Deanna Purvis, VMD, DipACVECC

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SHOCK
A Focus on Pathophysiology Fluid Choice - Is
There Need for Oxyglobin?
Deanna Purvis, VMD, DipACVECC CARE HOSPITAL
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Clyde 5 y.o. Mc OESD P.C. - HBC 90 minutes
prior to presentation PE - Conscious,
depressed, non-ambulatory, painful HR - 160
bpm RR- 60 bpm MM - Grey/Pink CRT - 2.5
seconds BP - 80/60 mmHg MAP - 50mmHg ECG -
Sinus tachycardia occasional unifocal
PVCs SaO2 - 89 T - 99.6 F Abdomen - Tense
on palpation. Thorax - Lung sounds all
fields. Pelvic fracture palpable per rectum
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PCV - 35 TS - 4.8 mg/dl Na - 145 mmol/L K - 4.0
mmol/L BUN - 26 mg/dl Glucose - 110 mg/dl Lactate
- 4.2 mmol/L pH - 7.25 HCO3 - 17 mmol/L pCO2 - 30
mmHg
Abdominocentesis - Hemorrhagic fluid PCV-37,
TS 4.0
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Shock? Yes / No If yes, what Stage of
Shock? Explain what is occurring at the cell
level. What are the initial treatment
goals? What are the treatments used to achieve
the goals? Should you reach for Oxyglobin?
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SHOCK
Tissue Economics
Supply lt Demand
Inciting event is a decrease in effective blood
flow and oxygen delivery to tissues such that the
delivery does not meet the demand. Decrease in
flow can be secondary to cardiac or vascular
mechanisms.
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Delivery of Oxygen to Tissues
Heart Rate (HR) X Stroke Volume (SV)
Cardiac Output (CO)
Content of Oxygen in Arterial Blood (CaO2)
X
Preload Afterload Contractility Synchrony
(1.34 x Hb x SaO2) 0.003 x PaO2
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ATP Production With and Without Oxygen
Glucose
Pyruvate
Glycolysis Net 2 ATP
Lactate
Cytosol
TCA Cycle
Mitochondria
Net 2 ATP
Oxidative Phosphorylation
Net 34 ATP
Total ATP Anaerobic - 2 Aerobic - 38
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Tissue Hypoxia

• Depletion of ATP
• Increase of Lactate/Lactic Acid
• Hypoxia and acidosis impair Na-K-ATPase leading
  to elevations of intracellular sodium and calcium
• Cellular swelling
• Lysosomal membrane destruction with enzyme release

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Tissue Hypoxia

• Cell membrane destruction - membrane
  phospholipids unable to reacylate
• Arachidonic acid cycle activation with production
  of prostaglandins, leukotrienes and kinins
• Local vasodilatation, increased capillary
  permeability
• Interstitial edema, maldistribution of blood flow
  (microthrombosis, vasoconstriction,
  vasodilatation)
• Organ dysfunction

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Pathophysiology

• Vasoactive Compounds
• Adenosine
• PO4
• Lactate
• Kinins
• Histamine
• CO2
• Serotonin
• Adenine Nucleotides

• Thromboxane
• IL-1
• IL-6
• TNF

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Pathophysiolgy

• Vasoactive compounds release from hypoxic tissue
• Increased capillary permeability
• Myocardial depression
• Coagulation activation (intrinsic and extrinsic)
• DIC Dead in Cage vs. Darned inconvenient
  complication.

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Oxygen Debt

• Oxygen deficit that accumulates during a period
  of ischemia which must be compensated or repaid
  in the post ischemia period.
• Patients unable to repay debt carry risk for
  persistent ischemia and organ damage/failure and
  death.
• May require supranormal oxygen delivery.

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Oxygen Debt and Survival from ShockPercent
Survival vs. Oxygen Deficit (cc/kg)
Magnitude of oxygen debt is directly proportional
to survival.
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GLUCOSE
ANAEROBIC GLYCOLYSIS
TCA Cycle
PYRUVIC ACID
LACTATE
AcetylCoA


H
From Glycolysis /- TCA cycle


LACTIC ACID
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Lactate

• Normal Arterial Values - 2 - 4 mM/L.
• Serum lactate levels can be used to assess the
  balance between oxygen supply to tissues and the
  metabolic oxygen consumption. Good marker to
  show, How well are the tissues being
  oxygenated?
• Lactate level correlates with the magnitude of
  oxygen debt.
• Quantifies severity of shock.

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Survival vs. Arterial Lactate (mM/L)
Lactate level is directly proportional to
survival - See handout
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HESKA I-STAT CG4
pH pCO2 pO2 HCO3 TCO2 BE sO2 Lactate
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Hypovolemia
Loss of baroreceptor stretch
Decreased CO
Increased serum osmolality
Medulla Oblongata
Hypothalamus
ACTH release
Increased sympathetic stimulation
Adrenal Medulla
Norepinephrine release
Renin-Angiotensin Activation
ADH release
Epinephrine release
Aldosterone release
Cortisol release
Vessels increase constriction
Heart increase rate contractility
Kidneys increase Na H2O retention
Liver gluconeogenesis protein synthesis
Increase intravascular volume and cardiac output
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Pathophysiology

• Sympathetic stimulation intensifies uneven blood
  flow
• ATP and Glucose are depleted. FFAs are utilized
  for energy
• Leukotriene, Prostaglandin, Thromboxane A2
• Vasoconstriction
• Myocardial Depression
• Platelet aggregation
• Lysosomal enzyme release
• WBC chemotaxis

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Pathophysiology

• Severe tissue hypoxia and decompensation of
  vital organs result due to severe flow
  maldistribution.

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Body Fluid and Blood Volumes
Fluid
Total body water 600 ml/kg 60 of LBM Whole
Blood 78ml/kg 8 of LBM Plasma 44 ml/kg 60
of WBV Erythrocytes 35 ml/kg 40 of
WBV Values expressed for lean body mass
(LBM).
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Stages of Shock

• Compensatory
• Early Decompensatory
• Late Decompensatory (Terminal)

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Compensatory Stage
Pathophysiology
Clinical Signs

• Decreased venous return.
• Decreased CO.
• Decreased baroreceptor stretch.
• Catecholamine, ADH, RAA release.
• Increased SVR, HR, venoconstriction, cardiac
  contractility.
• VR and Arterial flow increase.
• Hypermetabolism compensatory mechanisms require
  energy. Supranormal O2 must be delivered.

• Tachycardia.
• Shortened CRT.
• MM - Dark pink/red.
• NL - Increased pulse pressure.
• Increased RR.
• Alert mentation.
• Immediate intravascular volume expansion is
  required to remove the stimulus for
  hypermetabolic state.

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Early Decompensatory
Pathophysiology

• CO continues to decrease
• Arterial shunting
• O2 consumption becomes dependent on delivery
• Anaerobic glycolysis
• Lactic acid
• Inadequate ATP produced - Adenosine accumulation
  - vasodilation, renal vasoconstriction

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Early Decompensatory
Pathophysiology

• Hypoxia and lactic acidosis impair Na-K-ATPase
  function
• Cellular swelling
• Intracellular Calcium accumulation
• Toxic oxygen radical production
• Cell rupture
• AA accumulates
• Eicosanoids
• SIRS

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Early Decompensatory
Pathophysiology
Clinical Signs

• Ulceration of GI tract
• Bacterial translocation
• Hepatic venoconstriction - portal hypertension
• Pancreatic hypoxia - MDF release
• Pulmonary shunting
• Shunting from cortical to juxtamedullary
  nephrons. Renal-constriction of afferent
  arterioles limits RBF -Adenosine

• Tachycardia
• NL-decreased pulse pressure
• Prolonged CRT
• Pale MM
• Hypothermia
• Mental depression
• Oliguria (MAPlt60mmHg)
• Aggressive volume resuscitation required

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Effects of Hypoxia on Cellular Metabolism
O2
Lactic Acidosis
Eicosanoids
H2O
Na-K-ATPase
.
H
H
Ca
O2
H
AA
.
Ca
Na
H20
O2
H
.
.
H
O2
OH
Ca
.
.
OH
O2
H20
H2O
Ca
Na
Cell Swelling
Oxygen Radicals
H2O
Cell Membrane Disruption
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Late Decompensatory (Terminal)

• Pathophysiology
• Autoregulatory escape
• Circulatory collapse
• Heart and Brain hypoxia
• Sympathetic center in brain fails - chronotropic
  and inotropic cardiac responses not possible

• Clinical Signs
• Bradycardia
• Prolonged or absent CRT
• Diminished or absent peripheral pulses
• Worsened hypothermia (core and peripheral)
• Dementia/Stupor/Coma
• Anuria
• CV resuscitation and support of compromised
  organs needed

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Determinants of Oxygenation
Oxygen Delivery (DO2)
Oxygen Content (CaO2)
Cardiac Output (CO)
X
Hemoglobin
RBC
Plasma

CaO2 (1.34 X (Hb) X SaO2) (0.003 X PaO2)
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Determinants of Oxygenation
Oxygen Delivery Arterial Oxygen Content
X Cardiac Output (DO2) (CaO2)
(CO) Oxygen Extraction
Oxygen Consumption (VO2) Oxygen Delivery (DO2)
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Resuscitation End Point Goals

• Pink
• 1-2 seconds
• 80-120/180-200
• 70-100/80-140
• 5-8
• gt2
• 100-102.5
• Alert/Responsive
• 25-45

Perfusion Parameter
End Point Goals

• MM Color
• CRT (seconds)
• HR (bpm) dog/cat
• Arterial BP (mmHg) mean/systolic
• CVP (cmH20)
• Urine output (ml/kg/hr)
• Body temperature
• Mentation
• PCV

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The single most important factor in successful
resuscitation from shock is time
rapid

expeditious therapy in early stages may lead to
good results, but adequate therapy that is
delayed may be ineffective.
Shoemaker Kram
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Treatment for Shock

• Oxygen
• IV Catheterization
• Fluid Therapy
• Analgesia
• Antibiotics
• Glucocorticoids
• Blood/Blood Products
• /- Sodium Bicarbonate
• Pharmacological Cardiovascular Support

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Oxygen Therapy

• Face Mask or Blow By at 5 L/min
• Intranasal at 90 ml/kg/min
• Pulmonary shunt - Supplemental O2 adds mostly to
  dissolved fraction.
• Monitor by
• ABG
• Pulse Oximetry

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IV Catheterization

• Vascular access must be obtained. SQ or
  peritoneal fluids are inadequate for treatment of
  shock.
• Peripheral catheter first - Large bore, a 2 fold
  increase in inner diameter gives a 16 fold
  increase in flow. Flow inversely proportional to
  length.
• Q(Pin - Pout) x
• Central line (jugular) - CVP monitoring
• Venous cut down - Central vein unless mini
  cutdown. IO fluids also acceptable.

pr
4
8mL
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Fluid Therapy

• Crystalloids
• Hypertonic Saline
• Colloids
• Combination Crystalloid/Colloid/Hypertonic

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Crystalloids

• LRS, Plasmalyte, 0.9 NaCl
• Restores deficit within the interstitial fluid
  space
• Only 25 of crystalloid administered is
  intravascular at 30 minutes
• Dose
• Canine - 90 ml/kg
• Feline - 40-55 ml/kg

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Hypertonic Saline

• Immediate increase in CO, Arterial BP and
  peripheral perfusion
• Dose 4 ml/kg of 7 solution
• Improved hemodynamics due to increased plasma
  volume
• Fluid shift
• Direct positive inotropic effect
• Transient effect
• Canine 2 hr
• Feline 15-20 minutes

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Colloidal Solutions

• Synthetic Colloids
• Hydroxyethylstarch (Hetastarch)
• Dextran - 40
• Dextran - 70
• Gelatins
• Oxyglobin

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Colloidal Solutions

• Fresh Whole Blood
• Stored Whole Blood
• Plasma

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Colloidal Solutions

• Contain large molecular weight substances that do
  not readily cross the capillary membrane.
• Large negatively charged molecules pull water
  from the interstitium into the vasculature.

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Hydroxyethylstarch (Hetastarch)

• Average MW 69,000 Daltons
  Range 10,000 - 2,000,000
• 50 of oncotic activity at 24 hours
• Increase in Amylase
• Elevation in PT/PTT - No clinical problems noted
• Dose 10- 20ml/kg/day Canine
  10-15 ml/kg/day Feline

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Antibiotics

• Use with decompensatory stage of shock or in
  compensatory if there is obvious external trauma
• Bacterial translocation may occur during the
  decompensatory stage or during reperfusion injury
• Cefazolin 20 mg/kg slow IV q 8 hours

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Glucocorticoids

• Inhibition of phospholipase action on membranes
• Enhances energy use by liberating ATP from
  mitochondria
• Relaxation of pre and post capillary sphincters
  and arterioles
• Avoid rapid IV bolus or administration prior to
  IV fluids
• Potential for hypotension and CV collapse

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Glucocorticoids

• Inhibits production of TNF, IL-1, IL-6, PAF
• Inhibits cyclooxygenase and lipoxygenase activity
  thus inhibiting eicosanoid production
• Reduce reperfusion injury
• Prednisolone sodium succinate (10-20mg/kg IV)

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Glucocorticoids

• Arteriole and Venule dilation-hypotension
• GI Ulceration (anti-prostaglandin activity)
• Impairment of cellular immune response
• Administer early after volume loading if no
  evidence of SIRS or sepsis

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Analgesics
Besides the obvious humane reason for
administering analgesics, pain and the
physiologic response to pain can be detrimental
to the shock patient. The primary physiologic
responses to pain are manifested by the
cardiovascular system and include tachycardia,
vasoconstriction and arrhythmias.Vasoconstriction
, inadequate intravascular volume and poor
myocardial function can dramatically lower
cardiac output.
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Analgesics

• Opioids preferred - Cardiopulmonary monitoring
  recommended for possible hypoventilation/bradycard
  ia
• Butorphanol - Partial m agonist k agonist.
• Buprenorphine - Partial m agonist k antagonist.
  Morphine - Agonist m and k
• Oxymorphone - m agonist
• Hydromorphone - m agonist
• Fentanyl - m agonist
• Epidural analgesia

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Dobutamine

• Synthetic sympathomimetic agent that stimulates
  b1 receptors of the myocardium having a positive
  inotropic effect
• Weak stimulation of b2 receptors causing a mild
  vasodilatation
• Increases cardiac output without a dramatic
  increase in blood pressure
• 2-5 mg/kg/min (can increase up to 15 mg/kg/min)

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Dopamine

• Precursor of norepinephrine
• 1-5 mg/kg/min Stimulates d receptors, renal,
  cerebral, coronary causing arteriolar dilatation
• 5-10 mg/kg/min Stimulates b1 adrenergic receptors
  in sinus node and myocardium causing positive
  chronotropic and inotropic effect
• gt10 mg/kg/min Stimulates a1 adrenergic receptors
  causing arterial vasoconstriction and increased
  BP
• Side effect Ventricular arrhythmias

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Vasopressors

• Use for life threatening hypotension that is
  refractory to fluid resuscitation. Goal is to
  increase blood pressure to maintain blood flow to
  heart and brain.
• Temporary - avoid long term vasoconstriction in
  tissue beds which decreases blood flow and organ
  function.
• Epinephrine 0.1-0.3 mg/kg/min
• Norepinephrine 0.01 - 0.4 mg/kg/min
• Dopamine gt10 mg/kg/min

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Sodium Bicarbonate

• Treat metabolic acidosis that is secondary to
  poor tissue perfusion with improved perfusion.
• If patient has underlying disease predisposing to
  metabolic acidosis (renal, diarrhea) may require
  NaHCO3.
• Document metabolic acidosis with ABG/VBG
• If pH lt 7.1 or HCO3 lt 12 give bicarbonate
• Dose NaHCO3(mEq)BW(kg) x 0.4 x (12-pt HCO3)

Give 1/2 of above in IV fluids and give over 6
hours, or if severe slow IV.
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Shock? Yes Early Decompensatory
stage DO2ltVO2 Improve tissue oxygenation IV
fluid support Oxygen Restore perfusion
parameters to normal. Monitor BP, Lactate,
MM, CRT, CVP, HR Oxyglobin? Yes
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Oxyglobin Use in Hemorrhagic Shock
Summary Although hemoglobin solutions such as
Oxyglobin (Biopure Corporation) can increase the
amount of oxygen carried by blood, they may not
effectively deliver oxygen to tissues due to
vasoconstriction and reduced cardiac output.
Monitoring return of vascular pressures to normal
levels as an indicator of adequacy of
resuscitation may not be appropriate when
vasoactive hemoglobin solutions like Oxyglobin
are administered for the treatment of acute
hemorrhagic hypovolemia. The vasoactivity of
hemoglobin solutions, however, may prove useful
in the treatment of sepsis.
In Recent Advances in Veterinary Anesthesia and
Analgesia Companion Animals, R. D. Gleed and J.
W. Ludders (Eds.) Current Topics in Fluid
Therapy Oxyglobin (10-May-2001) R. Meyer
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Nitric Oxide
Vascular Endothelial Cell
L-Arginine
Nitric Oxide Synthetase
(NOS)
Nitric Oxide (NO)
GTP
cGMP
Guanylate Cyclase
cGMP-PK
NO
Actin
Myosin-P
Relaxation
Vascular Smooth Muscle Cell
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Nitric Oxide

• Acts on cytosolic guanylate cyclase to cause
• Blood vessel dilation
• Inhibition of thrombogenesis
• Cytotoxic responses
• Neuronal signaling

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Nitric Oxide

• Constitutive NOS - Continuously produced, Calcium
  dependent, causes a rapid vasorelaxation. NO via
  CNOS mediates response to AcetylCholine, NE,
  Histamine, Substance-P
• Inducible NOS - Produced prn by inflammatory
  cells (macrophage, PMN, Kuppfer cells) after
  exposure to cytokines. Delayed response (2-4 hrs)