE
• A) ß-lactam antibiotics
• B) vancomycin
• C) Monobactam (aztreonam) ?
• D) Carbapenem (imipenem) ?
• NOT AVAILABLE BEHAVIOR
• A) Macrolides
• B) Clindamycin

29
I.V.
P.O.
In vivo host, pathogen and antibiotic factors
that may influence the antimicrobial effect at
the site of infection
I.M.
Altered absorption
Tissue perfusion
CENTRAL COMPARTMENT (plasma)
hypometabolic elimination
Drug distribution Protein binding
hypermetabolic elimination

• Bacterial pathogen
• Inoculum
• Growth phase
• Glycocalyx
• Intra/extracellular

Site of infection
Immune function
Intracellular penetration
Extracellular fluid
cells
Y Y Y Y Y Y
Cellular compartment

• Oxygen tension
• Ion concentration
• pH

Environmental factors
30
Biofilm , Antimicrobial Resistance and
InfectionsStimulation of Staphylococcus
epidermidis growth and biofilm formation by
catecholamine inotropesThe ability of
catecholamine inotropic drugs to stimulate
bacterial proliferation and biofilm formation may
be an aetiological factor in the development of
intravascular catheter colonisation and catheter
related infection. The removal of iron from
trasferrin for subsequent use by S. epidermidis
is a possible mechanism by which catecholamine
inotropes stimulate bacterial growth as
biofilmsLancet 2003 361130-135Singh PK,
Parsek MR, Greenberg EP, Welsh MJ A component of
innate immunity prevents bacterial biofilm
development . Nature 2002 417552-5Drenkard E,
Ausubel FM Psedomonas biofilm formation and
antibiotic resistance are linked to phenotypic
variation. Nature 2002 416740-3
Planktonic growth
QS
QS
QS
Pili Flagella
Quorum Sensors (homoserine lactones)
QS
Antibiotic susceptibility
Proteases Hemolysins ExotoxinA Pyocyanin Superoxid
e dismutase Catalase
Transcriptional activators LasR RhIR
ANTIBIOTIC RESISTANCE
31
Mortality with and without appropriate antibiotics
Pierre Yves Bochem Intensive Care Med (2001) 27
32
Hospital mortality and rates of inadequate
antimicrobial treatment according to the most
common pathogens associated with bloodstrem
infections. OSSA oxacillin sensitive S aureus
CNS coagulase negative staphylococci VRE
vancomycin resistant enterococci Chest 2000
118146-155
33
Infection certain or suspected
Prophylactic therapy
PRECAUTIONARY THERAPY

• DEFINITIVE ANTIBIOTIC
• TREATMENT
• Antibiogram
• MIC
• Antibiotic serum concentration
• (peak and through)
• AUC24/MIC18 gt125

Microbiological monitoring
EMPIRIC ANTIBIOTIC THERAPY
Pre-emptive therapy
ADEQUATE
EARLY
APPROPRIATE
high doses endovenous bolus high
peak concentration polychemotherapy
rotation therapy 3 days and reassess
Primary cofactor Early start of chemotherapy (no
more than 6hrs from the admittance)
Way of treatment
Bacterical and fungine epidemiology of that
specific ICU
appropriate
inappropriate
SUCCESS
Inadequate 52.5
Adequate 47.5
Failure 5.7
Failure 23.3
FAILURE
OPTIMAL ANTIBIOTIC THERAPY IN ICU
34
Aztreonam Piperacillin Mezlocillin and at lower
concentration Cefuroxime Ceftazidime Cefotaxime
Imipenem Meropenem Mecillinam Cefepime
Immunocompromised Host Infection
septicaemia
Inadequate antibiotic therapy (e.g. penicillin
binding protein (PBP)-2 and 3 specific)
PBP2
PBP3
Conversion of bacilli to round, spheroidal cells
Induction of filamentous bacterial forms
High bacterial mass
Intermediate endotoxin release
High endotoxin release
Low endotoxin release
SEPTIC SHOCK
Tobramycin,Amikacin Gentamicin,Polymyxins Teicopla
nim,Vancomycin Ciprofloxacin,Moxifloxacin
Other factors
35
SCREEN Hemocultures Colonization
index Signs and symptoms of
sepsis
PROPHYLAXIS In high risk patient oral nasogastri
c Nystatin Fluconazole Yoghurt
Positive Fungal hemocultures
Negative Fungal hemocultures

-
SICK
NOT SICK
NOT SICK
NOT SEPTIC
SICK
Assess clinical scenario
SEPTIC
Surveillance Hemocultures plus Colonization
index
OK
SEPTIC
Removal of catheters To treat? To treat
Removal of catheters Antifungal therapy
bacterical sepsis plus 2 sites
gt2 sites or clinical or sterile site
positive. Sepsis in spite of antibiotics
Know the fungal species and antibiogram
(MIC) Fluconazole or Ambisome or Caspofungin or
both
Prophylaxis with high dose fluconazole
probably treatment
Treat like candida
36
TO PRESERVE VITAL ORGAN PERFUSION AND TO MAINTAIN
TISSUE OXYGENATION

• SUPPORTIVE THERAPY
• - Haemodynamic support
• Early goal directed therapy
• - Respiratory support
• Protective ventilation strategy
• MANAGEMENT OF COAGULOPATHY

37
FLUID RESUSCITATION IN SEPTIC SHOCK

• What is the endpoint of fluid resuscitation in
  septic shock?
• Answer (a) adequate tissue perfusion , grade
  E
• Does fluid resuscitation increase cardiac output
  in septic shock patients?
• Answer yes, grade C
• Should fluid infusion be the initial step in the
  cardiovascular support of septic shock patients?
• Answer yes , grade D
• Can the use of pulmonary artery catheter guided
  therapy improve outcome from septic shock?
• Answer uncertain, grade D

Intensive Care Medicine 2001 27 S80-S92
38
CHOICE OF FLUID IN SEPTIC SHOCK

• Is resuscitation with colloids or crystalloids
  associated with similar outcomes in septic shock?
• Answer uncertain, grade C
• Should albumin be avoided in resuscitation from
  septic shock
• Answer uncertain , grade C
• Can one recommend a minimum hemoglobin
  concentration in severe sepsis?
• Answer yes, 7-8 g/dl, grade B
• Can one recommend a minimum hemoglobin
  concentration in septic shock?
• Answer uncertain , grade E

Intensive Care Medicine 2001 27 S80-S92
39
VASOPRESSOR THERAPY IN SEPTIC SHOCK

• Does adrenergic support improve outcome from
  septic shock?
• Answer yes, grade E
• Is the combination of norepinephrine and
  dobutamine superior to dopamine in the treatment
  of septic shock?
• Answer uncertain , grade C
• Among adrenergic agents, are dopamine or
  norepinephrine the first line agents to correct
  hypotension in septic shock?
• Answer yes, grade E
• Should low dose dopamine be routinely
  administered for renal protection?
• Answer no, grade D

Intensive Care Medicine 200127S80-S92
40
INOTROPIC THERAPY IN SEPTIC SHOCKTHE SUPRANORMAL
APPROACH

• Is dobutamine the pharmacological agent of choice
  to increase cardiac output in the treatment of
  septic shock?
• Answer yes, grade D
• Are hyperkinetic patterns associated with better
  outcome in septic shock patients?
• Answer yes, grade C

Intensive Care Medicine 2001 27 S80-S92
41
Supplemental oxygen /- Endotracheal intubation
and Mechanical ventilation
Rivers E et al EGDT in the treatment of severe
sepsis and septic shock N Engl J Med 2001,
3451368-1377
Central venous and Arterial catheterization
Sedation,paralysis (if intubated) Or both
crystalloid
CVP
colloid
8-12 mmHg
lt65mmHg
MAP
Vasoactive agents
gt90mmHg
gt65 andlt90mmHg
ScvO2
gt70
lt70
Transfusion of red cells Until hematocritgt30
lt70
gt70
Inotropic agents
Goals achieved
NO
YES
ICU admission
42
Therapeutic interventions standard therapy
versus EGDT
A negative or positive value indicates how the
control group therapy compares with the treatment
group. a Plt0.001 , b P0.01, c P 0.02, d P
0.03, e P0.04. EGDT early goal directed
therapy
43
Outcome measures percentage change or
improvement, baseline to 72 hours
Baseline to 72 hours surviving to hospital
discharge

44
Charing Cross renal rescue protocol

• 1 Precondition- NORMOVOLEMIA
• GTN 2mg/h maintained throughout protocol
• Colloid challenge
• CVP/PCWP against SV and clinical
  endpoints
• Warm peripheries
• 2 Precondition-PATIENT RELATED NORMOTENSION
• Norepinephrine to achieve normal systolic
  blood pressure
• (as soon as normovolemic), Dobutamine if
  an inotropic support
• is necessary after echocardio
• 3 Offload work of the mTAL
• Furosemide 10 mg bolus, followed by 1-4
  mg/h
• (when 1 and 2 have been achieved)

45
MECHANISMS OF VASODILATORY SHOCK
Sepsis or tissue hypoxia with lactic acidosis
ATP, H , Lactate in vascular smooth muscle
Vasopressin secretion
Nitric oxide synthase
Nitric oxide
Vasopressin stores
Open KCa
Open KATP
cGMP
Cytoplasmic Ca2
Plasma vasopressin
Phosphorilated myosin
VASODILATATION
N Engl J Med 2001,345588-595
46
VASOPRESSIN AND ITS ANALOGS

• Vasopressin levels are low in advanced stages of
  vasodilatory shock
• A significant body of evidence from small
  randomized controlled trials, prospective cohort
  studies, and retrospective case series,
  indicates beneficial hemodynamic effects of low
  dose replacement therapy with vasopressin or its
  analog
• Despite reversal of catecholamine resistance, no
  obvious improvement in outcome can be derived
  from the available data, due to the small sample
  size of the two RCTs
• The currently available data on the side effects
  of vasopressin treatment for septic shock
  expecially regarding the splanchnic circulation
  are very limited, detrimental changes in
  splanchnic perfusion, metabolism, cannot be
  predicted by markers of global tissue oxygenation
• It has to be recommended judicious use of these
  compounds ideally inside RCTs and with adequate
  monitoring of regional perfusion

47
VASOPRESSIN INFUSION IN SEPTIC SHOCK

• Relative depletion of circulating vasopressin has
  been identified in established septic shock, and
  there is increasing interest in the
  administration of low dose exogenous vasopressin
  as an alternative vasopressor agent
• It has been showed immediate and sustained
  increases in mean arterial pressure during low
  dose (0.04 U/min)vasopressin infusion in septic
  shock refractory to traditional vasopressor
  agents. Urine output increased, and no
  significant changes in cardiac function , heart
  rate, oxygenation, metabolic parameters, or serum
  levels of atrial natriuretic peptide,
  aldosterone, angiotensin II or renin were noted
  (Crit Care Med 200129487-493)
• In a double blind trial comparing 4 hour infusion
  of vasopressin and norepinephrine in patients
  with severe septic shock, it has been showed that
  all patients maintained stable mean arterial
  pressure and cardiac index , gastric mucosal
  carbon dioxide tension and electrocardiographic
  ST segments. In contrast to patients receiving
  norepinephrine infusions, patients receiving
  vasopressin demostrated increased urine output
  and creatinine clearance (Anesthesiology 2002
  96576-582)
• A single injection of terlipressin, a long acting
  vasopressin analog,into patients with
  norepinephrine resistant septic shock produced a
  significant increase in blood pressure that
  lasted for at least 5 hours (Lancet
  20023591209-1210)

48
AIRWAY AND LUNG IN SEPSIS 1

• Provide adequate supplemental oxygen to maintain
  an oximetric saturation of 90 through use of
  simple oxygen delivery systems (i.e., face mask,
  Venturi mask), if possible. In endotracheally
  intubated patients, use of positive end
  expiratory pressure (PEEP) to increase mean
  airway pressure may be employed to reduce
  concentrations of inspired oxygen below
  potentially toxic thresholds (FiO2lt0.60)
• Avoid the use of non invasive positive pressure
  ventilation (NIV) in patients with sepsis-related
  acute lung injury (ALI)/ acute respiratory
  distress syndrome (ARDS)
• Use early placement of an endotracheal tube and
  institution of mechanical ventilation in patients
  with sepsis . Indications for institution of
  mechanical ventilation include severe tachypnea
  (respiratory rate gt40 bpm), muscular respiratory
  failure (use of accessory muscles), altered
  mental status and severe hypoxemia despite
  supplemental oxygen

49

• Am J Respir Crit Care Med ( 1994) 149818-824
• Am J Respir Crit Care Med (2001) 163 A 449
  (abst)

50
AIRWAY AND LUNG IN SEPSIS 2

• In mechanically ventilated ALI/ARDS patients with
  high inspiratory pressures or otherwise at risk
  for barotrauma or volutrauma, implement
  premissive hypercapnia through reduced tidal
  volume ventilation
• Mechanical ventilation of patients with ALI
  should be conducted with small tidal volumes
  (approximately 6ml/Kg ideal body weight) with the
  goal to maintain end inspiratory plateau
  pressures at levels less than 30 cmH2O
• Prone positioning may be considered in patients
  requiring high levels of inspired oxygen
  (FiO2gt0.60) in whom positional changes are not
  controindicated, and who are cared for at
  facilities experienced in the management of
  critically ill mechanically ventilated patients
• Restrict nitric oxide as an option for salvage
  therapy in patients with life threatening
  hypoxemia not responding to traditional
  mechanical ventilation strategies
• Judicious use of crystalloid fluid administration
  should be practiced in patients with ALI/ARDS.,
  with colloid solutions considered in hypo-oncotic
  patients with established ALI/ARDS. It is not
  clear wheter or not volume restriction improves
  outcome
• Do not routinely administer corticosteroids to
  patients at risk for, or meeting criteria for,
  ALI/ARDS. Consider intravenous methylprednisolone
  in patients with persistent or refractory ARDS
  after actively excluding infection
• All patients requiring acceptable levels of
  ventilatory support who are not overtly unstable
  should receive a spontaneous breathing trial on a
  daily basis to ascertain their ability to breathe
  unassisted

51
Mortality prior to hospital discharge in patients
receiving a tidal volume of 6 and 12 ml/Kg ideal
body weight
P0.007
Mortality()
The ARDS Network Investigators. Ventilation with
lower tidal volumes as compared with traditional
tidal volumes for acute lung injury and the
acute respiratory distress syndrome. The ARDS
Network. N.Engl. J. Med 2000 3421301-8
52
MAIN OUTCOME VARIABLEThe Acute Respiratory
Distress Syndrome Network (NIH)N Engl J Med
2000 3421301-8
53
ALBUMIN AND FUROSEMIDE IN ACUTE LUNG INJURY A
LITTLE STEP FORWARD ( Crit Care Med 2002
302175-2182)

• Serum protein level of lt/ 5.0 g/dl
• ongoing nutritional support
• on mechanical ventilation gt/ 48 hours
• PROTOCOL
• Continuous infusion of furosemide (1mg/ml),
  maximum dose
• allowed 8mg/hr (maximum 192 mg/day)
• Concomitant infusion with 25 mg of 25 human
  serum albumin
• Patients in ALI
• Intravenously every 8 hrs for 5 days
• Daily weight loss of /gt 1 kg/day
• Infusion suspended for hypotension persisting gt30
  mins
• (SBP lt90 mmHg) , serum Na gt154meq/L , serum K
  lt2.6meq/L
• Albumin and furosemide therapy improves fluid
  balance,
• oxygenation, hemodynamic in hypoproteinemic
  patients with ALI
• (patients with mild disease?resolution of
  permeability problems?)

54
Clinical diagnosis of ALI
If 150 gt PaO2/FiO2 gt100
If PaO2/FiO2 lt 100
Colloids and diuresis
Colloids and CVVH
Colloids and CVVH
55
THE KIDNEY IN SEPSIS

• Renal failure developing in the ICU carries a
  poor prognosis while combined renal and
  respiratory failure carries a considerably worse
  prognosis than respiratory failure alone
• In the absence of disease modifying therapies, it
  is impossible to measure the impact on mortality
  for preventing acute renal failure
• Renal salvage with furosemide, while having some
  theoretical benefits on reducing tubular cell
  energy consumption and flushing of debris out of
  tubules and ducts, has never been shown
  convincingly to improve either renal function or
  survival
• Similarly , the use of dopamine to increase renal
  flow is probably not advantageous and may be
  detrimental
• De Mendoca A,Vincent JL,Suter PM et al (2000)
  Acute renal failure in the ICUrisk factors and
  outcome evaluated by the SOFA score. Intensive
  Care Med 26915-921
• Sweet SJ, Glenney CU, Fitzgibbons JP, Friedman P,
  Teres D (1981) Synergistic effect of acute renal
  failure and respiratory failure in the surgical
  intensive care unit. Am J Surg 141492-496
• Brezis M, Agmon Y, Epstein FH (1994) Determinants
  of intrarenal oxygenation. I. Effects of
  diuretics. Am J Physiol 267 F1059-F1062
• Bellomo R, Chapman M, Finfer S, Hicking K,
  Myburgh J (2000) Low dose dopamine in pazienta
  with early renal dysfunction a placebo
  controlled randomized trial. Australian and New
  Zealand Intensive Care Society (ANZIC) Clinical
  Trial Group. Lancet 3562139-2143
• Galley HF (2000) Renal dose dopamine will the
  message now get through? Lancet 3562112-2113

56
Administration of low dose dopamine by
continuous intravenous infusion (2µg/Kg/min/)
to critically ill patients at risk of renal
failure does not confer clinically significant
protection from renal dysfunction Low dose
dopamine in patients with early renal
dysfunction A placebo controlled randomized
trial (ANZICS clinical trials group) Lancet
2000 3562139-43
low dose of dopamine is thought to be harmless.
That is not true. DOPAMINE suppress
respiratory drive increase cardiac output
increase myocardial VO2 trigger myocardial
ischaemia, arrhytmias induce hypokalaemia,
hypophosphataemia predispose to gut ischaemia
disrupt metabolic, immunological homoeostasis
(action on T cells function) There is no
justification for using renal dose dopamine
in the critically ill
57
A
C
B
Normal nonstressed function of the
hypothalamic- pituitary-adrenal axis
Normal function of the hypothalamic-pituitary- adr
enal axis during illness
Corticosteroid insufficiency during acute illness
Central nervous system disease, corticosteroids

Reduced feedback
-
Hypothalamus
-
-
Stress cytokines
CTRH
CTRH
CTRH
Pituitary apoplexy, corticosteroids
Pitutary
-
-
-
-
ACTH
ACTH
ACTH
Cytokines, anesthetics antiinfective
agents corticosteroids hemorrage, infection
-
Adrenal
Decreased cortisol and Decreased
corticosteroid Binding globulin
Binding of cortisol to corticosteroid binding
globulin
Increased cortisol and decreased
corticosteroid binding globulin
Cytokines,local corticosteroid activation
Cytokines Glucocorticoid resistance
-

Increased action in tissue
Decreased action in tissue
Normal action in tissue
Activity of the Hypothalamic-Pitutary-Adrenal
Axis under Normal Conditions (A), during an
Appropriate Response to Stress (B) and during an
Inappropriate Response to Critical Illness ( C )
58
Potential effetcs of corticosteroids during
septic shock
Activation of IKB-a
Correction of a relative adrenocortical deficiency
Decreased trascription for proinflammatory
cytokines, Cox-2, ICAM-1, VCAM-1. Increased
transcription for IL-1-RA
Inhibition of NFk-b
Reversal of adrenergic receptor desensitization
deficiency
Inhibition of inducible iNOS
Hemodynamic improvement
Decrease in the dosage of catecholamines
59
Nonresolving acute respiratory distress syndrome
Critical illness (especially if features of
corticosteroids insufficiecy are present
Randomly, timed measurement of cortisol level
THE SCHEME HAS BEEN EVALUATED FOR PATIENTS WITH
SEPTIC SHOCK Annane et al. JAMA
2000 2831038-1045 Annane et al JAMA
2002 288862-871
lt15µg/dl
15-34µg/dl
gt34µg/dl
Increase in response to corticotropin test
lt9µg/dl
gt9µg/dl
Functional hypoadrenalism unlikely
Hypoadrenalism likely
Initiate pharmacologic glucocorticoid therapy
Consider physiologic Corticosteroid replacement
Corticosteroid therapy Unlikely to be helpful
Investigation of adrenal corticosteroid function
in critically ill patients on the basis of
cortisol levels and response to the corticotropin
stimulation test. It must be borne in mind that
no cutoff value will be entirely reliable
60
Mild illness or condition (nonfebrile cough or
cold Dental extraction with Local anesthetic)
Moderate illness or condition(fever, minor
trauma,minor surgery)
Severe illness or condition (major
surgery, trauma, critical illness
Septic shock (cathecolamine dependency,
poor response to ACTH)
Increase dose to 15mg of prednisolone/day
or equivalent
Increase dose to 50mg of Hydrocortisone IM or IV
every 6 hr
50 mg of Hydrocortisone IV Every 6 hr with or
without 50µg of Fludrocortisone/ day
Return to normal dose 24 hr after resolution
Taper dose to normal by decreasing by 50 per day
Treat for 7 days
No change
Suggested corticosteroid replacement doses during
intercurrent and acute illness in patients with
proven or suspected adrenal insufficiency,
including those receiving corticosteroid therapy
61
KYBERSEPT TRIAL

• IN CONTRAST TO THE FAVORABLE RESULTS ACHIEVED IN
  THE PROWESS TRIAL, THE KYBERSEPT TRIAL DID NOT
  MEET ITS PRIMARY GOAL OF A SIGNIFICANT REDUCTION
  IN 28 DAY ALL CAUSE MORTALITY.
• THE OVERALL MORTALITY RATE, 28 DAYS AFTER TRIAL
  ENTRY, WAS 38.9 IN THE ANTITHROMBIN GROUP
  (n1157) AND 38.7 (pNS) IN THE PLACEBO GROUP
  (n1157)

These results were particularly
disappointing, in that
treatment with
Antithrombin had been convincingly
demonstrated to be of survival advantage
in multiple preclinical sepsis models,
several phase II trials and numerous
randomized clinical studies
Dickneite
G Antithrombin in animal models of sepsis and
organ failure Semin Thromb Haemost 19982461-9

Baudo F, Caimi TM, de Cataldo F et al
AntithrombinIII (ATIII) replacement
therapy in patients with sepsis and/or post
surgical complications a double
blind, randomized, multicenter study.
Intensive Care Med 199824336-42
Eisele B,
Lamy M, Thijs LG et al Antithrombin III in
patients with severe sepsis. A
randomized, placebo controlled, double blind,
multicenter trial plus a
meta analysis on all randomized, placebo
controlled, double blind trials with
antithrombin III in severe sepsis
Intensive Care Med 199824663-72

Fourrier F, Joudain M, Tournoys A Clinical
trial results with
Antithrombin III in sepsis Crit Care Med
200028S38-43 Opal SM
Therapeutic rationale for antithrombin in sepsis
Crit Care Med 28S34-7




62
PROWESS TRIAL

• THE MORTALITY RATE IN THOSE PATIENTS RANDOMIZED
  TO THE DROTRECOGIN ALFA (activated) GROUP (n850)
  WAS 24,7, WHILE PATIENTS IN THE CONTROL GROUP
  (n840) HAD A MORTALITY OF 30,8 (p0,005).
• THIS INDICATES AN ABSOLUTE REDUCTION IN MORTALITY
  RATE OF 6,1 AND A RELATIVE RISK REDUCTION (RRR)
  OF 19,4 ASSOCIATED WITH DROTRECOGIN ALFA
  (activated) TREATMENT.
• THIS TRANSLATED INTO A NUMBER NEEDED TO TREAT OF
  16 TO PREVENT ONE DEATH BY 28 DAYS, CONSIDERABLY
  LOWER THAN THE NUMBER NEEDED TO TREAT OF 56 TO
  PREVENT ONE DEATH BY 35 DAYS FOR INTRAVENOUS
  THROMBOLYSIS IN ACUTE MYOCARDIAL INFACTION

THESE RESULTS ARE A WELCOME DEPARTURE FROM
THE ALMOST UNIFORMLY DISAPPOINTING OUTCOMES FROM
A MYRIAD OF OTHER RECENT , RANDOMIZED CLINICAL
TRIALS FOR SEVERE SEPSIS
Opal SM, Cross AS Clinical trials for severe
sepsis Past failures and future hopes Infect
Dis Clinics N Am 199913285-97
63
PROWESS TRIAL
number of dysfunctional organ systems at baseline
gt 4
11
22
24
3
8
2
5
20
1
2
8

64
PROWESS STUDY
Serious bleeding events were defined as any
intracranial hemorrhage, any life threatening
bleed, any bleeding event requiring the
administration of gt 3 units of packed red blood
cells per day for 2 consecutive days, or any
bleeding event assessed as a serious adverse event
65
rhAPC, an anticoagulant , is the first
antiinflammatory agent that has proved effective
in the treatment of sepsis in a large , well
designed PRCT the PROWESS TRIAL

• APPROPRIATE USE OF rhAPC
• Use as early as possible (24-48 hrs) in patients
  with a precise diagnosis of severe sepsis
• Use with an APACHE II of 25 ore more?
  DISCUSSION
• Use with one organ failure (remember that severe
  sepsis is a sepsis 1 Organ Failure
• Use with two organ failures ? DISCUSSION
• Do not use with INR of 3.0 or more
• Do not use with platelets of 30,000 or less ,not
  suggest its use with plateletslt80,000?
• Do not use in patients with an identifiable
  hemorrhagic predisposition,such as
  gastrointestinal ulceration, or known
  gastrointestinal bleeding
• Do not use in meningitis ? DISCUSSION
• Do not suggest its use with severe acidosis or
  low urine output?
• Control APTT, d-dimers and platelets in
  sequence (coagulation monitoring)
• Know that a serious bleeding is an intracranial
  hemorrhage, a life threatening bleeding episode
  or a requirement for 3 or more units of blood
• Know that a potential adverse effect of rhAPC is
  hemorrhage (potent anticoagulant)
• Know that rhAPC has a linear kinetics with levels
  generally undetectable within 4.5 hours of
  stopping infusion ( t1/2 ß 13 min at 12µg/kg/h
  and 1.6hr at 30µg/kg/hr)
• Use rhAPC at the dose of 24µg/kg/hr for 96 hrs
• Do not use rhAPC with other anticoagulants.
  Heparin too ? DISCUSSION

66
INTENSIVE INSULIN THERAPY IN CRITICALLY ILL
PATIENTS

• Hyperglycemia associated with insulin resistance
  is common in critically ill patients, even those
  who have not previously had diabetes
• It has been reported that pronounced
  hyperglicemia may lead to complications in such
  patients, although data from controlled trials
  are lacking
• In diabetic patients with acute myocardial
  infaction, therapy to maintain blood glucose at
  level below 215 mg/dl (11.9 mmol/L) improves the
  long term outcome
• In nondiabetic patients with protracted critical
  illnesses, high serum levels of insulin-like
  growth factor-binding protein 1, which reflect an
  impaired response of hepatocytes to insulin,
  increase the risk of death
• Hyperglicemia or relative insuline deficiency (or
  both) during critical illness may directly or
  indirectly confer a predisposition to
  complications, such as severe infections,
  polyneuropathy, multiple organ failure and death

67
INTENSIVE INSULIN THERAPY IN CRITICALLY ILL
PATIENTS

• The group of Greet Van Den Berghe in Leuven
  performed a prospective, randomized, controlled
  trial to determine whether normalization of blood
  glucose levels with intensive insulin therapy
  reduces mortality and morbidity among critically
  ill patients
• The use of exogenous insulin to maintain blood
  glucose at a level no higher than 110 mg/dl
  reduced morbidity and mortality among critically
  ill patients in the surgical intensive care unit,
  regardless of whether they had a history of
  diabetes
• The result of the study offer a possible
  explanation of the failure of growth hormone (GH)
  therapy as anabolic treatment in patients with
  prolonged critical illness
• Growth hormone (GH) aggravates insulin
  resistance and hyperglycemia and doubles the
  mortality rate among critically ill patients,
  mainly because of multiple organ failure and
  sepsis

• Van Den Berghe G et al. N Engl J Med
  200113451359-67
• Takala J. et al.N Engl J Med 1999 341785-92

68
Mortality results
Insulin treatment ()
After correction for multiple interim analyses,
adjusted P0.036
69
INTENSIVE INSULIN THERAPY IN CRITICALLY ILL
PATIENTSmedian unbiased estimate of the
reduction in mortality 32 (adjusted
95confidence interval, 2 to 55 Plt0.04
Cumulative TISS 28 score gt5 days of ICU
median interquartile range
lt0.001
563 329-956
431 271-670
70
Appropriate action depending on blood glucose
level
71
OTHER SUPPORTIVE THERAPY IN SEPSIS 1

• Considering the frequent occurrence of
  independent risk factors for
• Deep Vein Thrombosis (DVT) in septic patients
  and the high percentage of sepsis /infected
  patients included in studies that have
  demonstrated efficacy of DVT prophylaxis in
  general, septic patients should be treated with
  DVT prophylaxis. Even though there is not a
  randomized study that establishes the impact of
  DVT prophylaxis on morbidity and mortality
  specifically in septic patients, the significant
  number of septic patients included in the
  populations of patients enrolled in other
  prospective randomized trials supports that the
  use of DVT prophylaxis reduces morbidity and
  mortality in septic patients.
• Septic patients who do not have a
  controindication to heparin use should receive
  prophylaxis with either low dose unfractioned
  heparin (5.000 U either two or three times daily)
  or low molecular weight heparin (At recommended
  doses grade A)
• For those septic patients who have an absolute
  controindication for heparin use (ie,
  thrombocytopenia, severe coagulopathy, active
  bleeding, recent intracerebral hemorrhage), the
  use of a mechanical prophylactic device is
  advised since this method has proven to be
  effective in postsurgical patients and therefore
  would likely work in septic patients (grade E)

72
Glycogen
COUNTER REGULATORY HORMONES CYTOKINES STRESS
Glucose
Pyruvate
Alanine
Glycolysis
LIVER
Glucose Pyruvate
Glucose Lactate
Gluconeogenesis
glycogen
Alanine
Lactate
Alanine
Lactate pyruvate
Glycolysis
Glycerol
Amino acids
Proteinolysis
Lipolysis
73
Glycogen Glucose-6-phosphate Pyruvate Acetyl
CoA
GLYCOGENOLYSIS
Glucose
GLUCOSE METABOLISM AND PATHWAYS OF PYRUVATE
GLYCOLYSIS
GLUCONEOGENESIS
ALT
LDH
Lactate
Alanine
PDH
Lipogenesis
Krebscycle oxidation

• Avoid hyperglycemia (blood glucose lt9mmol/l or
  even lt6mmol/l)
• Limit exogenous insulin treatment up to
  approximately 4-6 IU/l to prevent hepatic
  steatosis
• Adapt calorific support and/or consider replacing
  glucose by non glucose carbohydrates
• Use lipid emulsions to reduce CO2 load
  (tryglyceride levels lt3.5 mmol/l)
• Avoid epinephrine and pure alfa agonists

74
OTHER SUPPORTIVE THERAPY IN SEPSIS 2

• Sepsis produces a hypercatabolic state and leads
  to protein-energy malnutrition
• Protein loss is associated with poor outcome
• Nutritional support in septic patients is
  recommended
• The correlation of nutritional support with
  outcome in septic patients comes from data
  extrapolated from studies performed in
  perioperative patients and from expert opinion
  that allow us to establish this recommendation.
  Many important questions remain regarding what
  kind of nutrition and when in the course of
  sepsis should nutrition begin
• Enteral nutrition is the preferred method of
  nutritional support in the catabolic critically
  ill patient in general, inclusive of the septic
  patient (grade C).
• For those patients who cannot tolerate enteral
  nutrition for prolonged time or when
  contraindications do not allow its use
  (mesenteric ischemia, mechanical bowel
  obstruction), parenteral nutritional support
  should be used (grade E).
• Immune enhancing formulas may be better than
  other enteral formulations in critically ill
  patients, but effects on ultimate outcome (i.e.,
  survival) remain to be demonstrated in large
  randomized trials (grade B)

75
OTHER SUPPORTIVE THERAPIES IN SEPSIS 3

• The following are specific recommendations for
  septic patients, according to the guidelines
  established by the American College of Chest
  Physicians and American Society of Parenteral and
  Enteral Nutrition consensus conferences
• Daily caloric intake 25-30 kcal/kg usual body
  weight
• Protein 1.3-2.0 g/Kg per day
• Glucose 30-70 of total non protein calories,
  to maintain serum glucose level below 225 mg/dl
  (or serum glucose strict control with insulin)
• Lipids 15-30 of total non protein calories. O 6
  polyunsaturated fatty acid should be reduced in
  septic patients, maintaining that level which
  avoids deficiency of essential fatty acids (7 of
  total calories- generally 1g/kg per day)
• No specific recommendations are offered for use
  of medium chain triglycerides, branched chain
  amino-acids, or specific microelements added to
  the nutritional formulas. The use of any of these
  strategies , although supported in concept, does
  not have enough investigational evidence to
  determine any clinical benefit in outcome of
  septic patients

76
OTHER SUPPORTIVE THERAPIES IN SEPSIS 4

• No randomized trial has evaluated the effect of
  stress ulcer prophylaxis (SUP) on clinical
  outcome in septic patients. Therefore no
  definitive data exist in septic patients on the
  effectiveness of SUP in diminishing episodes of
  overt or clinically significant bleeding.
• Although no large randomized trial has addressed
  septic patients alone, abundant data exist
  regarding subgroups of septic patients with
  prolonged mechanical ventilation, hypotension and
  coagulopathy. For these patients the use of SUP
  is recommended (grade A). For other septic
  patients , SUP is recommended based on several
  small randomized trials in which SUP has proven
  efficacious in preventing bleeding and therefore
  reducing morbidity in critically ill patients
  (grade C)
• Several trials have confirmed the efficacy of
  antacids , sucralfate or histamine 2 receptor
  antagonists in the prevention of stress ulcer
  bleeding. Since the data are conflicting, no
  single one can be determined as preferable.
  General recommendations should be based on the
  individual experience in the use of one or
  another, the availability, or cost analysis in
  individual centers. In septic patients with risk
  factors , the use of enteral nutrition following
  the preventive strategies currently available may
  be beneficial for preventing stress ulcer bleeding

77
Selective decontamination of the digestive trait
(SDD) schemes and outcomes of prospective
randomized trials
78
ANTIOXIDANTS AND ENDOTHELIAL FUNCTION
THERAPEUTIC IMPLICATIONS

• The value of antioxidant supplementation in
  intensive care medicine is currently unclear.
  While some studies have shown positive effects on
  outcome, there are other studies which suggest
  that antioxidants are of no benefit. The problem
  may be related to the time of therapy. Those
  studies where antioxidants were initiated early
  in the course of illness generally show
  beneficial effects
• N-acetylcysteine significantly atenuates
  endotoxin induced alterations in
  leukocyte-endothelial adhesion and macromolecular
  leakage
• In a small prospective study in 18 trauma
  patients, the group of patients prophylactically
  treated with antioxidand showed fewer infectious
  complications (8 vs 18) and less frequent organ
  dysfunction (zero vs 9)
• In a prospective study in 37 severely burned
  patients the group of patients treated with high
  dose ascorbic acid (66mg/Kg/h) during the first
  24 hours after injury significantly reduced
  resuscitation fluid volume requirements, body
  weight gain and wound edema. A reduction in the
  severity of respiratory dysfunction was also
  apparent. The study did not show a reduction in
  mortality
• Antioxidant therapy may prevent endothelial
  dysfunction if given prophylactically or very
  early

79
ANTIOXIDANTS AND ENDOTHELIAL FUNCTION
THERAPEUTIC IMPLICATIONS

• Apart from the timing of therapy, there are other
  explanations why some antioxidants studies have
  failed to show a benefit in the critically ill
• In order to scavenge superoxide, antioxidants
  must be administered in very high concentrations
• Recycling processes are also important. When
  a-tocopherol react with a radical , it becomes
  the a-tocopheroxyl radical, which itself may
  partecipate in pro-oxidative events. Adequate
  concentrations of ascorbate are necessary for
  recycling of a-tocopherol. Glutathione is also
  required for the recycling of ascorbate.
• It seems likely therefore, that optimal
  antioxidant therapy may require a combination of
  different antioxidants
• Schmidt H,Schmidt W, Muller T, Bohrer H, Gebhard
  MM, Martin E (1997) NAC attenuates endotoxin
  induced leukocyte endothelial adhesion and
  macromolecular leakage in vivo . Crit Care Med
  25858-863
• Porter JM, Ivatury RR, Azimuddin K, Swami R
  (1999) Antioxidant therapy in the prevention of
  organ dysfunction syndromr and infections
  complications after trauma early results of a
  prospective randomized study. Am Surg 65478-483
• Tanaka H, Matsuda T, Miyagantani Y, Yukioka T,
  Matsuda H, Shimazaki S (2000) Reduction of
  resuscitation fluid volumes in severely burned
  pazienta using ascorbic acid administration. Arch
  Surg 135326-331
• Jackson TS, Xu A, Vita JA, Keaney JFJ (1998)
  Ascorbare prevents the interaction of superoxide
  and nitric oxide only at very high physiological
  concentrations. Circ Res 83916-922

80
ANTIOXIDANT SUPPLEMENTATION IN CRITICALLY ILL
PATIENTS
Antioxidant supplementation within 24 hours of
admission to the ICU a-tocopherol
(dl-a-tocopheryl acetate 1,000 IU q8h per naso
or oro-gastric tube and 1,000 mg ascorbic acid
given intravenously in 100 ml D5W q8h for the
shorter of the duration of admis