Cell Injury

in relation with the patho-physiology of

peri-operative problems
Kiki Lukman
Division of Digestive Surgery, Dept. of Surgery
Hasan Sadikin Hospital/Medical School of Universitas Padjadjaran

Introduction :
Common Critically Surgical illnesses

What happens?
Multiple injuries: airway &

breathing problems,
bleeding, pain
Hypoxia/ischemia
Cell injury
Inflammation: SIRS
Metabolic changes
MODS, MOF?

Introduction :
Common Critically Surgical illnesses
What

happens?

Infection
Local inflammation:

vasodilatation,
microvasc.
permeability , WBC
accumulation
SIRS, MODS, MOF?
Abdominal
compartment
syndrome

Introduction :
Common Critically Surgical illnesses
What happens?
Mechanical obstruction
Ischemia
Sepsis
MODS ? MOF?

Challenges:
Resuscitation & Surgery

Introduction :
Common 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

in surgical patients
Respiratory

problems , e.g. COPD

Cardiovascular problems, e.g. ASHD:
OMI, Hypertension
Renal problems
Endocrinal diseases, e.g. Diabetes
Liver diseases, etc.
Hematological problems

Problems (1) : Pre-operative

care
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 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 ?

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 ?
The

Holy Quran (61): As Shaff 1

Whatever 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:
Range of functions & structures
Genetic programs of

metabolisms,
differentiation, &
specialization
Constraints of
neighboring cells
Availability of metabolic
substrates

Cell signaling system

Definition
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 injury

NORMAL CELL
(homeostasis)
Stress,
Increased
demand

Injurious
stimulus

ADAPTATION
Inability
To adapt

CELL INJURY
CELL DEATH

Etiology:
Oxygen

deprivation: ischemia & hypoxia

Physical agents
Chemical agents and drugs
Infectious agents
Immunologic reactions
Genetic derangements
Nutritional imbalances

Cellular Responses to injury

Acute

injury:

Reversible injury
Cell Death (Irreversible injury)

Necrosis
Apoptosis
Sub-cellular

alterations
Cellular adaptation
Intracellular accumulation
Pathologic calcification
Cell aging

Cell Injury

Cell responses to injury

General 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 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 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.

Biochemical mechanisms

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

Cell responses to
ischemia/hypoxia

Apoptosis
Programmed

cell death (regulated by DNA)

describes a set of regulated physiologic and
morphologic changes leading to cell death

No

inflammation

Termination

has subsided

of inflammation once infection

Cell apoptosis

Determining factors:
Intensity

and duration of the stimulus

The rapidity of the death process
The extent of ATP depletion by the cell
Necrosis & apoptosis overlap and share certain
common mechanism

What happens in major trauma

and surgery ?

Physiologic response to injury

(1):
Surgery
The philosophy
+
Insult :
Injury

Initial
physiologic
condition

Supportive
treatments

Physiologic
Response :
CNS
hormonal
immune system
mediators
metabolic

New
Equilibrium:
Adjusted
physiologic
condition

Death ?
Sequelae?

Physiologic responses to
injury (2) :

What happens in major trauma?

Insult
Fear

Injury
Pain
Severe injury
Shock -

Pro-inflammation

Pro-inflammatory
responses

Counterinflammation

Severe injury
+ shock
Pro ~ Counter
Inflammation

SIRS MARS CARS

Viscero
Cutaneus
reflex

ISCHEMIA

Massive dyshomeostasis induced

by major trauma
Major Trauma

Hemorrhage

Central asphyxia

Low flow conditions

Airway obstruction

Debris
Bacterial/endotoxin
translocation

Severe chest injury

Immuno-inflammatory
response
dyshomeostasis

Inflammation

Sequential events

Bacterial invasion
Counter Inflammation
Immuno depression

SEPSIS

Faist E, Angele M & Wichmann M, Trauma 5th edit.

Clinical sequences of SIRS & MODS

Ischaemic injury

Cytokines effect on SIRS

Cellular metabolism in
ischemia/hypoxia
CO
2

36ATP
Oxygen

AEROBIC
NAD+

Respiratory
Enzyme
Chain

NADPH

Citric
Acid
Cycle

H2O
2ATP

Glucose

ANAEROBIC

Glycolysis

Pyruvate
NAD+
NADPH

NADPH : Nicotinamide Adenine Dinucleotide

Lactate

Metabolic changes: Increased

anaerobic metabolisms
TNF, IL-1,6

Metabolic changes:

CAPILLARY

TNF,IL-1

Triglyceride

MITOCHONDRIA
Carnitine

Fatty acids

ATP

TNF
Fatty acid

Fatty acid
Triglycerides

glycerol

oxidation

CYTOPLASMA

SIRS in critically ill patients

Capillary leak in late shock

Nitric Oxide Production

The effects of NOS

Decompensated shock: Vasodilatory

shock

Mechanism of cellular death in

hemorrhage
Hemorrhage

Stress

ATP/ADP depletion

Xanthine oxydase

Inflammatory mediators

Free radicals

Mitochondrial disruption

+ ATP
Apoptosis

- ATP
Necrosis

Coagulopathy 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 in trauma - 2
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

Pathophysiology of Lethal triad of death

Coagulopathy

Acidosis
Severe trauma

Bleeding

Tissue
hypoxia
Hypothermia

Colloid and
Crystalloid infusion
Massive RBC
transfusion
Moore EE : Am J Surg 172: 405-410 1996

Dilution of
Coagulation factors
And platelets

What happens in SEPSIS ?

Definition :
Systemic Inflammatory Responses
Syndrome due to infection
(ACCP-SCCM Consensus, 1992)

(ACCP-SCCM - Consensus Conference Chest,

1992 : 1001 - 1004 )

Early event of Acute

Inflammation

Immune responses in
Sepsis

Toll Like Receptor

Degree of host responses

Downloaded from: Robbins & Cotran

Pathologic Basis of Disease (on 31 March
2005 03:59 PM)

Malignant intravascular
inflammation in sepsis

Alterations of coagulation
cascade

Balance of Coagulation +
Precipitating Event
(e.g. infection or sepsis)

Mechanisms of
DIC

Tissue Factor Release

Excess Thrombin
Microvascular

Microvascular

Clotting

Clotting

Thrombocytopenia

Consumption of
Clotting Factors

Conversion of Plasminogen
To Plasmin

Fibrinolysis with Excess

FDPs

Excess Clotting

Excess Bleeding

Ischemia
Impaired Organ Perfusion
End-Organ Damage

Shock
Hypotension
Increased Vascular Permeability

Severe Sepsis

Metabolic changes

Metabolic failure

ARDS

Robert W. Schrier, M.D., Wei Wang, M.D., NEJM,

Volume 351:159-169 July 8, 2004 Number 2

Renal Failure

Robert W. Schrier, M.D., Wei Wang, M.D., NEJM,

Volume 351:159-169 July 8, 2004 Number 2

What is the outcome?

Determinants of outcome

Clinical sequelae

What Happens in the Abdominal

Compartment Syndrome ?

Release of Mediators in IAH

& ACS
First Hit

POST INJURY

Systemic Activation of
Inflammatory Cells

Second Hit

Primed
Inflammatory
Cells

Lung
INITIAL INSULT
Local Activation of
Inflammatory Cells

LOCAL
TISSUE
RESPONSE

Systemic Release
of Cytokines

Liver

Primed
WBCs

Gut

Primed
WBCs

Other
Organs

Primed
WBCs
SYSTEMIC RELEASE OF
TOXIC MEDIATORS

Demling et al. Surg Clin North Am 74(3); 1994., by modification

GENERALIZED TISSUE INJURY

The Vicious Circle created by

IAH
Splanchnic hypoperfusion
Hepatic ischemia

Coagulopathy
Hypothermia
Acidosis

Gut mucosal acidosis

Bowel edema

IAH

unrelieved
Free oxygen radicals
Distant organ damage
Intra-abdominal
bleeding

ACS

Ivatury RR et al. Surg Clin North Am 1997; 77: 796.

IAH : Intraabdominal hypertension, ACS : Abdominal Compartment Syndrome

Conclusions:
Cell

injury forms the basis of the pathophysiological process of organ responses in

surgical patients.

Inflammation

is an essential response to
physiological derangements in surgical
patients.

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