cell-injury periop course revisedok
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Cell InjuryCell Injuryin relation with the patho-physiology of in relation with the patho-physiology of
peri-operative problemsperi-operative problems
Kiki LukmanDivision of Digestive Surgery, Dept. of Surgery
Hasan Sadikin Hospital/Medical School of Universitas Padjadjaran
Introduction : Introduction : Common Critically Surgical illnessesCommon Critically Surgical illnesses
What happens?
– Multiple injuries: airway & breathing problems, bleeding, pain
– Hypoxia/ischemia– Cell injury– Inflammation: SIRS– Metabolic changes– MODS, MOF?
Introduction :Introduction : Common Critically Surgical illnessesCommon Critically Surgical illnesses
What happens?– Infection– Local inflammation:
vasodilatation, microvasc. permeability , WBC accumulation
– SIRS, MODS, MOF?– Abdominal
compartment syndrome
Introduction :Introduction : Common Critically Surgical illnessesCommon Critically Surgical illnesses
What happens?
– Mechanical obstruction– Ischemia– Sepsis – MODS ? MOF?
Challenges: Challenges: Resuscitation & SurgeryResuscitation & Surgery
Introduction :Introduction : Common Elective SurgeryCommon Elective Surgery
What seems to be the problems?– What is the cancer
stage?– Is it operable?
Resectable?– Any comorbid diseases?– Risk of surgery?
Common concomitant problems Common concomitant problems in surgical patients in surgical patients
Respiratory problems , e.g. COPDCardiovascular problems, e.g. ASHD:
OMI, HypertensionRenal problemsEndocrinal diseases, e.g. DiabetesLiver diseases, etc.Hematological problems
Problems (1) : Pre-operative Problems (1) : Pre-operative carecare
What happens to the Organs (disease process)?
What happens to the cells ?
What would happen if there is any co-morbid diseases?
How do we manage the patient ?
Problems (2) : Post-operative careProblems (2) : Post-operative care
What will happen to the patient ?
– Patient responses to surgery ?
– Damage control surgery: Recovery ?
– Complications : SIRS, MODS, MOF ?
– The need of Intensive care Unit ?
– Prognosis ?
What is the answer ?What is the answer ?
The answer:The answer:
Pathogenesis of the underlying diseases:– Primary surgical diseases
Patho-physiology of concomitant diseases/disorders The physiologic responses to injury (surgery)
The mechanisms of organ injury “ The pathology of Cell Injury”
Why Cell ?Why Cell ?
The Holy Qur’an (61): As Shaff 1Whatever is In the heavens an on Earth, declares The Praises and Glory of Allah: for He is The Exalted in Might, The Wise.
Prof. DR. Nurhalim Shahib, dr. :“ Cellular Molecular declares The Praises and Glory of Allah”
Cell Survival: Cell Survival: Range of functions & structuresRange of functions & structures
Genetic programs of metabolisms, differentiation, & specialization
Constraints of neighboring cells
Availability of metabolic substrates
DefinitionDefinition
Cell Injury :
Functional and structural cell changes as a result from the failure of cell adaptation to overcome the physiologic stress or pathologic stimuli that disturbs normal homeostasis. (Robbins, 2005)
Cell responses to injuryCell responses to injuryNORMAL CELL(homeostasis)
ADAPTATION CELL INJURY
Stress,Increased
demand
InabilityTo adapt
Injuriousstimulus
CELL DEATH
Etiology:Etiology:
Oxygen deprivation: ischemia & hypoxiaPhysical agentsChemical agents and drugsInfectious agents Immunologic reactionsGenetic derangementsNutritional imbalances
Cellular Responses to injuryCellular Responses to injury Acute injury:
– Reversible injury– Cell Death (Irreversible injury)
NecrosisApoptosis
Sub-cellular alterations Cellular adaptation Intracellular accumulation Pathologic calcification Cell aging
Cell InjuryCell Injury
Cell responses to injuryCell responses to injury
General principles of cell injuryGeneral principles of cell injury
The cellular response to injurious stimuli depends on the type of injury, its duration and its severity.
The consequences of cell injury depend on the type, state, and adaptability of the injured cell.
General principles of cell injuryGeneral principles of cell injury
The structural & biochemical element of the cell are so closely interrelated that whatever the precise point of initial attack, injury at one locus lead to wide ranging secondary effects.
General principles of cell injuryGeneral principles of cell injury
The morphologic changes of cell injury become apparent only after some critical biochemical system within the cell has been changed.
Four vulnerable intracellular systems: cell membrane integrity, aerobic respiration, protein synthesis, preservation of the integrity of genetic apparatus of the cell.
Figure 1-10 Cellular and biochemical sites of damage in cell injury.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 31 March 2005 03:59 PM)© 2005 Elsevier
Biochemical mechanismsBiochemical mechanisms
Cell responses to Cell responses to ischemia/hypoxiaischemia/hypoxia
ApoptosisApoptosisProgrammed cell death (regulated by DNA)
describes a set of regulated physiologic and morphologic changes leading to cell death
No inflammation
Termination of inflammation once infection has subsided
Cell apoptosisCell apoptosis
Determining factors:Determining factors:
Intensity and duration of the stimulusThe rapidity of the death processThe extent of ATP depletion by the cell
Necrosis & apoptosis overlap and share certain Necrosis & apoptosis overlap and share certain common mechanismcommon mechanism
What happens in major trauma What happens in major trauma and surgery ?and surgery ?
Physiologic response to injury Physiologic response to injury (1): (1): The philosophyThe philosophy
Initial physiologiccondition
PhysiologicPhysiologicResponse :Response :
CNSCNShormonalhormonal
immune systemimmune systemmediatorsmediatorsmetabolicmetabolic
New Equilibrium:
Adjusted physiologiccondition
Death ?Sequelae?
Insult :Insult :InjuryInjury
Surgery Surgery ++
SupportiveSupportivetreatmentstreatments
Physiologic responses to Physiologic responses to injury (2) :injury (2) :
What happens in major trauma?What happens in major trauma?Insult
InjuryFear
Severe injuryShock - Severe injury
+ shock
Pain
Pro-inflammatoryresponses
Pro-inflammation Counter-inflammation
Pro ~ CounterInflammation
SIRS MARS CARS ISCHEMIA
VisceroCutaneus
reflex
Massive dyshomeostasis induced Massive dyshomeostasis induced by major traumaby major trauma
Faist E, Angele M & Wichmann M, Trauma 5th edit. 2004
Central asphyxiaLow flow conditions
Debris
Hemorrhage
Airway obstruction
Major Trauma
Immuno-inflammatoryresponse
dyshomeostasis
Bacterial invasion
SEPSIS
Bacterial/endotoxintranslocation
Severe chest injury
Inflammation
Counter Inflammation
Sequential events
Immuno depression
Clinical sequences of SIRS & MODSClinical sequences of SIRS & MODS
Cellular metabolism in Cellular metabolism in ischemia/hypoxiaischemia/hypoxia
RespiratoryEnzymeChain
CitricAcid
Cycle
GlycolysisGlucose Pyruvate
Lactate
NAD+
NADPH
ANAEROBICANAEROBIC
AEROBICAEROBICCO2
Oxygen
2ATP
36ATP
H2O
NAD+
NADPH
NADPH : Nicotinamide Adenine Dinucleotide NADPH : Nicotinamide Adenine Dinucleotide PhosphatePhosphate
Metabolic changes: Increased Metabolic changes: Increased anaerobic metabolismsanaerobic metabolisms
TNF, IL-1,6
Metabolic changes:Metabolic changes:
Triglyceride
TNF
Fatty acid
glycerol
CAPILLARY
MITOCHONDRIAFatty acids ATP
oxidationFatty acid
Carnitine
TNF,IL-1
Triglycerides CYTOPLASMA
SIRS in critically ill patientsSIRS in critically ill patients
Capillary leak in late shockCapillary leak in late shock
Nitric Oxide ProductionNitric Oxide Production
The effects of NOSThe effects of NOS
Decompensated shock: Vasodilatory Decompensated shock: Vasodilatory shockshock
Mechanism of cellular death in Mechanism of cellular death in hemorrhagehemorrhage
Hemorrhage
ATP/ADP depletion
Free radicalsInflammatory mediators
Mitochondrial disruption
Xanthine oxydase
Stress
- ATP+ ATP
Apoptosis Necrosis
Coagulopathy in trauma - 1Coagulopathy in trauma - 1 Massive hemorrhage after traumatic injury is frequently
a combination of surgical and coagulopathic bleeding Results from impairments in platelet function, fibrin
formation, or enhanced degradation, or combination of all these mechanisms
Early coagulopathy post-injury is observed in 25% to 36% of trauma victims upon admission to the emergency department and correlate with severity of trauma
Coagulopathy can develop during, or the result of the “Traditional Aggressive” fluid resuscitation of hemorrhagic shock
It can also develop late, due to surgical complications such as sepsis or MOF
Coagulopathy in trauma - 2Coagulopathy in trauma - 2
Pathophysiology of Lethal triad of death Pathophysiology of Lethal triad of death
Coagulopathy
Severe trauma Bleeding
Acidosis
Tissuehypoxia
Hypothermia
Colloid andCrystalloid infusion
Dilution of Coagulation factors
And platelets
Massive RBCtransfusion
Moore EE : Am J Surg 172: 405-410 1996
What happens in SEPSIS ?What happens in SEPSIS ?
Definition : Systemic Inflammatory Responses Syndrome due to infection (ACCP-SCCM – Consensus, 1992)
((ACCP-SCCM - Consensus Conference Chest, ACCP-SCCM - Consensus Conference Chest, 1992 : 1001 - 1004 )1992 : 1001 - 1004 )
Early event of Acute Early event of Acute InflammationInflammation
Toll Like ReceptorToll Like Receptor
Degree of host responsesDegree of host responses
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 31 March 2005 03:59 PM)
Malignant intravascular Malignant intravascular inflammation in sepsisinflammation in sepsis
Alterations of coagulation Alterations of coagulation cascadecascade
Balance of Coagulation +
Precipitating Event(e.g. infection or sepsis)
Tissue Factor Release
Excess Thrombin
Microvascular
Clotting
ThrombocytopeniaFibrinolysis with Excess
FDPs
IschemiaImpaired Organ Perfusion
End-Organ Damage
Conversion of PlasminogenTo Plasmin
Microvascular
Clotting
Consumption ofClotting Factors
Excess Clotting Excess Bleeding
ShockHypotension
Increased Vascular Permeability
Mechanisms of Mechanisms of DICDIC
Severe SepsisSevere Sepsis
Metabolic failureMetabolic failure
ARDSARDS
Robert W. Schrier, M.D., Wei Wang, M.D., NEJM,Robert W. Schrier, M.D., Wei Wang, M.D., NEJM, Volume 351:159-169Volume 351:159-169 July 8, 2004 Number 2Number 2
Renal FailureRenal Failure
Robert W. Schrier, M.D., Wei Wang, M.D., NEJM,Robert W. Schrier, M.D., Wei Wang, M.D., NEJM, Volume 351:159-169Volume 351:159-169 July 8, 2004 Number 2Number 2
What is the outcome?What is the outcome?
What Happens in the Abdominal What Happens in the Abdominal Compartment Syndrome ?Compartment Syndrome ?
Release of Mediators in IAH Release of Mediators in IAH & ACS& ACS
PrimedPrimedWBCsWBCs
PrimedPrimedWBCsWBCs
PrimedPrimedWBCsWBCs
PrimedPrimedInflammatoryInflammatory
CellsCellsLung
Liver
Gut
OtherOrgans
Systemic Releaseof Cytokines
Local Activation ofInflammatory Cells
LOCALLOCALTISSUETISSUE
RESPONSERESPONSE
INITIAL INSULTINITIAL INSULT
SYSTEMIC RELEASE OFTOXIC MEDIATORS
GENERALIZED TISSUE INJURY
“First Hit” POST INJURYPOST INJURYSystemic Activation of
Inflammatory Cells“Second Hit”
Demling et al. Surg Clin North Am 74(3); 1994., by modification
The Vicious Circle created by The Vicious Circle created by IAHIAH
Splanchnic hypoperfusion
Hepatic ischemia Gut mucosal acidosisBowel edema
CoagulopathyHypothermia
Acidosis
Intra-abdominalbleeding
IAH
unrelieved
ACS
Free oxygen radicalsDistant organ damage
Ivatury RR et al. Surg Clin North Am 1997; 77: 796.IAH : Intraabdominal hypertension, ACS : Abdominal Compartment Syndrome
Conclusions:Conclusions:
Cell injury forms the basis of the patho-physiological process of organ responses in surgical patients.
Inflammation is an essential response to physiological derangements in surgical patients.
Conclusions:Conclusions:
Over whelming injurious stimuli may lead to systemic inflammatory responses syndrome that can give rise to uncontrolled physiological derangements (organ dysfunctions)
The understanding of cellular biology in surgical patients is essential for surgeons in managing peri-operative problems
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