By  Dr  Rubia  Khan  ST1,  Histopathology    Derriford  Hospital  

�  60%  of  lean  body  weight  is  water  �  2/3  as  intracellular  �  1/3  as  extracellular    �  (mostly  as  interstitial  fluid  )  �  (only  5  %  of  total  body  water  is  plasma)  

Edema  � Accumulation  of  interstitial  fluid  within  tissues  � Based  on  location  �  1.  Hydrothorax  �  2.  Hydropericardium  �  3.  Hydroperitoneum  (ascites)  �  4.  Anasarca  

Types  of  edema  �  1.  Inflammatory  edema  –  protein  rich  exudate  that  is  result  of  

increased  vascular  permeability  

 �  2.  Non-­‐inflammatory  edema  –  edema  caused  by  increased  

hydrostatic  pressure  or  reduced  plasma  protein  is  typically  protein  poor  fluid  called  transudate.  

What  causes  edema  �  1.  Increased  Hydrostatic  Pressure  �  2.  Reduced  Plasma  Oncotic  pressure  �  3.  lymphatic  obstruction  �  4.  Sodium  and  water  retention  

Increased  hydrosta5c  pressure    Deep  vein  thrombosis  Congestive  heart  failure  

� Constrictive  pericarditis  � Venous  obstruction  or  compression                Thrombosis              External  pressure  (mass)              Lower  extremity  inactivity  with  prolonged  dependency  

� Arteriolar  dilatation            Heat            Neurohumoral  dysregulation  

Reduced  Plasma  Onco5c  Pressure  � Protein  –losing  glomerulopathies  (nephrotic  syndrome)  

�  Liver  cirrhosis  (ascites)  � Malnutrition  � Protein-­‐losing  gastroenteropathy  

Lympha5c  obstruc5on  �  Inflammation  � Neoplastic  � Postsurgical  � Postirradiation  

Sodium  and  water  reten5on  �  Increased  tubular  resorption  of  sodium  �  Increased  renin-­‐angiotensin-­‐aldosterone  secretion  

�  Seen  in  poststreptococcal  glomerulonephritis  and  acute  renal  failure  

Morphology  � Can  be  easily  recognised  grossly  � Microscopically  –  it  is  appreciated  as  clearing  and  separation  of  the  extracellular  matrix  and  subtle  cell  swelling.  

� Most  commonly  seen  in          -­‐Subcutaneous  tissue        -­‐Lungs        -­‐Brain        Dependent  edema  Nephrotic  syndrome    

Clinical  correla5on  � Ranges  from  merely  annoying  to  fatal  �  Subcutaneous  edema  used  primarily  to  recognise  underlying  

cardiac  or  renal  disease  ,  if  severe  can  impair  wound  healing  or  clearance  of  infection  

� Pulmonary  edema-­‐  LVF,  can  also  occur  with  renal  failure,  ARDS,  and  infection  and  inflammation  of  lungs.  Can  cause  death  by  interfereing  with  normal  ventilatory  function.  

� Brain  edema  is  life  threatening.  When  severe  can  cause  herniation  of  brain.  Compression  of  brain  stem  vascular  supply  

Shock  Shock  is  characterised  by  systemic  hypoperfusion  of  tissues;  it  can  be  caused  by  diminished  cardiac  output  or  by  reduced  effective  circulating  blood  volume.    Consequences  are  impaired  tissue  perfusion  and  cellular  hypoxia.    

Major  types  of  shock  

� Neurogenic  shock    � Anaphylactic  shock  

Pathogenesis  of  Sep5c  Shock  � Kills  20%  of  its  victims  � Number  one  cause  of  ICU  deaths.  �  Increasing  incidence  due  to                                                                                          1.  improved  life  support  for  critically  ill  patients  

     2.  increase  in  invasive  procedures        3.  growing  number  of  immunocompromised                                                                                                                          population  

� The  innate  leukocytes  include:  Natural  killer  cells,  mast  cells,  eosinophils,  basophils;  and  the  phagocytic  cells  including  macrophages,  neutrophils,  and  dendritic  cells,  and  function  within  the  immune  system  by  identifying  and  eliminating  pathogens  that  might  cause  infection  

Pathophysiology  of  Sep5c  shock  �  Factors:  �  inflammatory  mediators  � Endothelial  cell  activation  and  injury  � Metabolic  abnormalities  �  Immune  suppression  � Organ  dysfunction  

1.Inflammatory  mediators  �  innate  immunity  cells  recognise  a  host  of  microbe  derived  susbtances  containing  so  called  pathogen  associated  molecular  patterns(  PAMPs).  

� Activation  of  pathogen  recognition  receptors  by  PAMPs  triggers  the  innate  immune  response  that  drive  sepsis  

� Upon  activation  ,  inflammatory  cells  produce    � TNF  (proinflammtory  cytokines)  

�  IL-­‐1  (proinflammtory  cytokines)  

� Cytokine  like  mediators  HMGB-­‐1  � Reactive  oxygen  species  � Prostaglandins  � Platelet  activation  factor  

2.Endothelial  cell  ac5va5on  and  injury  � Three  main  sequelae:    �  1.thrombosis  �  2.increased  vascular  permeability  �  3.vasodilatation  

Thrombosis  � Pro  inflammatory  cytokines  result  in  increased  tissue  factor  production,  at  the  same  time  dampening  fibrinolysis  by  increased  PAI  expression.    

� Production  of  other  endothelial  anticoagulant  factors  such  as  tissue  factor  pathway  inhibitor,  thrombomodulin  and  protein  C  is  also  diminished.  

� Procoagulant  tendency  is  further  enhanced  by  decreased  blood  flow  within  small  vessels,  which  produces  stasis  and  diminished  washout  of  activated  coagulation  factors.  

Increased  vascular  permeability  �  Inflammatory  cytokines  loosen  the  endothelial  cell  tight  junctions.  

Vasodilata5on    �  Increase  NO  production  and  vasoactive  inflammatory  mediators  leads  to  systemic  relaxation  of  vascular  smooth  muscles,  producing  hypotension  and  further  reduction  in  tissue  perfusion.  

3.  Metabolic  abnormali5es  �  Septic  patients  exhibit  insulin  resistance  and  hyperglycemia  

� Cytokines  and  stress  induced  hormones  drive  gluconeogenesis.  

� Pro-­‐inflammatory  cytokines  suppress  insulin  release  while  simultaneously  promoting  insulin  resistance  in  skeletal  muscles  and  other  tissues  

� Hyperglycemia  suppress  neutrophil  function-­‐  decreases  bactericidal  activity-­‐  increased  adhesion  molecule  expression  on  endothelial  cells.  

4.  Immune  suppression  � Hyper-­‐inflammatory  state  initiated  by  sepsis  can  paradoxically  lead  to  state  of  immunosuppression.  

� Proposed  mechanism  include  production  of  anti-­‐inflammatory  mediators  and  wide  spread  apoptosis  of  lymphocytes  in  the  spleen  and  lymph  nodes,  cause  of  which  is  uncertain.  

Organ  dysfunc5on  � High  level  of  cytokines  and  secondary  mediators  can  reduce  myocardial  contractility  

�  Increased  vascular  permeability  and  endothelial  injury  in  pulmonary  circulation  leads  to  ARDS  

� Ultimately,  these  factors  conspire  to  cause  multiorgan  damage  resulting  in  death.  

Outcome    � Difficult  to  predict  �  Standard  care  remains  treatment  with  appropriate  antibiotics  ,  intensive  insulin  therapy  ,  fluid  resuscitation  and  physiological  doses  of  corticosteroids  to  correct  relative  adrenal  insufficiency  

Stages  of  Shock  �  Stage  1:  Initial  �  Stage  2:  Non-­‐progressive  stage.  (stage  1  &  2  are  grouped  

together)  

�  Stage  3:  Progressive  stage  �  Stage  4:  Irreversible  stage  

Stage  1&  2  � Neurohumoral  mechanisms  :  �  1.baroreceptor  reflexes  �  2.release  of  cathecholamines  and  ADH  �  3.  activation  of  renin-­‐angiotensin-­‐aldosterone  axis  �  4.generalised  sympathetic  stimulation  

Net  effect  �  1.  tachycardia  �  2.peripheral  vasoconstriction  �  3.renal  fluid  conservation  

Stage  3  �  Persistent  O2  deficit,  causes  activation  of  anaerobic  glycolysis,  increased  production  of  lactic  acid.  

�  Resultant  lactic  acidosis  lowers  the  tissue  pH,  which  blunts  the  vasomotor  response  resulting  in  arteriolar  dilatation  and  pooling  of  blood  in  microcirculation.  

�  This  reduces  cardiac  output  further,  endothelial  cell  injury  due  to  hypoxia  with  subsequent  DIC.  

� Widespread  tissue  hypoxia,  vital  organs  are  affected  and  begins  to  fail.  

Stage  4  � Widespread  cell  injury  is  reflected  in  lysosomal  enzyme  leakage.  

� Myocardial  contractile  function  worsens  �  Ischemic  bowel  may  allow  intestinal  flora  to  enter  circulation  

� Ultimately  death.