Progressive Shock by sanmelody


									Pathophysiology of Shock
Physiology of Perfusion

 -   Body cells require a constant supply of oxygen and nutrients and
     elimination of carbon dioxide and waste products
 -   Needs fulfilled by circulatory system in conjunction with respiratory
     and gastrointestinal systems
1.   Pump ( heart)‫‏‬
2.   Content (blood)‫‏‬
3.   Container (blood vessels)‫‏‬
 Any derangement of any of these components can affect
 Tissue Perfusion
 Tissue perfusion is dependent on circulatory system and oxygenation by
     respiratory system
 Inadequate tissue perfusion caused by
     - Inadequate pump
 •    Inadequate preload
 •    Inadequate cardiac contractile strength
 •    Excessive afterload
 •    Inadequate heart rate
     - Inadequate fluid volume
 •   Hypovolemia
  - Inadequate container
 • Excessive dilation without change in fluid volume
 • Excessive systemic vascular resistance

Shock is a condition in which the cardiovascular system fails to perfuse tissues
adequately. Inadequate tissue perfusion can result in:
    generalized cellular hypoxia (starvation)        widespread impairment of
    cellular metabolism        tissue damage      organ failure     death
1- Hypovolemic shock (decreased blood volume)‫‏‬

•   Hemorrhage ( Internal or external)‫‏‬
•   Surgery
•   Burns
•   Dehydration from GI losses
•   Diabetic ketoacidosis
•   Excessive sweating

2-Distributive shock (marked vasodilatation; Also called Vasogenic
   or low resistance shock)‫‏‬
• Fainting (neurogenic shock)‫‏‬
• Anaphylaxis
• Sepsis (also causes hypovolemia due to increased capillary
   permeability with loss of fluid into tissues)‫‏‬
• Anesthesia
• CNS injuries
• Addisonian crisis
• No sympathetic response
3- Cardiogenic shock (inadequate output by a diseased heart)‫‏‬
• Myocardial infarction
• Congestive heart failure, Heart valve dysfunction
• Arrhythmias

4- Obstructive shock (obstruction of blood flow)‫‏‬
• Tension pneumothorax
• Pulmonary embolism
• Cardiac tumor
• Cardiac tamponade

              Low blood volume

              Low venous return

              Low cardiac output

      Fall in systolic blood pressure

             Fall in pulse pressure

          Diminished blood flow to

Low Po2          High Pco2            High [H+]
   All Types of shock eventually result in impaired tissue perfusion & the
   development of acute circulatory failure or shock syndrome.

        Cells switch from aerobic to anaerobic metabolism

                             lactic acid production

                        Cell function ceases & swells

                    membrane becomes more permeable

                   electrolytes & fluids seep in & out of cell

                            Na+/K+ pump impaired

                             mitochondria damage
                                    cell death
COMPENSATORY MECHANISMS (-ve FB): Sympathetic Nervous System
(SNS)-Adrenal Response
  1- SNS - Neurohormonal response Stimulated by baroreceptors
  Increased heart rate
  Increased contractility
  Vasoconstriction (Afterload) (the effect is greater
  in maintaining BP than COP) [Br,& H are spared constr]
  Increased Preload
  2- Renin-angiotension system
  Decrease renal perfusion
  Releases renin           angiotension I
  angiotension II           potent vasoconstriction &
  releases aldosterone from adrenal cortex
  sodium & water retention
  3- Antidiuretic Hormone
  Osmoreceptors in hypothalamus stimulated
  ADH released by Posterior pituitary gland
     -Vasopressor effect to increase BP
     -Acts on renal tubules to retain water
4- Adrenal Cortex
Anterior pituitary releases adrenocorticotropic hormone (ACTH)‫‏‬
Causing the adrenal Cx to release glucorticoids
Blood sugar increases to meet increased metabolic needs
5- CNS ischemic response (only activated if BP drops below 50
   mmHg) [causes the most intense of all symp discharge in 4-8
   min after complete circulatory failure]
6- Reverse stress-relaxation of the circulatory system: constriction
   to accommodate the diminished BV.
7- Other mechanisms to bring BV back towards normal: (GIT
   absorption of water, Na, Thirst, Na appetite, absorption of water
   from interstitial spaces (may require 1-48 hr)‫‏‬
                    Negative Feed back Mechanism
                           Baroreceptor Reflexes


                           Mean arterial pressure
                             Pulse pressure

                         Stimulation of baroreceptors
                           (carotid & aortic sinus)‫‏‬

                                Vagal tone
                              Sympathetic tone

                            Vasoconstriction HR,
                           Myocardial contractilely

                            Mean arterial pressure

Vasoconstriction: cutaneous, skeletal muscle, splanchnic. Heart and Brain spared.
Negative Feed back Mechanism
      Cerebral Ischaemia


       Arterial pressure
         (40 mm Hg)‫‏‬

        Cerebral ischaemia

  Activation of sympathoadrenal

     Sympathetic activity

     Myocardial contraction

       Arterial Pressure
Negative Feed back Mechanism
    Chemoreceptor Reflexes


       Arterial pressure

   Hypoxia in chemoreceptors
    (carotid & aortic body)‫‏‬

    Chemoreceptor activity


         Venous return

        Arterial Pressure

                Fall in systolic pressure

          Fall in capillary hydrostatic pressure

               Filtration < Reabsorption


                                                        LOW PLASMA VOLUME

                     Atrial receptors
                                                            Reduced RBF         Liver
          ADH                                 ANF
                                                              Renin-          Release &
           Renal                              Renal         Angiotensin      Synthesis of
           water                             sodium           System          Albumin
         retention                          retention
                                                           Angiotensin II
                                    RESTORATION                                 OF
       OF WATER
Failure of Compensatory Response (Progressive shock)‫‏‬

• Decreased blood flow to the tissues causes            cellular
•   Anaerobic metabolism begins
•   Cell swelling, mitochondrial disruption, and eventual
    cell death
•   If Low Perfusion States persists:

          IRREVERSIBLE             DEATH IMMINENT!!
 Stages of Shock
 Initial stage - tissues are under perfused, decreased CO, increased
  anaerobic metabolism, lactic acid is building
 Compensatory stage – (BP drop <45% of normal) Reversible. SNS
  activated by low CO, attempting to compensate for the decrease tissue
 Progressive stage - Failing compensatory mechanisms: profound
  vasoconstriction from the SNS              ISCHEMIA          Lactic acid
  production is high            metabolic acidosis (acids infiltrates the
  blood),+ Blockage of small BV (sludged blood) caused by microagglutination
  in small BV (by acids and ischemic products)         Further reduction in
  blood flow, further ischemia…ect
 Irreversible or refractory stage - Cellular necrosis and Multiple Organ
  Dysfunction Syndrome ( MODS) may occur
                          DEATH IS IMMINENT!!!!
    Pathophysiology Systemic Level

•   Net results of cellular shock:
     systemic lactic acidosis
     decreased myocardial contractility ( COP causes decrease
      Coronary BF      further weakness of CarMs)‫‏‬
     decreased vascular tone
     decrease blood pressure, preload, and cardiac output

       Deterioration of COP is progressive during
       shock. In the beginning the COP can
       withstand the shock (can increase by 300-
       400%), later (after 4 Hrs of shock) the
       deterioration is progressive because the
       coronary BF is reduced a lot.
  Assessment & Management
S/S vary depending on severity of fluid loss:

• 15%[750ml]- compensatory mechanism maintains CO

• 15-30% [750-1500ml- Hypoxemia, decreased BP & UOP

• 30-40% [1500-2000ml] -Impaired compensation & profound shock
  along with severe acidosis

• 40-50% - refaractory stage:
    loss of volume= death
   Clinical Presentation
   Hypovolemic Shock

• Tachycardia and tachypnea
• Weak, thready pulses
• Hypotension
• Skin cool & clammy
• Mental status changes
• Decreased urine output: dark & concentrated
• Most common causes:
     Hemmorhage
     Dehydration
    Initial Management Hypovolemic Shock

Management goal: Restore circulating volume,
    tissue perfusion, & correct cause:
• Early Recognition- Do not relay on BP! (30% fld loss)‫‏‬
•   Control hemorrhage
•   Restore circulating volume
•   Optimize oxygen delivery
•   Vasoconstrictor if BP still low after volume loading
Events of Hypovolemic Shock
Changes in Red Cell Volume, plasma volume and total Plasma
              Proteins following hemorrhage

  Erythropoieten stimulates the bone marrow to increase RBC synthesis.
Positive Feedback Mechanisms that
lead to progression of Shock:

•Cardiac Failure
•Central Nervous System
•Aberrations of blood Clotting
•Depression of Reticuloendothelial
      Positive Feedback Mechanisms

Cardiac Failure

             Coronary blood flow
          Depress Cardiac Function
           Blood Flow to Tissues
          vasodilator metabolites
             Peripheral Resistance
     Positive Feedback Mechanisms

            Inadequate Blood Flow
            Anaerobic metabolism
          Lactic acid and Metabolites
                     H+
   Responsivity of vascular system and Heart
Positive Feed Back Mechanism
Central Nervous System Depression

           Severe Hypotension

       Inadequate cerebral perfusion

Cardiovascular center in brainstem depressed

        Loss of sympathetic tone

 Peripheral resistance - cardiac output
                   Positive Feed back Mechanism
                       Aberration of Blood Clotting

Initial Phase: Hypercoagulability

                             Ischaemic tissues

                             Thromboxane A2

                            Platelet aggregation

                             Intravascular clots

 (Note: Prolonged clotting tendency – Anticoagulant e.g. heparin may help.)‫‏‬

 Secondary phase: Hypocoagulability and fibrinolysis
            Positive Feed Back Mechanism
             Depression of Reticuloendothelial System (RES)‫‏‬


                             RES function

            Antitoxin and Antibacterial Defense mechanisms


Nitric oxide synthase in the smooth muscle of blood vessels

                            Nitric oxide

Cellular Damage: Reduced Oxygen

-    ATP synthesis.(ATP       ADP     AMP       Adenosine
    diffuses outside the cells   Re synthesis of Adenosine
    is very slow-2%/hr-)‫‏‬
-   Na+ - K+ pump failure.
-   K+ leakage.
-   Anaerobic glycolysis.
-   Lactic acidosis.
-   Rupture of lysosomes.
-   Cell death; tissues die, organ systems fail; death
    ultimately ensues
Failure of Transfusion to prevent death in Irreversible Shock

                            Cardiac output (percentage of

  Transfusion may temporarily increase the COP, but in the *irreversible stage* the
  •Myocardium is already severely damaged.
  •So much destructive enzymes are released in the body fluids.
  •So much generalized tissue damage had already occurred.
  •So much acidosis was induced.
  •Lots of destructive factors are in progress
    To Sum Up : Acute Blood loss
•   Induces hemodynamic changes: tachycardia, hypotension, generalized
    arteriolar constriction and generalized venoconstriction.

•   Invokes a number of Negative Feed Back mechanisms (Compensatory):
    Baroreceptor and chemoreceptor reflexes, reabsorption of tissue fluids,
    release of endogenous vasoconstrictors and renal conservation of water and

•   Induces a number of Positive Feed Back mechanisms (Decompensatory):
    Cardiac failure, acidosis, central nervous system depression, aberration of
    blood coagulation and depression of reticuloendothelial system.

•   Outcome depends on sum of gains of negative and positive feed back
    mechanisms and the interaction between these mechanisms.
          Cardiogenic Shock
• The impaired ability of the heart
  to pump blood
• Pump failure of the right or left
• Most common cause is LV MI
• Occurs when > 40% of
  ventricular mass damage
• Mortality rate of 80 % or >
Vasogenic/Distributive Shock
•   Inadequate perfusion of tissues through mal distribution of blood flow
•   Cardiac pump & blood volume are normal but blood is not reaching the
•   Etiologies
     – Septic Shock (Most Common)‫‏‬
     – Anaphylactic Shock
     – Neurogenic Shock
     Anaphylactic Shock
• Antigen exposure
• body stimulated to produce IgE antibodies specific to antigen
     – drugs, bites, contrast, blood, foods,
• Re-exposure to antigen
     – IgE binds to mast cells and basophils
• Anaphylactic response
Anaphylactic Response

 •   Vasodilatation
 •   Increased vascular permeability
 •   Bronchoconstriction
 •   Increased mucus production
 •   Increased inflammatory mediators
     recruitment to sites of antigen interaction
•   A type of distributive shock that results from the loss or suppression of sympathetic tone
•   Most common etiology: Spinal cord injury above T6
•   Neurogenic is the rarest form of shock!

                  Distruption of sympathetic nervous system
                           Loss of sympathetic tone
                       Venous and arterial vasodilation
                           Decreased venous return
                           Decreased stroke volume
                          Decreased cardiac output
                       Decreased cellular oxygen supply
                          Impaired tissue perfusion
                        Impaired cellular metabolism

  • Hypotension (SBP < 90 or > 40 reduction from baseline) &
  • Tissue perfusion abnormalities, invasion of the body by
    microorganisms & failure of body’s defense mechanism.
                                         Initiated by gram-negative (most
  Risk Factors:                        common) or gram positive bacteria,
  •   Age                                          fungi, or viruses
                                     •Cell walls of organisms contain
  •   Malnutrition                   Endotoxins
  •   General debilitation           •Endotoxins release inflammatory
  •   Use of invasive catheters      mediators (systemic inflammatory
  •   Traumatic wounds               response)‫‏‬causes…...
                                     •Vasodilation & increase capillary
                                     permeability leads to
•The effects of the bacteria’s
                                     •Shock due to alteration in peripheral
endotoxins can continue even after   circulation & massive dilation
the bacteria is dead!!!
Pathophysiology of Septic Shock
           Microorganisms enter body

                 Mediator Release
 Activation of Complement, kallikrein / kinin/ coagulation
      & fibrinolytic factors, platelets, neutrophils &
       macrophages>>damage to endothelial cells.
                ORGAN DYSFUNCTION
 Septic shock
• Vasodilation especially the infected tissue.
• High COP (may be in half of patient) because of
  vasodilation in infected tissue (and high
  metabolic rate by high fever, elswhere in the
• Degenerating tissue causes RBC agglutination
  (Sludged blood).
• Micro blood clots all over the body (disseminated
  intravascular coagulation).
• Clotting factors are used up leading into
  hemorrhages in many tissues. (eg GIT)‫‏‬
                        A deficiency of Oxygen in the tissues

Types of Hypoxia
•   Hypoxic Hypoxia: Low arterial PO2 which is inadequate to saturate the
    hemoglobin fully.

•   Anemic Hypoxia: PO2 is normal but the amount of hemoglobin available
    to carry oxygen is reduced.

•   Stagnant or Ischaemic Hypoxia : : Blood flow to a tissue is so low that
    adequate oxygen is not delivered (normal PO2 & hemoglobin).

•   Histotoxic Hypoxia: Inability of tissues to use the oxygen (normal PO2,
    hemoglobin & transport).

Hypoxic Hypoxia(low art.      tissue

 Anaemic Hypoxia( low         O2
 Hb, or RBC count)‫‏‬

 Stagnant Hypoxia              O2

 Histotoxic Hypoxia            O2

                      No O2 uptake by tissue
    Causes of Hypoxia

1- Hypoxic Hypoxia

Extrinsic causes:
      Low pressure of O2 in air (Mines, High altitude).
    Neuromuscular disorders (Bulbar poliomyelitis, Guillean Berri syndrome, Cervical cord transaction).
Pulmonary Diseases:
i.   Increased airway resistance.
ii.  Decrease pulmonary compliance.
iii. Uneven alveolar ventilation perfusion ratio.
iv.  Diminished respiratory membrane diffusion.

Congenital heart disease:
Right to left” cardiac shunt.
                    Causes of Hypoxia
2- Anemic Hypoxia:
•   Lack of hemoglobin.
•   Carbon monoxide poisoning (CO has 250 times greater affinity for Hb
    as compared to O2).

3- Stagnant or Ischaemic Hypoxia:
•   Decreased cardiac output and blood flow to the organs e.g. heart
    failure, impaired venous return, hemorrhage or shock.

4- Histotoxic Hypoxia:
•   Poisoning of cellular enzyme e.g. cyanide poisoning paralyses
    cytochrome oxidase.
•   Narcotics depress tissue oxidation – interference with dehydrogenase
Effects of Hypoxia
• Sudden fall of PO2 (20 mmHg) eg. cabin pressure lost in a plane
flying above 16,000       m causes loss of consciousness in
about 20 sec. and death in 4-5 min.
     Less severe hypoxia  impaired judgment, drowsiness, dulled
pain sensibility, excitement,    disorientation, loss of time
sense, headache, anorexia, nausea, vomiting.

•       Tachycardia, hypertension

•        Rate of ventilation proportional to severity of hypoxia of
carotid chemoreceptor cells.
Composition of alveolar air in individuals breathing
air ( 0-6100m) and 100% O2 (6100-13.700m)‫‏‬


          RAPIDITY      AND    SEVERITY

                      OF THE

1) FULMINANT hypoxia
                                                                                      (Arterial Po2<20mmHg)‫‏‬
                                     (eg.aircraft loses cabin pressure above 30,000 feet and no supplemental O2 available)‫‏‬

                                                      Occurs in seconds                 Unconsciousness in 15-20 sec

                                                                                                Brain death in 4-5 min

2) ACUTE hypoxia
                                                                      (25mmHg<Arterial Po2<40mmHg)‫‏‬
                                                                                       (eg.altitudesof 18,000-25,000 feet)‫‏‬

Symptoms similar to those of ethyl alcohol(lack of coordination,slowed reflexes, overconfidence)‫‏‬

                                                                           Coma and death (in minutes to hours)‫‏‬
                                                        if the regulatory mechanisms of the body are inadequate
3) CHRONIC hypoxia
                                                               (40mmHg<Arterial Po2<60mmHg)‫‏‬
                                                ( altitudes of 10,000-18,000 feet for extended periods of time)‫‏‬


Most clinical causes of hypoxia are in these category

                             Symptoms similar to those of severe fatigue

                                                                                    SHORTNESS OF BREATH
                                                                                RESPIRATORY ARRHYTHMIAS

1. Cyanosis (bluish color of tissue)
    caused by more than 5g of deoxyhemoglobin/dl in capillary blood(or less than 13ml O2
                                                                     per 100ml of blood)‫‏‬

•       Tachycardia
        (peripheral chemoreceptor reflex response to Po2 )‫‏‬

3. Tachypnea and Hyperpnea
  O2 therapy in different types of Hypoxia
• Atmospheric hypoxia: Can be corrected completely by O2

• Hypoventilation hypoxia: Extremely beneficial (but this will
  not correct the hypercapnia caused by hypoventilation).

• Impaired alveolar membrane diffusion: O2 therapy can
  increase PO2 in lungs from normal value of 100 mmHg to as
  high as 600 mmHg, so increase the O2 gradient between
  alveoli and blood from 60 to 560 mmHg. This has same
  beneficial effect to (2).

• Hypoxia by anemia, abnormal Hb, physiological shunt: Little
  effect. O2 is already available in the alveoli here. Sometimes
  small extra amounts of O2 (7-30%) can be transported
  dissolved in blood, when the alveoli O2 is maximum conc.

• Hypoxia due to inadequate tissue use of oxygen (cyanide
  toxicity). O2 therapy is of hardly any measurable benefit.

      1) Hypoxia is widespread in tumors

      2) Most human solid tumors have pO2 values lower
         than their normal tissues of origin.
                     THIS IS CAUSED BECAUSE

           Tumor blood vessels are highly irregular and


           Tumors do not get enough O2 and nutrients
But tumor cells are usually proliferating
       faster than normal cells.


       the ability of tumor cells to
sense and adapt to low oxygen (hypoxia)‫‏‬
       is essential for tumor growth.
What is HIF-1?
HIF-1: Hypoxia Inducible Factor – 1

    HIF-1 is a protein with DNA binding

                                                Relative HIF-1 Expression
It is composed of two subunits:
HIF-1 and HIF-1.

   Where is HIF-1?
It is transcripted in the m-RNA of every cell
    of the human body

                                                                            Oxygen Concentration
                    HIF-1 expression increases exponentially when O2 conc. is low
What does HIF-1 do?

•    Helps normal tissues as well as tumors to survive under hypoxic conditions
•    HIF-1 is a transcription factor that turns on genes needed for survival under
     hypoxic conditions.
•    So far, more than 40 target genes have been found to be regulated by HIF-1.
•    These genes can be classified into 3 main groups:

    Nitric Oxide synthase2 (NOS2)‫‏‬
    Transferrin                                      Group 1:
    Transferrin receptors                            O2
    Vascular Endothelial Growth
    Factor (VEGF)‫‏‬
    VEGF receptor
Aldolase A
Aldolase C
Enolase 1 (ENO1)
Glucose transporter 1
Glyceraldehyde phosphate dehydrogenase
                                         Group 2: Glucose
Hexokinase 1
Hexokinase 2
Lactate dehydrogenase A
Phosphofructokinase L
Phosphoglycerate kinase 1
Pyruvate kinase M

  Insulin-like growth factor 2 (IGF-2)
  IGF binding protein 1                   Group 3:
  IGF binding protein 3                   Cell Proliferation
  p21                                     /Viability

 Among the first responses at the onset of hypoxia
 is an increase in the protein levels of
 hypoxia-inducible factor-1 (HIF-1)

                                             The oxygen and nutrients
                                             display a gradient away
                                             from the necrotic center

                                      O2, glucose,
                         gradient     growth factors

                              An idealized diagram
                              of a tumor cross section
HIF-1 Correlates with Tumor Vascularity

  The expression of HIF-1 is positively
   correlated with tumor vascularity, indicating HIF-1 plays a
    crucial role in tumor angiogenesis progression.

 Low oxygen tension is associated with increased
 metastasis and decreased survival of patients

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