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					                                                     Shock


Shock is a physiologic state characterized by a systemic impairment in oxygen delivery as a result of reduced
tissue perfusion, almost universally mediated by low blood pressure. The general physiologic mechanisms of
how shock leads to irreversible cell damage and death include:

        1.   Cell membrane ion pump dysfunction
        2.   Intracellular edema
        3.   Leakage of intracellular contents into the extracellular space
        4.   Inadequate regulation of intracellular pH.



Symptoms/Signs:
        Features common to all forms of shock include:

        1. Cardiovascular System – Hypotension (SBP<90) is near universal, however, early in the course, the
           hypotension may be only relative to the patient’s baseline BP.
        2. Nervous System – A patient’s mental status typically moves from agitation to delirium to coma, as
           the perfusion abnormalities become worsened. Although hypoperfusion is the predominantly
           underlying cause of these symptoms, it is important to note that metabolic problems (e.g. acidosis,
           uremia, hypoglycemia, etc… may also be contributing)
        3. Pulmonary System – Shock is often accompanied by hyperpnea (to compensate metabolic
           acidoses), in which the respiratory muscles may consume large amounts of oxygen, and if demand
           outstrips supply, may worsen accumulation of lactic acid.
        4. Skin – As a result of potent peripheral vasoconstriction, the patient will typically have cool clammy
           skin, moist palms, and the lips and nailbeds may appear blue. Early in the course of septic shock,
           skin temperature and color may actually be warm and red due to initial peripheral vasodilatation – a
           condition often referred to as “warm shock”.
        5. Kidneys – Decreased renal perfusion leads to oliguria, increased urine osmolality, and increased
           BUN:creatinine ratio.
        6. GI System – A patient may develop varying degrees of GI hemorrhage from gastritis, stress ulcers,
           and scattered mucosal erosions. Adynamic ileus is common, and severe shock can lead to bowel
           infarction. Amylase may be increased due to pancreatic damage. Lastly, hepatic injury may occur,
           and eventually lead to hepatic necrosis in severe cases. Signs of hepatic injury in shock include
           elevated bilirubin, hypoglycemia, hypoalbuminemia, elevated INR. Hepatic dysfunction may also
           worsen lactic acidosis.
        7. Hematologic System – Varying degrees of coagulopathy may occur due to diffuse platelet
           activation, decreased clotting factors, and endothelial injury (ultimately leading to DIC).
        8. Diffuse cellular injury – Metabolic acidosis frequently occurs due to build-up of lactate.




Physiologic description of the categories of shock:

Perfusion pressure = MAP – CVP = CO x SVR = HR x SV x SVR


SV is diminished by reduced preload, elevated afterload, and reduced contractility.
The etiology of shock can be roughly divided into three categories:

    1. Distributive shock – Due to low SVR.
    2. Cardiogenic shock – Due to low contractility.
       Although low HR and decreased preload from an intrinsic cardiopulmonary process (e.g. tamponade,
       tachyarrhythmias) both can lead to shock, these conditions have specific treatments that are distinct
       from primary myopathic processes and which are best discussed separately.
    3. Hypovolemic shock – Due to low preload from a process external to the cardiopulmonary system.



Additional equations useful in assessing and treating shock:

                   DO2 = CO x 10 [(1.34 x Hb x SaO2) + (0.003 x PaO2)] ≈ CO x 13 x Hb x SaO2
                                      VO2 ≈ CO x Hb x 13 x (SaO2 – SvO2)
                                           O2ER = (VO2 / DO2) x 100


MAP – Mean arterial pressure                                 PaO2 – Partial pressure of oxygen in arterial blood
CVP – Central venous pressure                                CO – Cardiac output (L/min)
SVR – Systemic vascular resistance                           Hb – Hemoglobin concentration (g/dL)
HR – Heart rate                                              SaO2 – Oxygen saturation of mixed arterial blood
SV – Stroke volume                                           SvO2 – Oxygen saturation of mixed venous blood
DO2 – Peripheral oxygen delivery (mL/min)                    O2ER – Oxygen extraction ratio
VO2 – Peripheral oxygen uptake (mL/min)




Etiologies:

Distributive (Vasodilatory) Shock
          SIRS (a.k.a. Systemic Inflammatory Response Syndrome)
                   Sepsis
                   Pancreatitis
                   Extensive burns
                   Multiple traumatic injuries
                   Toxic shock syndrome (80% of cases involve tampon use. Diarrhea and a diffuse erythematous rash are
                        common findings which are not typically seen in most other causes of distributive shock.)
          Anaphylaxis (Radiocontrast dyes are the most common cause of anaphylaxis in the US)
          Toxic ingestions
                   Insect bites
                   Transfusion reactions
                   Heavy metal poisoning
                   Narcotics
                   Barbituates
                   Anesthetics
                   Arterial and venous vasodilators
          Myxedema coma
          Neurogenic shock
                   Spinal cord injury
                   Cerebral damage
                   Severe dysautonomia
          Post cardiopulmonary bypass
Hypovolemic Shock (an acute loss of 25% of a patient’s intravascular volume is needed to place him/her into hypovolemic
   shock. The ability of the body to compensate for hypovolemia diminishes with age.)
        Loss of blood volume (as in from hemorrhage)
                 External blood loss
                           Trauma
                           GI bleeding
                           Massive hemoptysis
                 Internal blood loss
                           Ruptured aortic aneurysm
                           Hemothorax
                           Hemoperitoneum
                           Retroperitoneal hemorrhage
        Loss of plasma volume
                 GI losses
                           Diarrhea/Vomiting
                 Renal losses
                           DKA
                           Hyperosmotic non-ketosis
                           Diabetes insipitus
                           Overzealous use of diuretics
                 Transcutaneous losses
                           Extensive burns
                           Inadequate repletion of insensible loses
                 Internal losses (a.k.a. “third-spacing”)
                           Pancreatitis
                           Intestinal ischemia
                           Peritonitis

Cardiogenic Shock
        Myopathic (reduced contractility)
                 Myocardial infarction (shock occurs in 5-10% of patients hospitalized for MI. Risk factors for developing
                      cardiogenic shock during an acute MI include age>65, EF<35%, CK-MB>160IU/L, diabetes, and a
                      history of previous MI. The mortality for postinfarction cardiogenic shock is <75%.)
                 Cardiomyopathy
                 Advanced septic shock
                 Myocarditis
                 Severe acidosis
        Arrhythmogenic
                 Tachyarrhythmias
                 Bradyarrythmias
        Intracardiac mechanical abnormalities
                 Papillary muscle rupture resulting in acute severe mitral regurgitation
                 Acute aortic insufficiency from an aortic dissection
                 Critical aortic stenosis
                 Septal rupture
        Inadequate diastolic filling (a.k.a. obstructive shock, which is sometimes considered as distinct from cardiogenic
             shock)
                 Massive pulmonary embolus
                 Tension pneumothorax
                 Pericardial tamponade
                 Severe pulmonary hypertension
                 Severe constrictive pericarditis
                 Positive pressure ventilation
                 Intracardiac tumors

Unique forms of shock
        Adrenal insufficiency (should always be considered if patient appears septic without evidence of infection)
        Hemoglobin/Mitochondrial Toxins
                 Carbon Monoxide
                 Cyanide
                 Iron intoxication
Diagnosis:
The initial work-up for a patient in shock should include the following (where possible):

   Aspects of history     Details of physical exam                Lab Tests                     Additional tests
Food and drug allergies   Assessment of volume       CBC with differential                 CXR
Potential acute drug          status and JVP         Chem 7                                Abdominal CT (if etiology
    intoxications         Thorough external          LFTs                                    is not obvious and
Presence of immuno-           examination for        Amylase/lipase                          patient is stable
    compromised states        signs of trauma        Fibrinogen/fibrin split products        enough for the
Past medical history      Thorough cardiac,          Lactate                                 procedure)
Medication history,           pulmonary, and         Cardiac enzymes                       EKG
    focusing on recent        abdominal exams        Venous and arterial blood gases.      Nasogastric suction (if
    changes               Rectal exam with guauic    Toxicology screen                       etiology is not obvious)
                          Examination for signs of   UA, urine culture, urine gram stain   Consider echocardiogram
                              DVT                    Blood cultures                          based on the
                          Overall assessment of      Sputum cultures (if patient is c/o      preceding information.
                              mental status             productive cough)
                          Skin exam                  Peritoneal cultures (if ascites is
                                                        present)



Initial treatment:
Before an etiology (or even an etiologic category) is determined, treatment of shock must be initiated. A systolic
BP of at least 80 mmHg is needed to adequately perfuse the brain, and at least 60 mmHg is needed to perfuse
the heart. Rapid infusion of crystalloid fluid (~1000mL) is generally safe even initially in the presence of
cardiogenic shock, though patients who are not clearly in cardiogenic shock should probably receive at 2000mL
of fluid immediately. If the patient remains hypotensive at this point, and the etiology is still unclear, a modest
dose of dopamine (e.g. 5 μg/kg/min) can be started. In addition, intubation should be considered if depressed
consciousness places the patient’s airway in jeopardy.



The Pulmonary Artery Catheter (a.k.a. Swan-Ganz catheter):
The pulmonary artery catheter allows measurement of three types of data:
       1. Central venous, pulmonary artery, and pulmonary capillary occlusion (or “wedge”) pressures
       2. Cardiac output and vascular resistence
       3. Sampling of mixed venous blood

PA catheters are most helpful when used to diagnose right heart infarctions, estimate fluid status in non-
cardiogenic pulmonary edema or ARF, diagnose pulmonary hypertension, or guide the management of severe
CHF.

Complications from PA catheters:

    1. Arrhythmias – Most common in the setting of electrolyte abnormalities
    2. Complete heart block – Can occur in the setting of pre-existing left bundle branch block, when catheter
       insertion causes a transient right bundle branch block. This is most frequent in patients with a relatively
       new LBBB from a recent MI.
    3. Pneumothorax – 1-2% risk in the internal jugular approach. Slightly higher in the subclavian approach.
    4. Knotting of the catheter – Most common in patients with dilated right ventricles.
    5. Pulmonary infarction – Caused by the balloon being left in the wedge position too long.
    6. Pulmonary artery rupture – Caused by over-inflation in a distal branch of the PA when the tip of the
       catheter has migrated inwards. The risk of occurrence is 0.2%, but this complication carries a 50%
       mortality.
    7. Infection
    8. Thrombosis/Embolism
Data Analysis:

As the catheter is advanced from the RA to the RV to the PA, and is finally wedged in a branch of the PA, a
number of distinct pressure tracing are seen, one for each chamber:

Right Atrium




Right Ventricle

RVSP should equal PASP, except in
cases of RV outflow tract obstruction.




Pulmonary Artery

PA diastolic pressure is generally 1-3
mmHg greater than PCWP, except in
cases or ARDS, hypoxia, or pulmonary
fibrosis, in which case the gradient may
be substantially higher. A PCWP that is
greater that PADP is very rare, and
suggests erroneous placement of the
catheter tip in zones 1 or 2 of the lung.




Pulmonary capillary wedge
pressure

PCWP usually correlates well with left
atrial pressure. It should be measured
at end-expiration (top of the tracing in
spontaneously breathing patients, and
bottom of the tracing in patients on
positive pressure ventilation). In theory,
the catheter tip should be in zone 3 of
the lung for accurate measurements of
PCWP, but lateral decubitus positioning
may convert a zone 2 position into zone
3 by placing the tip in a dependent
position relative to the LA.
In addition to pressure tracings, the PA catheter also allows for measurement of cardiac output. There are
currently two methods commonly employed:



Fick Method

           O2 consumption = CO x (O2 content of mixed venous blood – O2 content of arterial blood)

                                 O2 consumption ≈ 250 mL O2/min in a 70kg man

                               Therefore:      CO = 250 / [Hb x 13 x (SaO2 – SvO2)]




Thermodilution

Although all PA catheters can provide a sample of mixed venous blood for determination of CO via the Fick
method, thermodilution capability allows for more rapid and convenient measurements. In this method, a bolus
of cold fluid is introduced to the RA via the catheter, where it mixes with warm venous blood into a
thermohomogenous fluid. The thermistor then records the thermal curve generated when the mixture washes
past the proximal PA. The relationship linking output to temperature is the Stewart-Hamilton formula:


         CO = V (TB – TI) K1 K2 / ∫ TB(t)dt          V – Injected volume
                                                     TB – Core temperature
                                                     TI – Injectate temperature
                                                     K1, K2 – Constants
                                                     TB(t)dt – Change in blood temperature as a function of time


Most technical errors in the thermodilution method overestimate cardiac output. A valid temperature-time profile
shows a rapid early descent to a trough level, smoothly returning to baseline within 10-15 seconds. Sources of
error include the catheter being impacted against the vessel wall, tricuspid regurgitation, intracardiac shunting,
and imprecise measurement of injectate temperature. Although the temperature of the PA blood varies
throughout the respiratory cycle, it is unclear if this variation is clinically significant.




Using the above data, the etiologic category of shock can be determined as follows:

     Categories of Shock        PCWP / CVP           CO              SVR              SvO2
         Hypovolemic                 ↓                ↓                ↑                ↓
          Distributive              ↓/↔               ↑                ↓                ↑
         Cardiogenic                 ↑                ↓                ↑                ↓
General Treatment Principles:


Replacement Fluids

Fluids can be classified as either crystalloid or colloid based on whether they do or do not readily pass through
the capillary walls, respectively. The predominant effect of volume resuscitation with crystalloid fluids is to
expand the interstitial volume. Colloid fluids have a greater tendency to stay intravascular.


Crystalloid Fluids
                                +        -       +          +2        +
                 Fluid       [Na ]    [Cl ]    [K ]   [Ca        [Mg ]      Buffers        pH      Osmolality
                                                        ]                                          (mOsm/L)
       Plasma                141      103      4.5      5         2       Bicarbonate     7.4        289
       0.9% NaCl             154      154                                                 5.7        308
       (normal saline)
       Lactated              130      109       4       3                   Lactate       6.4          273
       Ringer’s
       Plasma-lyte           140       98       5                 3       Gluconate       7.4          295


Although some feel that lactated Ringer’s solution more closely approximates plasma, there is little evidence
that it is superior to isotonic saline. LR has been shown to help correct metabolic acidosis more quickly than
normal saline. However, there are some circumstances in which LR is clearly contraindicated, as its calcium
can bind to certain drugs and reduce their bioavailability (e.g. amphotericin, ampicillin, doxycycline). In addition,
there is the theoretical concern that the calcium in LR can bind to the citrated anticoagulant in blood products,
resulting in the formation of blood clots in the donor blood (though this has not been demonstrated by the clinical
studies). Addition of 5% dextrose to fluids in critically-ill patients is generally not recommended due to the
potential to enhance CO2 and lactate production.


Colloid Fluids

             Fluid           Oncotic Pressure          Ratio of increase in plasma          Serum Half-Life
                                                        volume to volume infused
       5% Albumin                20 mmHg                         0.7 – 1.3                      16 hours
       25% Albumin               70 mmHg                         4.0 – 5.0                      16 hours
       6% Hetastarch             30 mmHg                         1.0 – 1.3                      17 days


Volume expansion with 25% albumin occurs at the expense of the interstitial fluid volume, so this should not be
used for resuscitation in hypovolemia. Hetastarch (a.k.a. hydroxyethyl starch) is a polysaccharide structurally
similar to glycogen, whose side effects include increased PTT, transient thrombocytopenia, and allergic
reactions. FFP can provide another source of colloid protein, but because this carries risk of an allergic
reaction, it should be reserved only for cases in which hypovolemia and coagulapathy occur together (e.g.
severe hemorrhage).


Much controversy exists regarding which type of fluid (crystalloid vs. colloid) is superior for volume resuscitation.
Although the more expensive colloid fluids should be theoretically better, no data to date has shown a benefit to
their use. Although some small studies have evaluated the safety of hypertonic saline solution (7.5% NaCl) for
resuscitation, this also has not been shown superior to standard isotonic saline, with the exception of patients
with traumatic brain injury.
Vasopressors

This is a broad class of IV medications (colloquially referred to as “pressors”) which are used to increase tissue
perfusion. Although only drugs which increase vasoconstriction are technically vasopressors, those which
increase inotropy (contractility) and chronotropy (heart rate) are often included in this category as well.



Alpha adrenergic receptors – Located in vascular walls, activation of these receptors induces vasoconstriction.
Alpha 1 receptors are also located in myocardium and can increases inotropy without increased chronotropy.

Beta adrenergic receptors – Activation of beta 1 receptors in the heart increases both inotropy and
chronotrophy. Activation of beta 2 receptors in vascular walls induces vasodilatation.

Dopamine receptors – Stimulation of these receptors, present in the renal, mesenteric, coronary, and cerebral
vascular beds, leads to vasodilatation.



Important clinical pearls in vasopressor therapy:

    1. Hypovolemia must be corrected prior to the institution of vasopressor therapy. Pressors are generally
         not helpful in hypovolemic shock. In septic shock, patients generally require at least 2L of fluid
         replacement in order for pressors to be maximally effective. Fluid replacement is only relatively
         contraindicated in the setting of severe pulmonary edema due to ARDS or CHF.
    2. A given drug may have an effect on multiple receptors, and which receptors it interacts with may be
         dose dependent.
    3. A given agent may affect systemic blood pressure through both direct actions, as well as indirect reflex
         actions.
    4. No controlled trials have demonstrated a benefit of adding a third pressor, when the first two tried are
         inadequate to maintain a perfusing BP.
    5. Responsiveness to any given pressor decreases with time due to tachyphylaxis.
    6. The bioavailability of medications given subcutaneously (e.g. insulin, heparin) may be diminished during
         pressor therapy due to peripheral vasoconstriction.
    7. Patients receiving MAO inhibitors are excessively sensitive to vasopressors in general.
    8. There is currently no data to support the use of “renal-dose” dopamine. This is the practice by which
         low-dose dopamine (1-3mcg/kg/min) is used to prevent or treat ARF or mesenteric ischemia through its
         ability to cause vasodilation in these vascular beds.
    9. Although initial studies found that supranormal CI (i.e. >4.5L/min) might be beneifical in shock, larger
         trials have failed to show any benefit.
    10. Epinephrine is generally considered a second or third line agent in most causes of shock, due to
         concerns over reduced mesenteric perfusion and induced coronary ischemia.
                                                                      +    +2       +
    11. Pressors may be ineffective when serum concentrations of K , Ca , or Mg are markedly abnormal.
    12. Shock that does not respond to volume and pressor therapy should be considered to be due to adrenal
         insufficiency, until proven otherwise.
    13. There is no absolute limitations for vasopressor doses in shock.
    14. Improved mental status, adequate urine output (>0.5 mL/kg/hr), evidence of adequate digit perfusion,
         and reasonable oxygenation are better markers of successful treatment than BP, CO, or PCWP.
       Drug           Alpha-   Beta-1   Beta-2   Dopa.    Effect on SVR      Effect    Effect on       Typical Dose
                        1                                                    on HR    contractility
Phenylephrine          +++       0        0       0             ↑↑           ↔/↑          ↔            20-200 μg/min
Vasopressin             0        0        0       0             ↑↑             ↔          ↔           0.01-0.04 U/min
(mechanism of
action poorly
understood)
Norepinephrine         +++       ++       0       0              ↑↑            ↑           ↑           0.5-20 μg/min
Epinephrine            +++      +++      ++       0       ↓ (low dose)         ↑           ↑            2-10 μg/min
                                                         ↔ / ↑ (high dose)
Dopamine                                                                                              1-20 μg/kg/min
(μg/kg/min) 0.5 – 2    0          +       0       ++            ↔             ↑           ↑
             5 – 10    +         ++       0       ++            ↑             ↑           ↑
           10 – 20    ++         ++       0       ++            ↑↑            ↔           ↔
Dobutamine            0/+       +++      ++        0            ↓             ↑          ↔/↑          2.5-20 μg/kg/min
Isoproternol           0        +++      +++       0            ↓             ↑           ↑             1-10 μg/min

Milrinone (acts as      0        0        0       0             ↓             ↔            ↑↑         Load: 50 μg/kg
a phosphodi-                                                                                             over 10 min
esterase inhibitor)                                                                                   Maintenance:
                                                                                                         0.375 – 0.75
                                                                                                         μg/kg/min




N-monomethyl-L-arginine (L-NMMA) – A nitric oxide synthase inhibitor that results in a dose-dependent
increase in SVR. However, CO and HR both decrease such that MAP is only minimally affected. The clinical
utility of this drug is current uncertain.



Complications from vasopressor therapy:
                                                                      5
       1. Hypoperfusion – Occurs when SVR>1300 dynes x sec/cm , which is most often seen in the setting of
          inadequate CO or incomplete volume resuscitation. In its extreme manifestation, this may result in
          frank necrosis and autoamputation of digits. Inadequate mesenteric perfusion increases the risk of
          gastritis, shock liver, intestinal ischemia, and translocation of the gut’s bacterial flora.
       2. Dysrhythmias – Due to excessive beta 1 stimulation. The most common arrhythmias are sinus
          tachycardia, atrial fibrillation, AVNRT, and ventricular tachyarrhythmias.
       3. Myocardial ischemia – Due to excessive chronotropy and inotropy from beta 1 stimulation.
       4. Local skin necrosis – Occurs when vasopressors are infused through peripheral veins
       5. Hyperglycemia – Due to inhibition of insulin secretion, most pronounced with norepinephrine and
          epinephrine.
                                            Hypovolemic Shock

Classification of hemorrhage based on extent blood loss:


                  Parameter             Class I         Class II         Class III         Class IV
             % loss of blood            < 15%           15-30%            30-40%            > 40%
             volume
             Heart rate                 < 100            > 100            > 120            > 140
             Supine BP                  Normal          Normal          Decreased        Decreased
             Urine output               Normal           Mildly          Severely          Anuric
                                                       decreased        decreased
             Mental Status             Anxious          Agitated        Confused          Lethargic


Use of the hematocrit to estimate acute blood loss is unreliable, as it may take 8-12 hours for the hematocrit to
fully reflect the degree of loss.



Treatment of hypovolemic shock generally consists of four issues:

        1.   The choice of replacement fluid
        2.   The total amount and rate of fluid replacement
        3.   Identification and treatment of the source of fluid loss
        4.   The role of buffer therapy in patients with concurrent lactic acidosis


Vasopressors such as norepinephrine and dopamine generally should not be administered since they do not
correct the problem, and may actually worsen tissue perfusion. The Trendelenburg position is generally not
recommended for treatment of low BP due to hypovolemia.



Choice of replacement fluid

The choice of replacement fluid largely depends upon the fluid that is being lost. Some debate exists whether
colloid or crystalloid solutions should be used, however both randomized controlled trials and meta-analyses
have failed to demonstrate outcome benefit of colloid solutions over the cheaper and more readily available
crystalloid.



Amount and rate of replacement fluid

It is frequently not possible to predict the total fluid deficit in a patient in hypovolemic shock, however, a very
rough estimate can be made by the following:

1. Calculate total blood volume: 66mL/kg in men, 60mL/kg in women (reduce by 10% in the obese and elderly).
2. Determine the % of blood loss
3. Multiple total blood volume by the % loss
4. If using colloid fluids, the total amount needed will be approximately 1.5 times the result in step 3.
   If using crystalloid fluids, the total amount will be approximately 4 times the result in step 3.
In practice, most patients will benefit from immediate resuscitation with a bolus of at least 1-2 L of isotonic
saline. Peripheral veins are preferred for resuscitation because the shorter catheter provides less resistance to
fluid flow. Flow rate can be further increased by the use of pressure bags, and by lowering the infusing blood’s
viscosity by either warming it or infusing 100-200cc of normal saline prior to infusion. Fluid resuscitation should
remain at a very rapid rate until blood pressure and signs of systemic perfusion (e.g. mental status, urine output)
improve. Peripheral edema may result from acute dilutional hypoalbuminemia, and should not be used as a
sign of adequate fluid resuscitation. CVP can also help guide fluid repletion, and in patients in whom CVP
cannot be measured, a high degree of respirophasic variation in arterial systolic pressure may indicate the
presence of persistent hypoperfusion (although no specific cutoff values of this variation are currently defined).

One widely cited study found benefit of delaying fluid resuscitation in patients with hypovolemic shock due to
hemorrhagic injuries from gunshots and stab wounds, in which patients were resuscitated only to a SBP of 70
mmHg until operative intervention could be undertaken. The theory is that aggressive fluid rehydration might
result in worsened blood loss from augmented BP, dilution of clotting factors, and hypothermia. This study has
been criticized because it included only young, otherwise healthy patients, and the mean time from injury to
operation was only 2 hours. However, animal studies also suggest that over-resuscitation in the setting of on-
going non-lethal hemorrhage, may make the injury lethal. At this time, delayed fluid administration should only
be considered if emergent surgical exploration can be performed immediately at the time of presentation to the
ED.


Common endpoints of volume                 1.   CVP = 15 mmHg
resuscitation:                             2.   PCWP = 10-12 mmHg
                                                               2
                                           3.   CI > 3L/min/m
                                                                     2
                                           4.   VO2 > 100mL/min/m
                                           5.   Blood lactate < 4 mmol/L
                                           6.   Base deficit = -3 to +3 mmol/L


In patients who are in hypovolemic shock from exsanguination and who require massive transfusion, a number
of specific problems arise. First, as a formal cross-match procedure requires 45-60 minutes, O-negative blood
may be given initially. However, ABO determination alone takes ~10 minutes, and the small amount of plasma
in O-negative blood may contain antibodies which can react to the recipient’s RBCs resulting in minor
transfusion reactions. Therefore type-specific blood is preferred except in the most emergent of circumstances.

Additional problems arising from massive transfusion (>10 units pRBCs over 24 hours) including the following:

        1. Dilutional thrombocytopenia and coagulopathy – These usually become evident after the transfusion
           of about 5 units of pRBCs. To maintain a normal clotting profile, 2 units of FFP and 6 units of
           platelets should be transfused per 6-10 units of pRBCs.
        2. ARDS – Risk of this complication may be reduced by use of blood filters to remove component
           microaggregates.
                                                                              -
        3. Hypokalemic alkalosis – This is due to the generation of HCO3 from transfused citrate. This is
           usually clinically insignificant and self-correcting.
        4. Hypothermia – Risk reduced by prewarming infused blood.
                                               +
        5. Hyperkalemia – Occurs due to K leakage from stored pRBCs.
        6. Transfusion-related infection – The risk of viral hepatitis infection (HBV or HCV) is about 1 in
           150,000 per unit of transfused blood. The risk of HIV is between 1 in 50,000 and 1 in 500,000 per
           unit of transfused blood component.


Buffer therapy

Patients with pH<7.10 from lactic acidosis in the setting of profound hypovolemia may benefit from sodium
bicarbonate, although this therapy is controversial and is without evidence.
                                             Sepsis and SIRS

Definitions:
SIRS (Systemic inflammatory response syndrome) – A systemic level of inflammation that may or may not be
   due to infection, generally manifested as a combination of vital sign abnormalities including fever or
   hypothermia, tachycardia, and tachypnea.
Severe SIRS – When at least 1 major organ system fails in the setting of SIRS.
Sepsis – SIRS which is secondary to infection.
Severe Sepsis – Severe SIRS which is secondary to infection.
Septic Shock – Severe sepsis resulting in hypotensive cardiovascular failure.
MODS (Multiple organ failure) – The presence of altered function of more than one organ in an acutely ill
   patient, which requires intervention in order for the patient to maintain homeostasis (e.g. mechanical
   ventilation, hemodialysis). The term, primary MODS, is used when the organ failure is attributable to the
   initial insult itself (ARF following rhabdomyolysis). Secondary MODS occurs when the organ failure is a
   result of the host response to the initial insult (e.g. ARDS in pancreatitis).


Diagnostic Criteria:

                 SIRS                                                        Severe SIRS
       Requires 2 of the following:                       Must meet criteria for SIRS, plus 1 of the following:

a. Temp >38.3° or <36.0° C                          a. Altered mental status
b. Tachypnea (RR>20 or MV>10L)                      b. SBP<90mmHg or fall of >40mmHg from baseline
c. Tachycardia (HR>90, in the absence               c. Impaired gas exchange (PaO2/FiO2 ratio<200-250)
   of intrinsic heart disease)                      d. Lactic acidosis (pH<7.30 & lactate > 1.5 x upper limit of
                        3          3
d. WBC > 10,000/mm or <4,000/mm or                      normal)
   >10% band forms on differential                  e. Oliguria or renal failure (<0.5mL/kg/hr)
                                                    f. Hyperbilirubinemia
                                                                                                       3
                                                    g. Coagulopathy (platelets < 80,000-100,000/mm , INR >2.0,
                                                       PTT >1.5 x control, or elevated fibrin degredation products)


In order for a pathophysiologic state to be referred to as “sepsis”, there must be clinical evidence of infection in
addition to the above criteria (e.g. positive cultures, perforated viscus, WBCs in a normally sterile fluid,
radiographic evidence of pneumonia, or a syndrome associated with unusually high rate of infection such as
ascending cholangitis.)



Venn diagram
displaying the various
terminology surrounding
sepsis and SIRS:




(Adapted from: Marini JJ, et
al. Critical Care Medicine,
2nd ed. 1997.)
Risk Factors for                   Extremes of age                    Diabetes
Developing Sepsis:                 Indwelling lines/catheters         Cirrhosis
                                   Immunocompromised states           Altered mental status
                                   Malnutrition                       Male sex
                                   Alcoholism                         Genetic predisposition?
                                   Malignancy




Pathophysiology:
Approximately 70-80% of all patients with septic shock will have a specific bacterial agent identified. Although
the distribution is approximately 50% gram negative, 50% gram positive, a further breakdown is not relevant as
all patients will require broad-spectrum antibiotics regardless. The severity of the sepsis syndrome is not
dependent on the inciting organism (or even on whether an organism exists at all, as in cases of severe SIRS),
but rather on the host response to the triggering event. Although inflammation is essential to host response
against infection, SIRS results from a dysregulation of the normal response, with massive, uncontrolled release
of pro-inflammatory mediators. In simplest terms, the current model of how SIRS develops, involves a multistep
cascade in which an initial trigger leads to the production of a limited number of early mediators, followed over
several hours by a larger number of secondary mediators:




Mechanism of the development of hypotension in SIRS/sepsis:

                    Vasodilation                                          Intravascular Volume Depletion
                             +
Activation of ATP-sensitive K channels in the                   Increased capillary permeability leading to third-
    vascular smooth muscle                                          spacing of fluid
Increased synthesis of NO as a result of increased              Concurrent volume loss from vomiting or diarrhea
    levels of the enzyme, inducible NO synthase
Deficiency of vasopressin




Laboratory tests which have been investigated as methods to diagnosis SIRS/sepsis prior to its clinical
recognition include procalcitonin, C-reactive protein, specific cytokines, and endotoxin. In addition, evidence
exists that in early sepsis, a biphasic waveform develops in the determination of aPTT. However, none of these
tests have been found to be adequately specific enough for clinical use.
Prognosis:
Overall mortality from SIRS/sepsis in the U.S. is approximately 20%. Mortality is roughly linearly related to the
number of organ failures, with each additional organ failure raising the mortality rate by 15%.

Risk Factors for              Male sex                                    Hypothermia (mortality rate of 80%)
Mortality in Sepsis:          Non-white                                   Leukopenia
                              Age>40                                      Nosocomial infection
                              AIDS                                        Pseudomonas bacteremia
                              Cirrhosis                                   Arrival to the ICU as a result of an
                              Malignancy                                     intrahospital or interhospital transfer
                              Immune suppression                             (as opposed to an admission directly
                                                                             from the ED)


On average, survivors of severe SIRS/shock require 7-10 days of mechanical ventilation, 7-14 days of ICU level
care, and a total of 3-5 weeks of hospitalization. Hemodialysis, mechanical ventilation, or vasopressor therapy
is rarely needed beyond 3 weeks.




Treatment:

Fluid resuscitation

Rapid, large volume infusions are generally indicated in all patients with septic shock. Some patients require up
to 10L of crystalloid in the first 24 hours, with an average requirement of 4-6L. Although resuscitation with
colloid will necessitate less overall volume of fluid, there is no difference between patients treated with colloid
versus crystalloid in the development of pulmonary edema, length of stay, or survival.



Vasopressors

These are second line agents in the treatment of septic shock (after volume resuscitation). A goal MAP should
be 60-65mmHg, although urine output, mental status, and skin perfusion are better variables to use in
monitoring adequate perfusion. Norepinephrine, dopamine, and phenylephrine are all commonly used as the
initial pressor, though there is minor evidence that norepinephrine may be the best choice (due to improved
splanchnic circulation compared to other choices).

One non-randomized study suggested that vasopressin may be beneficial as a second pressor in the treatment
of refractory sepsis, as endogenous vasopressin stores in the posterior pituitary are rapidly depleted in septic
shock.

Some patients with septic shock develop reversible myocardial dysfunction as a result of either circulating
cytokines or NO, characterized by reduced EF and ventricular dilation. Inotropic agents such as dobutamine
may be beneficial in these patients by increasing both stroke volume and HR. Although epinephrine also
increases cardiac output, its use should be limited in sepsis due to its impairment of splanchnic blood flow.

Although vasodilation in patients with severe sepsis is thought partly due to increased levels of circulating NO,
attempts to use L-NMMA resulted in increased mortality, presumably from pulmonary hypertension and right-
sided heart dysfunction.
Eradication of infection

Any potential source of infection should be addressed (e.g. removal of potentially infected catheters, drainage of
abscesses). The specific timing of such intervention must be determined on a case-by-case basis.



Antibiotics

Empiric antibiotic therapy should be instituted immediately after appropriate cultures have been drawn. Empiric
therapy should take into consideration the likely source of infection, and in general should include two effective
agents from different classes, for example, a beta-lactam and an aminoglycoside (although several clinical trials
                                 rd
suggest monotherapy with a 3 generation cephalosporin or a carbapenem may be adequate). Although little
data exists that antibiotics alter the morbidity or mortality of sepsis in the first few days of illness, patients with
sepsis who do not have the causative organism identified have a 10-20% higher mortality rate compared to
those who do (who presumably receive treatment aimed at the specific microbe).


Empiric antibiotic treatment in life-threatening community-acquired infections:

                                                            Suspected Site of Origin
                          Lung                 Abdomen              Skin/Soft Tissue         Urinary Tract        Central Nervous
                                                                                                                     System
                  Strep. pneumoniae,      E. coli                  (Often polymicrobial)     E. coli             Strep. pneumoniae,
Common
Pathogens in      H. influenzae           Bacteroides fragilis     Group A strep             Klebsiella sp.      Neisseria meningiditis
Community                                                                                                        (rare>50 yrs),
Acquired          Legionella sp.                                   Staph. aureus             Enterobacter sp.
                                                                                                                 Listeria
Infections
                  Chlamydia                                        Clostridium sp.           Proteus sp.         monocytogenes
                     pneumoniae                                                                                  (rare<50 yrs),
                                                                   Pseudomonas
                  Pneumocystis carinii                                                                           E. coli
                                                                   Anaerobes
                                                                                                                 H. influenzae

                                           Imipenem-cilastatin          Vancomycin           Ciprofloxacin +/-       Vancomycin +
Empiric               Azithromycin +           (Primaxin)                                      Gentamicin            Ceftriaxone +
Antibiotic             Ceftriaxone                                                                                     Ampicillin
Therapy                                             OR                       AND                       OR
                            OR
                                              Piperacillin-                                     Ampicillin +               OR
                       Moxifloxacin       Tazobactam (Zosyn)       Either:   Imipenem           Gentamicin
                                            + Metronidazole
                            OR                  (Flagyl)                        or                     OR            Vancomycin +
                                                                                                                      Meropenem
                       Gatifloxacin                 OR                        Zosyn,            Ceftriaxone

                                           Ampicillin + Flagyl +                 or                    OR
                  A quinolone should        (Ciprofloxacin or
                  always be used if           Gentamicin)                     ticarcillin-         Zosyn
                  legionella or bioter-                                      clavulanate
                  rorism is suspected                                         (Timentin)
Empiric antibiotic treatment in life-threatening nosocomial infections:

                                                          Suspected Site of Origin
                            Lung                Abdomen                 Skin/Soft          Urinary Tract         Central
                                                                         Tissue                                  Nervous
                                                                                                                 System
Common
                      Aerobic gram-        Gram-negative rods       Staph. aureus,        Aerobic gram-     Pseudomonas
Pathogens in          negative rods                                                       negative rods
Nosocomial                                 Anaerobes                Aerobic gram-                           E. coli
Infections                                                          negative rods         Enterococci
                                           Candida species                                                  Klebsiella sp.

                                                                                                            Staph. sp.
Empiric Antibiotic
                         Imipenim or             Imipenem              Vancomycin            Ampicillin +     Vancomycin +
Therapy
                         Meropenim                                                           Gentamicin       Ceftriaxone +
                                                    OR                                                          Ampicillin
(should be tailored          OR                                               AND                OR
to resistance                                 Zosyn + Flagyl
                        Cefipime + anti-                                                        Zosyn                 OR
patterns of the          pseudomonal                OR              Either:    Imipenem
specific hospital)      aminoglycoside                                                           OR
                       (e.g. gentamicin,    Ampicillin + Flagyl +                   or                        Vancomycin +
                          tobramycin.        (Ciprofloxacin or                                 Timentin        Meropenem
                                               Gentamicin)                      Zosyn,
                                                                                                 OR
                                                                                    or
                                                                                              Imipenem
                                           Can consider adding                 Timentin
                                           an antifungal                                         OR

                                                                                             Meropenem



Respiratory Support

Nearly all patients with sepsis require supplemental oxygen, and approximately 80% require mechanical
ventilation. Use of mechanical ventilation not only may improve oxygenation, but the necessary sedation +/-
paralysis may improve organ perfusion by diverting blood flow away from the diaphragm. In non-ARDS
patients, plateau pressure should be kept below 35cm H2O to prevent barotrauma, which usually necessitates
reducing TV to 5-6 ml/kg with resultant hypercapnia. SaO2 should generally be kept > 90%, except possibly in
younger, otherwise healthy patients. FiO2 should be kept below 0.6, and if greater oxygenation is required,
sequential upward titration of PEEP be initiated. In most cases, PEEP of 5-10cm H2O is sufficient. A discussion
of ventilatory strategy for septic patients with ARDS should be sought elsewhere. Clinical trials have not
consistently shown benefit to increasing peripheral O2 delivery to supranormal levels by increasing FiO 2, Hb, or
CO.


Transfusions

As hemodilution accompanies aggressive fluid resuscitation, administration of pRBCs is often required to
maintain Hb concentrations around 10-12g/dL. However, clinical trials have failed to demonstrate an outcome
benefit related to raising hemoglobin above 10 g/dL in the non-bleeding patient without active cardiac ischemia


Recombinant Activated Protein C (a.k.a. drotrecogin alfa, Xigris)

In a 2001 study (the PROWESS trial), patients who received a 96hr infusion (24μg/kg/hr) of APC within 24 hours
of presentation had a statistically lower 28-day mortality rate (25% vs. 31%), with a number needed to treat of
only 16. Treatment was of greater benefit in the most acutely ill patients (APACHE II score ≥ 25). However,
patients treated with APC had an increased rate of serious bleeding (3.5% vs 2.0%), including fatal intracranial
hemorrhage, and the study itself excluded a large number of patients, including those with metastatic cancer,
pancreatitis, and most organ transplant recipients. Finally, APC has been found to not be cost effective in those
patients with APACHE II scores <25 or in those with relatively low life-expectancy even in the event of survival
from sespis.

Contraindications to APC:          Active internal bleeding
                                   Recent (≤3 months) hemorrhagic stroke
                                   Recent (≤2 months) intracranial or intraspinal surgery or severe head trauma
                                   Trauma with increased risk for life-threatening bleeding
                                   Presence of an epidural catheter
                                   Intracranial neoplasm or mass lesion
                                   Evidence of cerebral herniation.


Corticosteroids

Patients with vasopressor-dependent septic shock not uncommonly have an inappropriate cortisol response to
the shock state. One large trial of physiologic dose steroid replacement (50mg of hydrocortisone q8h + 50μg of
fludrocortisone per NGT) in these patients failed to see a significant improvement in outcome in the absence of
an abnormal ACTH-stimulation test at the onset of therapy. While there is no consensus regarding the definition
of adrenal insufficiency during sepsis, suggestions have been made to use either failure to increase serum
cortisol levels by 9μg/dL in response to 250μg of ACTH, or a baseline cortisol less than 25μg/dL during shock,
as diagnostic.

There is currently no evidence to use supraphysiologic corticosteroids in septic patients either with or without
adrenal insufficiency. However, some evidence exists that some patients may have a state of “relative adrenal
insufficiency”, who have a baseline cortisol > 34μg/dL which could not be increased by greater than 9μg/dL after
administration of ACTH.

Based on several subsequent studies, there may be benefit to the evaluation of adrenal function in conjunction
with low-dose corticosteroid supplementation (hydrocortisone 50mg q6h + fludrocortisone 50μg/day) in patients
with vasopressor-dependent septic shock that persists despite adequate fluid resuscitation. However, routine
use of corticosteroids in all patients is not recommended.


Glycemic Control

Maintenance of blood glucose concentration between 90 and 110 mg/dL is associated with improved outcomes
in critically-ill patients.


Nutrition

Proper enteral nutrition is necessary for maintaining the integrity of the gut mucosal, though it does not appear
that this goal requires full nutritional support in the short term. In general, a mixture of carbohydrate, lipid, and
protein should be given via an enteral route after hemodynamic stability is achieved. Though there is no
compelling evidence for any particular formula, however, the following offers some rough guidelines for
nutritional support in the septic patient:

       Caloric intake:     25 – 30 kcal/kg/day           Protein:     1.3 – 2.0 g/kg/day
                                                         Glucose      70% of total non-protein calories/day
                                                         Lipids       30% of total non-protein calories/day

Early enteral nutrition rich in branched-chain amino acids may confer survival benefit. Parenteral nutrition
should be reserved for patients with gut dysfunction anticipated for >5 days.
Experiemental Therapies for Sepsis

NSAIDs – Although NSAIDs showed benefit in animal models of sepsis, they have not produced a significant survival benefit
in human trials (despite decreasing fever, tachycardia, O2 consumption, and lactic acidosis).

Anti TNF-α antibody – One study found a 3.6% reduction in mortality in septic patients treated with the TNF antibody, MAK-
195 (afelimomab), who also had IL-6 levels greater than 1000pg/mL at the onset of therapy. However, questions have been
raised regarding the statistical analysis of this finding, which may not have been statistically significant.

Antithrombin – One multicenter, prospective, randomized, double-blind, placebo-controlled trial was conducted with
antithrombin in 2314 patients with severe sepsis, which found no difference in mortality between the placebo and
antithrombin groups (though there was a trend towards improved survival in those patients who received no heparin at any
point in addition to the antithrombin).

Tissue factor pathway inhibitor – One multicenter, prospective, randomized, double-blind, placebo-controlled trial was
conducted with TFPI in 1754 patients with severe sepsis and INR>1.2, which had no effect on all-cause mortality.

Additional innovative therapies currently being investigated include naloxone, anti-endotoxins, IL-1 receptor antagonists,
TNF receptor antagonists, antioxidants, hemofiltration, and plasma exchange.




Protocol for Early Goal
Directed Therapy in the
ED:




(Adapted from NEJM 2001;
345:1368-77, in which patients
receiving this goal directly
therapy had improved in-
hospital mortality compared to
those with “standard” therapy,
31% to 47%.)

				
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