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What Is Sepsis Presentation Transcript

  • 1. What is Sepsis?
    • Introduction & Learning Objectives
    • What is The Sepsis Paradigm?
    • What is meant by SIRS, sepsis and septic shock?
    • Describe the Inflammatory Cascades
    • What Vascular Injuries occur in sepsis?
    • What is the role of  Nitric Oxide in sepsis?
    • What are the Mechanisms of Peripheral Vascular Failure and Capillary Leak in SIRS?
    • Describe the Imbalance of Coagulation and Fibrinolysis in sepsis
    • What is the role of Activated Protein C in sepsis?
    • How does sepsis effect the various organs of the body?
    • What is The Gut Origin Theory?
    • What is the Lung Origin Theory?
  • 2. Clinical Approach Scenario 1
    • A 64 year old female was admitted following a motor vehicle collision. In the emergency room she was complaining of a sore ankle and moderate abdominal pain. She had a bi-malleolar fracture of her ankle and was admitted to an orthopedic service with reassurance.
    • 24 hours after admission she developed worsening abdominal pain and became progressively oliguric. 2 hours later, she developed hypotension and hypoxemia. CT of her abdomen revealed a small bowel rupture at the duodeno-jejunal junction.
  • 3.   The Sepsis
    • Initially injury :- infection, trauma or inflammation.
    • activation of host defense mechanisms, release of inflammatory cytokines, particularly interleukin-6 and tumor necrosis factor alpha.
    • Tachypnea, tachycardia, leucocytosis and pyrexia, and we call this the systemic inflammatory response.
    • Mechanical ventilation, often with cardiovascular support.
    • further injury.
    • At this point one of three things may happen
    • 1,2) the injury and inflammatory and or inflammatory response may persist .
    • 3) The patient may develop a second (or third or fourth) injury, such as nosocomial pneumonia, ventilator induced lung injury or bacterial translocation from the gut,.
  • 4.
    • Persistent inflammation leads to
    • widespread endothelial dysfunction, and ischemic tissue injury
    • The result of this is multi organ dysfunction.
    • multi-organ dysfunction becomes multi-organ failure.
    • mechanical ventilation,
    • inotropes and vasopressors,
    • renal replacement therapy,
    • continuing blood product transfusions etc.
    • The patient becomes severely catabolic,
    • The majority of patients who develop multi organ failure succumb, due to inability to wean external interventions (usually mechanical ventilation and vasopressors).
    • Death is inevitably as a result of withdrawal of this support.
  • 5. What is meant by SIRS, sepsis and septic shock?
    •   These terms included sepsis, septicemia, bacteremia, infection, septic shock, toxic shock etc.
    • 1. There were no strict definitions for the terms used, and often these words or phrases were used incorrectly.
    • 2, An emerging body of evidence arose which led us to believe that systemic inflammation, rather than infection, was responsible for multi-organ failure.
    • In the early 1990s a consensus conferences laid out a new series of definitions for what is inflammation and what is sepsis
    • The terminology has come into common usage.
  • 6. ACCP/SCCM Consensus Conference Definitions (3)
    • the new definitions published in the summer of 2002.
    • Infection A host response to the presence of micro-organisms or tissue invasion by microorganisms.
    • Bacteremia.
    • The presence of viable bacteria in circulating blood
    • Systemic Inflammatory Response Syndrome (SIRS)
    • The systemic inflammatory response to a wide variety of severe clinical insults, manifested by two or more of the following conditions:
    • Temperature > 38°C or < 36°C
    • Heart rate > 90 beats/min
    • Respiratory rate > 20 breaths/min or PaCO2 < 32 mm Hg
    • WBC count > 12,000/mm3 , < 4000/mm3 , or > 10% immature (band) forms.
  • 7. Sepsis
    • The systemic inflammatory response to infection. In association with infection, manifestations of sepsis are the same as those previously defined for SIRS. It should be determined whether they are a direct systemic response to the presence of an infectious process and represent an acute alteration from baseline in the absence of other known causes for such abnormalities. The clinical manifestations would include two or more of the following conditions as a result of a documented infection:
  • 8.
    • Severe Sepsis/SIRS.
    • Sepsis (SIRS) associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria , or an acute alteration in mental status.
    • Refractory (Septic) Shock/SIRS Shock.
    • A subset of severe sepsis (SIRS) and defined as sepsis (SIRS) induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria , or an acute alteration in mental status. Patients receiving inotropic or vasopressor agents may no longer be hypotensive by the time they manifest hypoperfusion abnormalities or organ dysfunction, yet they would still be considered to have septic (SIRS) shock.
    • Multiple Organ Dysfunction Syndrome (MODS).
    • Presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.
  • 9. What is Sepsis?  Inflammation A Description of the Inflammatory Cascades
    • The presence of pathogens in the bloodstream elicits an inflammatory response.
    • There is an intricate linkage between the inflammation and coagulation. Here is, briefly, a description of the inflammatory cascade.
    • Tissue injury or pathogens (bacterial, viruses, fungi or parasites) causes stimulation of monocytes,
    • the kingpins of the immune system within tissues, produce interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα).
    • These cytokines modulate the release and activation of different agents – interleukin-8, complement, histamine, kinins,, serotonin, selectins, ecosanoids and, of course neutrophils.
    • The result of the activation of these compounds is local vasodilatation
  • 10.  
  • 11.  
  • 12.  
  • 13. Vascular Injuries
    • Vasodilatation – due to loss of normal sympathetic tone, caused by the combination of local vasodilator metabolites,, and the production of inducible nitric oxide synthetase, which produces excessive amounts of nitric oxide.
    • Reduced stroke volume, due to the presence of a circulating myocardial depressant factor. There is reversible biventricular failure, a decreased ejection fraction, myocardial edema and ischemia. Although you may have noted that cardiac output usually increases in sepsis, this is invariably due to an increase in the heart rate.
    • Microcirculatory failure this is the major area of cardiovascular injury. The small blood vessels vasodilate, and there is widespread capillary leak, In addition, there is initial activation of the coagulation system, and deposition of intravascular clot, causing ischemia.
    • Sepsis is a microcirculatory disorder, the problem starts there and finishes there, and that is where future therapies (starting with activated protein C) .
  • 14. Nitric Oxide
    • . Nitric Oxide is produced from l-arginine by nitric oxide synthetase (NOS), and its actions are mediated by cGMP.
    • NO is an essential to the normal functioning of the vascular system.
    • So what happens in sepsis?
    • It appears that there are two forms of the enzyme nitric oxide synthetase,
    • constitutive form, produced as part of the normal regulatory mechanisms,
    • inducible form, whose production appears to be pathologic. Inducible NOS (iNOS) appears to be produced as an off shoot of the inflammatory response,
    • by TNF and other cytokines. It results in massive production of nitric oxide, causing widespread vasodilatation
    • Nitric oxide has a physiological antagonist, endothelin-1, a potent vasoconstrictor whose circulating level is increased  in cardiogenic shock and following severe trauma.
    • The major cause of vasodilation in sepsis appears to be mediated by ATP-sensitive potassium channels in smooth muscle. We do not know for certain what agents cause activation of these channels. The result of activation is increased permeability of vascular smooth muscle cells to potassium, and hyperpolarization of the cell membranes, preventing muscle contraction, leading to Vasodilation.
    • In addition to potassium channels and inducible nitric oxide, there is a relative deficiency of vasopressin in early sepsis,
  • 15. Coagulopathy
    • The activation of the coagulation cascades appears to be an essential component in the development of multi-organ failure
    • Damage to the endothelium exposes a procoagulant factor known as “tissue factor”.
    • Tissue factor binds to activated factor VII. The resulting complex activates in turn factors IX and X.
    • Factor X converts prothrombin into thrombin, which cleaves fibrinogen into fibrin, a blood clot. At the same time, the fibrinolytic system is inhibited.
    • At the same time, the fibrinolytic system is inhibited. Cytokines and thrombin stimulate the release of  plasminogen-activator inhibitor-1 (PAI-1), from platelets and the endothelium. In the human body, when a clot forms, it is ultimately broken down plasmin, which is activated by tissue plasminogen activator (TPA) [from plasminogen]. PAI-1 inhibits TPA.
    • Thrombin, itself, is an activator of inflammation and inhibitor of fibrinolysis. The latter is achieved by the activation of TAFI (thrombin-activatable fibrinolysis inhibitor).
    • Thrombomodulin, another modulator of fibrinolyis, is impaired by inflammation and endothelial injury. The function of this compound is to activate protein C. Activated protein C modifies the inflammatory and coagulant response at several different levels; a deficiency occurs due to inhibition of thrombomodulin in sepsis.
  • 16.  
  • 17. What is Sepsis?  Multi-Organ Failure                   How does sepsis effect the various organs of the body?
  • 18. Autoregulated Organs
    • The brain and kidneys are normally protected from swings in blood pressure by autoregulation:
    • In early sepsis - autoregulation curve shifts rightwards (due to and increase in sympathetic tone).
    • In late sepsis - vasoplegia occurs- and autoregulation fails, making these organs susceptible to the swings that occur in systemic blood pressure. In addition, “steal phenomena” may occur (areas of ischemia may have their blood stolen by areas with good perfusion). This is known as “vasomotor neuropathy
  • 19.
    • CNS
    • Patients become confused, delirious and ultimately stuporose and comatose due to a variety of insults: hypoperfusion injury, septic encephalopathy, metabolic encephalopathy and, of course drugs used for sedation.
    • Heart
    • Myocardial O2 supply is dependent on diastolic blood pressure, which falls following vasoplegia, and intravascular volume depletion. This may lead to ischemia. There is reversible biventricular dilatation, decreased ejection fraction, and decreased response to fluid resuscitation and catecholamine stimulation. A circulating myocardial depressant substance is responsible for this phenomenon. This substance has been shown to represent low concentrations of TNF-alpha and IL-1beta acting in synergy on the myocardium through mechanisms that include NO and cGMP generation (8).
    • Lungs
    • Ventilation / perfusion mismatches occur, initially due to increased dead space (due to hypotension and fluid shifts), subsequently due to shunt (due to acute lung injury (19)). Up to 70% of patients develop nosocomial pneumonia.
    • The most dramatic manifestation of sepsis on the lung is acute respiratory distress syndrome .
    • Kidneys
    • Acute renal failure is common in sepsis, due to fluid redistribution, hypoperfusion and circulating nephrotoxins, many of which are liberated following cell injury.
  • 20.
    • Liver
    • ICU jaundice
    • Uncontrolled production of inflammatory cytokines by the kuppfer cells (of the liver), primed by ischemia and stimulated by endotoxin (derived from the gut), leads to cholestasis and hyperbilirubinaemia.
    • Splanchnic Circulation
    • GUT mucosa is usually protected from injury by autoregulation. Hypotension and hypovolemia leads superficial mucosal injury. This leads to atrophy and translocation of bacteria into the portal circulation and stimulate liver macrophages causing cytokine release and amplification of SIRS.
    • Metabolic and Endocrine
    • Metabolic abnormalities in sepsis include hyperglycemia due to sepsis & catecholamines (both cause insulin resistance), lactic acidosis, a generalized catabolic state which leads to muscle breakdown. There is relative hypothyroidism, hypopituitarism and adrenal insufficiency.
  • 21. Gut Origin Theory
    • Following any acute injury, there is large increase in circulating adrenaline. As this is designed as a “fight or flight” response, blood is redistributed to essential organs, the heart, the brain (an, to an extent, the muscles). The gut is a non-essential organ, and as one is unlikely to eat while doing battle (or bleeding to death), splanchnic blood flow is cut off, until the situation changes. In sepsis, the flow of blood to the gut may be shut off for hours or days, depending on the quality of fluid resuscitation and the restoration of perfusion pressure. This, and the simultaneous loss of tropic nutrients in the gut lumen (if the patient is not being fed), serves to starve the mucosa of food and nutrients, and it gradually atrophies and breaks down. Simultaneously, the gut bacteria become hungry, and go looking for food. With loss of the mucosal barrier, these bacteria are able to translocate into the portal circulation, where they make their way to the liver, to amplify the systemic inflammatory response.
    • Loss of splanchnic blood flow, starvation and bacterial translocation may well be the motor which drives the systemic inflammatory response (17;21) . Modern management strategies involve aggressive splanchnic resuscitation (17;22) (e.g. with dobutamine), and early enteral nutrition.
  • 22.
    • Loss of splanchnic blood flow, starvation and bacterial translocation may well be the motor which drives the systemic inflammatory response
    • Grinnell BW, Joyce D. Recombinant human activated protein C: A system modulator of vascular function for treatment of severe sepsis. Crit Care Med 2001; 29(7):S53-S61.
    • Modern management strategies involve aggressive splanchnic resuscitation (e.g. with dobutamine), and early enteral nutrition.
    • Marik PE. Total splanchnic resuscitation, SIRS, and MODS. Crit Care Med 1999; 27(2):257-258.
  • 23.  
  • 24.  
  • 25.  
  • 26.  
  • 27. Lung Origin Theory
    • Recent research however has led to an alternate and frightening possibility: it is the use of mechanical ventilation which is the motor of the systemic inflammatory response. How can this be? There is compelling evidence that mechanical ventilation with large tidal volumes is associated with higher mortality.
    • Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342(18):1301-1308.
    • (mechanical ventilation can damage the lungs. It has been suggested that cytokines released as a consequence of ventilator induced lung injury may have adverse effects at distant organs .
    • Dreyfuss D, Saumon G. From ventilator-induced lung injury to multiple organ dysfunction? Intensive Care Med 1998; 24(2):102-104.
    • This hypothesis was confirmed from data in the ARDS trial .
    • Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342(18):1301-1308.
  • 28.
    • Blood samples were obtained from 204 of the first 234 patients for measurement of plasma interleukin-6 concentration. Levels of this cytokine were significantly higher in the high stretch (tidal volume 10-12ml/kg) compared with the low stretch (tidal volume 5-6ml/kg) group. In addition to lower mortality, this group had a significantly lower incidence of non pulmonary organ injury.
    • It is clear then that medical intervention can be a significant factor in the development of systemic sepsis, whether it is due to ventilator induced organ injury, line sepsis, parenteral nutrition, gut mucosal atrophy, wound infection or nosocomial pneumonia (associated with endotracheal intubation).
    Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342(18):1301-1308.
  • 29. What is Sepsis?  Activated Protein C
    • Protein C is an important player in the body’s response to inflammation, systemic sepsis and the concomitant intravascular coagulopathy. The main effect of protein C is to reduce the production of thrombin, by inactivating factors Va and VIII. As we have seen, thrombin is proinflammatory, procoagulant and antifibrinolytic (16). In addition, protein C inhibits the influence of tissue factor on the clotting system, reduces the production of IL-1, IL-6, and TNF-α by monocytes, and has profibrinolytic properties by inactivating PAI-1 (it inactivates the inhibitor of the activator of the agent that converts plasminogen into plasmin)(17).
    • There is now compelling evidence that the exogenous administration of activated protein C to patients, in severe sepsis, improves outcome (18), presumably by the mechanisms described above. Note, however, that the use of this agent must be balanced by the risk of increased bleeding.
  • 30.  
  • 31.  
  • 32. Activated Protein C (APC) Inactive Protein C Active Protein C Pro-inflammatory cytokines Thrombin/ thrombomodulin Anti-thrombotic Anti-inflammatory Pro-fibrinolytic
    • Recombinant Human APC (drotrecogin alpha activated)
    • Entry Criteria
    • SIRS
    • Infection
    • Organ Dysfunction
    • APC: 24mcg/kg/hr x 96 hrs
    • 28 Day Mortality
    • Placebo ---- 30.8%
    • APC -------- 24.7%
    • Bernard, 2001
    Concerns: Bleeding, single study, cost, severity of illness
  • 33. Treating Septic Shock
    • Introduction
    • Immediate Stabilization
    • Re-establishing the circulation: Fluid
    • Fluid resuscitation picture gallery
    • Re-establishing the circulation: Vasopressors
      • Dopamine
      • Dobutamine
      • Norepinephrine ( noradrenaline )
      • Epinephrine (adrenaline)
      • Vasopressin, Dopexamine , Phenylephrine , Phosphodiesteradse Inhibitors
    • Clinical Approach to the Source
    • Empiric Therapy: Antibiotics + Scenarios
    • Empiric Therapy: Activated Protein C
    • Finding the Site and Source Control
    • Sepsis - source unknown
    • Enteral and Immunonutrition
    • Endpoints of Resuscitation
    • Avoiding Iatrogenic Injuries
    • Reviewing the therapeutic plan
    • Metabolic and Neuroendocrine issues in severe sepsis
    • Conclusions and Key Points
  • 34. Introduction
    • Severe sepsis is characterized by stimulation of a series of inflammatory cascades leading to extensive cardiovascular derangement, the most overt signs of which are hypotension due to vasoplegia, relative hypovolemia, and widespread dysfunction of the microvasculature (“capillary leak”) .
    • Simultaneously, there is activation of the coagulation cascades , the formation of intravascular thrombus, and subsequent tissue injury and multi-organ dysfunction.
    • The two major priorities in management of septic patients are
    • 1) To maintain delivery of oxygen to the tissues, by way of optimization of cardiac output and peripheral resistance, and
    • 2) To modulate the procoagulation response. It is essential to obtain maximal results from minimal interventions. In particular, it is important to avoid using excessive amounts of catecholamines, in under-resuscitated patients.
  • 35.  
  • 36.
    • Step A  = Airway:   ensure that the airway is protected; if not intubate the patient.
    • Step B = Breathing: address oxygenation and ventilation, administer oxygen and, if intubated, commence mechanical ventilation.
    • Step C = Circulation: restore circulating volume with  fluid resuscitation, invasive monitoring and vasopressors if necessary:.
    • Step D = Diagnosis / Detective work: obtain a history, examine the patient and make a “best 
    • guess” as to the source.
    • Step E = Empiric therapy: start empiric antimicrobials, and activated Protein C if indicated.
    • Step F = Find and control the source of infection
    • Step G = Gut : feed it to prevent villus atrophy and bacterial translocation
    • Step H = Hemodynamics: assess adequacy of resuscitation and prevention of organ failure.
    • Step I =  Iatrogenic : avoid hospital acquired injuries (DVT, line sepsis, pressure sores) and
    • address other supportive issues – analgesia, sedation and psychospiritual welfare, control blood sugar and think about adrenal insufficiency.
    • Step J = Justify your therapeutic plan and reassess
    • Step KL = Keep Looking. Have we adequately controlled the source? Are there secondary sources of infection/inflammation.
    • Step MN = Metabolic and Neuroendocrine control. Tight control of blood sugar. Address adrenal insufficiency. Think about early aggressive dialysis in renal failure.
  • 37. Stages ABC: Immediate Stabilization
    • Immediate resuscitative efforts involve maintaining patency and adequacy of the airway, and ensuring oxygenation and ventilation. Initial management of hypotension is by aggressive volume resuscitation, either with isotonic crystalloids, or in combination with colloids. Do not interfere with the heart rate: tachycardia is a compensatory maneuver.
  • 38.
    • The initial treatment priority in patients with severe sepsis is to reverse life threatening physiologic abnormalities. The airway must be controlled and the patient oxygenated and ventilated. This usually requires endotracheal intubation and commencement of mechanical ventilation. The objective of all resuscitation efforts is to maintain oxygen delivery. Indications for intubation and mechanical ventilation are: failure to protect the airway (altered mental status etc), failure to ventilate and failure to oxygenate. When in doubt, it is rarely wrong to intubate patients. In sepsis, supplemental oxygen is almost always required. Accelerated oxygen demand by respiratory muscles may cause oxygen debt and acidosis: mechanical ventilation reduces this. Care must be taken when administering anesthetic agents for gaining airway control. Many of these, propofol in particular, are potent vasodilators, and may worsen hypotension. This situation may get worse when positive pressure ventilation is applied, as the increase in interthoracic pressure will reduce venous return,
  • 39. Stage C: re-establishing the circulation
    • Volume Resuscitation
    • Hypotension is caused by myocardial depression, pathological vasodilatation and extravascation of circulating volume due to widespread capillary leak. The initial resuscitative effort is to attempt to correct the absolute and relative hypovolemia by refilling the vascular tree. There is good evidence that early goal directed aggressive volume resuscitation improves outcomes in sepsis (1).
    • Conventionally clear resuscitation fluids (crystalloids) such as normal saline or Ringer’s lactate are used (hypo-osmolar dextrose based fluids have no role). In this process, very large amounts of fluid may be required due to redistribution to extravascular “3rd” spaces (which sequester fluid), and the patient may become extremely edematous. Large volume saline resuscitation may be associated with acidemia, due to hyperchloremia (so called “dilutional acidosis”). Lactate cannot safely be given to patients with severely impaired liver function. Acetate buffered fluids (such as Normisol) have not yet gained widespread use.
  • 40. Clinical Scenario
    • A 52 year old male is admitted with abdominal pain, hypotension (BP 70/30, pulse 150), hypoxemia (PaO2 50mmHg on 60% oxygen), acidosis (pH 7.21, base deficit -10), oliguria, pyrexia and leucocytosis. On chest x-ray there are diffuse infiltrates throughout the lung fields and free air under the diaphragm.
    • What do you think?
  • 41.
    • This patient is in septic shock, presumably due to a perforated intra-abdominal viscus. He requires immediate intubation and volume resuscitation. I would establish wide bore intravenous access x2 and have my assistants squeeze in 2 to 3 liters of lactated ringers solution. For intubation I would use etomidate and succinyl choline, and intubate while cricoid pressure is being held. I would have a syringe of phenylephrine available in case pressure falls precipitously.
    • I would then attach the patient to a mechanical ventilator and focus on the efforts to re-establish the blood pressure. If there is no response to the first two liters of fluid, I would give him a liter of hydroxyethyl starch and another liter of lactated ringers solution. I would send CBC,, coagulation profiles, amylase, lipase, liver function tests and repeat the blood gas. I would send blood cultures and treat the patient empirically with ampicillin+ +.
    • If at this stage the patient has not responded, I would continue to volume load, alternating colloids (including fresh frozen plasma if the patient is coagulopathic) and crystalloids at a rate of not less than 1 liter per hour, and insert a central line to more closely monitor volume status.
    • At this stage my endpoints of resuscitation are
    • 1. blood pressure,
    • 2. heart rate,
    • 3. urinary output,
    • 4. base deficit,
    • 5. central venous pressure (CVP). The patient requires a second chest x-ray to confirm the position of the endotracheal tube and central line.
  • 42.
    • I would choose a high CVP number such as 14 to 16cmH2O and continue to volume load until the pressure has risen to this level and stayed there. If the patient is still hypotensive/oliguric, it is time to start vasoactive “pressor” support. As the classic hemodynamic upset in sepsis is biventricular dilatation and reduced stroke volume with vasoplegia, the ideal agent would be an inotrope-vasoconstrictor. As Noradrenaline is the agent with the most favorable effect on heart rate, blood pressure, acid base status and splanchnic perfusion, it is the agent I would choose, and would escalate my therapy until blood pressure begins to rise. If the pressure rises to target (the normal mean arterial pressure for that particular patient) and the patient remains oliguric I would use a beta agonist such as dobutamine, as a splanchnic vasodilator and inotropic agent. If, on the other hand, the patient remains resistant to escalating doses of noradrenaline, I would add a second, more specific vasoconstrictor. As most of the other agents available (Adrenaline) act by way of the same receptor as noradrenaline, I would use arginine-vasopressin, which is emerging as a useful agent to treat catecholamine resistant vasodilated shock.
  • 43.  
  • 44. Individual Agents
    • The modern use of vasoactive agents emphasizes organ perfusion along the continuum: first brain, then heart, then splanchnic (gut, liver and kidneys) then all else. The gut had previously been the forgotten organ. It has acquired a level of importance due to the emergence of the “gut origin” theory of sepsis. So if we are going to choose a vasoactive agent to maintain blood pressure, we would prefer to use one that not only maintains brain and heart perfusion, but renal, liver and gut mucosal perfusion also
    •   Bellomo R, Cole L, Ronco C. Hemodynamic support and the role of dopamine. Kidney Int Suppl 1998; 66:S71-S74.
  • 45. Proposed Algorithm for the Management of Hyperdynamic Shock Hypotension/Hypoperfusion Cardiac Index Cardiac Index (CI<4.5 l/min/m ) (CI>4.5 L/min/m ) 2 2 Preload (EDV) Preload Preload Preload (PAOP<15 mmHg) (PAOP>15) (PAOP<15) (PAOP>15) Volume Inotrope Volume Inotrope Vasopressor
  • 46. Dopamine
    • The effects of dopamine elsewhere, though, may cause concern.
    • Firstly, dopamine drives up heart rate, and may precipitate myocardial ischemia.
    • Secondly, the effects of this agent on the splanchnic circulation appear complex: dopamine, whilst increasing overall mesenteric blood flow, may preferentially steal blood from the mucosa, and redistribute it to the larger vessels .
    • Thirdly, the effects of exogenous administration of this drug at distal sites in the central nervous system and gut remain to be clarified: dopamine may interfere with pituitary , thyroid function and have an immunosuppressive effect .
    •   Denton R, Slater R. Just how benign is renal dopamine? Eur J Anaesthesiol 1997; 14(4):347-349.
  • 47. Dobutamine
    • Dobutamine is a potent beta-1 agonist, with predominant effects in the heart where it increases myocardial contractility and thus stroke volume and cardiac output. Dobutamine is associated with much less increase in heart rate than dopamine. Dobutamine has a mild vasodilatory effect (inodilator), reducing mean arterial pressure: thus the heart pumps “downhill”, which makes this agent very effective in cardiogenic shock. Dobutamine differs from isoproteranol in that it has less beta-2 activity (bronchodilation) and has less effect on heart rate (isoproteranol is predominantly used as a stop-gap in patients requiring a pacemaker due to it’s chronotrophic effect). In sepsis, dobutamine, although a vasodilator, increases oxygen delivery and consumption. Dobutamine appears particularly effective at splanchnic resuscitation, increasing pHi (gastric mucosal pH) and improving mucosal perfusion in comparison with dopamine (1). It appears that dobutamine is a useful second line agent to add in septic shock, to improve cardiac performance and to improve splanchnic perfusion. The combination with nor-adrenaline would appear appropriate.
    •   Neviere R, Mathieu D, Chagnon JL, Lebleu N, Wattel F. The contrasting effects of dobutamine and dopamine on gastric mucosal perfusion in septic patients. Am J Respir Crit Care Med 1996; 154(6 Pt 1):1684-1688.
  • 48. Noradrenaline
    • complex and much misunderstood drug. Remember that this agent is the neurotransmitter at the majority of adrenergic post synaptic terminals in the body. pharmacologic effects on both alpha-1 and beta-1 adrenoceptors. In low dosage ranges, the beta effect is noticeable, and there is a mild increase in cardiac output. In most dosage ranges, vasoconstriction and increased mean arterial pressure are evident. The main beneficial effect is to increase organ perfusion by increasing vascular tone.
    • It appears that norepinephrine is as effective as dopamine at improving renal perfusion, as long as the patient is adequately resuscitated  (3).
    • Norepinephrine appears to be most effective at splanchnic resuscitation if used in combination with dobutamine. This combination improves oxygen delivery and consumption compared with dopamine (4). (5)
    • The increase in splanchnic blood flow associated with dobutamine and norepinephrine appears to arise from beta adrenergic activity .
    •    (1)    Levy B, Bollaert PE, Charpentier C, Nace L, Audibert G, Bauer P et al. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study. Intensive Care Med 1997; 23(3):282-287.
    •    (2)    Marik PE, Mohedin M. The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. JAMA 1994; 272(17):1354-1357.
    •    (3)    Martin C, Saux P, Eon B, Aknin P, Gouin F. Septic shock: a goal-directed therapy using volume loading, dobutamine and/or norepinephrine. Acta Anaesthesiol Scand 1990; 34(5):413-417.
    •    (4)    Hannemann L, Reinhart K, Grenzer O, Meier-Hellmann A, Bredle DL. Comparison of dopamine to dobutamine and norepinephrine for oxygen delivery and uptake in septic shock. Crit Care Med 1995; 23(12):1962-1970.
    •    (5)    Hoogenberg K, Smit AJ, Girbes AR. Effects of low-dose dopamine on renal and systemic hemodynamics during incremental norepinephrine infusion in healthy volunteers. Crit Care Med 1998; 26(2):260-265.
  • 49. adrenaline
    • inotrope/vasopressor, and indeed it is what “God gave us” to deal with shock. It remains the agent of choice when patients are in-extremis – such as in anaphylactic shock or cardiac arrest. Otherwise, we now reserve the use of adrenaline as an add on vasopressor (with noradrenaline) or when the cause of hypotension is unclear (it is a most reliable “backs to the wall” pressor).
    • It has potent beta-1, beta-2 and alpha-1 adrenergic activity, though the increase in mean arterial pressure in sepsis is mainly from an increase in cardiac output (stroke volume).
    • 1. It increase myocardial oxygen demand.
    • 2. It ncreases serum lactate –
    • 3. adverse effects on splanchnic blood flow.
    •   Meier-Hellmann A, Reinhart K, Bredle DL, Specht M, Spies CD, Hannemann L. Epinephrine impairs splanchnic perfusion in septic shock. Crit Care Med 1997; 25(3):399-404.
  • 50. Other Vasoactive Drugs
    • Vasopressin
    • Vasopressin is emerging as an alternative vasoconstrictor in septic (and other forms of distributive) shock, in patients who have become resistant to catecholamines (1). In addition there appears to be a quantitative deficiency of this hormone in sepsis (2-5) . Experience and published data are limited, but we do know that pharmacological doses are much lower in vasodilated patients, as compared to normal (6). At present the most efficacious dose appears to be 0.04units/minute (7). Effects on splanchnic perfusion and the extremities are probably adverse (remember that vasopressin has traditionally been used to reduce splanchnic blood flow, in the treatment of bleeding esophageal varices), particularly as the dose escalates. Currently the principle use of this agent is as a physiologic replacement for depleted endogenous stores.
    • Dopexamine
    • Dopexamine was designed to combine the inodilatory effects of dobutamine and the dopaminergic effects of dopamine (it is a synthetic analogue of dopamine), thus improving cardiac output and splanchnic perfusion. To date, most of the studies utilizing this agent have been disappointing, and it is not in common usage.
    • Phenylephrine
    • Phenylephrine is an almost pure alpha-1 agonist, and is used predominantly in anesthesia practice to increase blood pressure without increasing heart rate in patients with vasoplegia, due to spinal-epidural anesthesia or to reverse the afterload reducing effects of propofol and volatile inhalation agents. Phenylephrine has traditionally been used in intensive care units as a vasoconstrictor to improve SVR (systemic vasccular resistance) in patients (in whom PA catheters had been inserted) in septic shock. This agent may be useful as an additional vasoconstrictor in fluid loaded patients where catecholamines are causing excessive tachycardia
    • Phosphodiesterase Inhibitors
    • There is little available data on the use of phosphodiesterase inhibitors in sepsis. These agents (milrinone/enoximone) are potent inotropes, but also cause vasodilatation and tachycardia, which limits their use in sepsis. Interestingly, these drugs have lusitropic properties – they relax the heart in diastole, compared to inoconstrictor type drugs, which appear to impair diastolic relaxation (9). These agents thus are of more value in cardiogenic shock.
    •   Malay MB, Ashton RC, Jr., Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 1999; 47(4):699-703.
  • 51. Step D: Detective work - history, physical, immediate investigation
    • Take a history (or obtain a collateral one), examine the patient, and quantify the extent of sepsis: temperature, white cell count, acid-base status and cultures. The choice of antimicrobial is determined by the source of infection and a best guess of the organism involved.
    • It is extraordinary how often the diagnosis can be made by taking a good history alone, and how few doctors bother going through the trouble of teasing out the salient details. Even if the patient is too sick to give a history, a good collateral one is usually available. Certain aspects of the history can tip you off to the source:
  • 52. What symptoms do you have?
    • “ I have been experiencing sharp episodes of chest pain on inspiration”: lower respiratory tract infection.
    • “ I have severe abdominal pain boring through to my back”: pancreatitis.
    • “ I have been having pain passing urine”: urinary tract infection.
    • “ Persistent dry cough”: atypical pneumonia.
    • Likewise, even with a collateral history, it is possible to establish the source:
    • Has he any medical problems? Yes he has gallstones (cholecystitis, cholangitis), rheumatoid arthritis (steroids /immunosuppressants), etc.
    • Has she had recent surgery? Yes she just had bowel surgery (post operative complication).
    • Has he been out of the country recently? Yes he just came back from India, and has been complaining of persistent diarrhea (bacterial overgrowth).
    • Has she had any recent injuries? Yes, she was in a car crash two days ago, but was sent home from the hospital (many possibilities).
    • Does he take drugs? Yes, he injects heroin (endocarditis).
    • Any problems recently? Yes, he lost his job and has been drinking heavily (pancreatitis).
  • 53. Scenario 1
    • Beware of the missed injury:
    • A 64 year old female was admitted following a motor vehicle collision. In the emergency room she was complaining of a sore ankle and moderate abdominal pain. She had a bi-malleolar fracture of her ankle and was admitted to an orthopaedic service with reassurance.
    • 24 hours after admission she developed worsening abdominal pain and became progressively oliguric. 2 hours later, she developed hypotension and hypoxemia. CT of her abdomen revealed a small bowel rupture at the duodenal-jejunal junction.
  • 54. Step E: Empiric Therapy - Antibiotics
    • The selection of specific antibiotics depends on:
    • The presumed site of infection (see table 1 below).
    • Gram's stain results
    • Suspected or known organisms
    • Resistance patterns of the common hospital microbial flora.
    • Patient’s immune status (especially neutropenia and immunosuppressive drugs), allergies, renal dysfunction, and hepatic dysfunction.
    • Antibiotic availability, hospital resistance patterns, and clinical variables of patient to be treated
  • 55. Frequency of Source of Infection
    • Respiratory Tract                  25%
    • Abdominal / Pelvic                25%
    • Bacteremia                            15%
    • Urinary Tract                          10%
    • Skin                                        5%
    • IV Catheter                             5%
    • Other source                          15%
  • 56. In intensive care units approximately
    • 25% of infections are confirmed gram negative,
    • 25% gram positive,
    • 20% mixed gram positive/gram negative,
    • and 3% fungal.
  • 57. Of the gram negative organisms, the organisms in order of likelihood are
    • e.coli (25%),
    • klebsiellla/citrobacter (20%),
    • pseudomonas (15%),
    • enterobacter (10%)
    • and proteus (5%);
    • the remaining 25% is made up of dozens of different bacteriae.
  • 58. Of the gram positive infections, by far the most common is
    • staphylococcus aureus (35%),
    • followed by enterococcus (20%),
    • coagulase negative staphylococcus (15%)
    • and streptococcus pneumoniae (10%).
    • The vast majority of fungal infections are candidal.
  • 59. A 75 year old male presents with hypotension, pyrexia and leucocytosis. Presumed diagnosis - sepsis, cause unknown.
    • Broad spectrum coverage is required, to cover gram positives, gram negatives and pseudomonas. Suggested modalities are:
    • Combining either antipseudomonal cephalosporin (ceftazidine) or antipseudomonal penicillin (piperacillin + azobactam) (particularly if anaerobes are suspected) with either an aminoglycoside (gentamycin or amikacin) or a fluoroquinolone (ciprofloxacin). If an antipseudomonal cephalosporin is used and anaerobes are a possible cause, the addition of metronidazole or clindamycin should be considered.
    • Piperacillin+Tazobactam/Imipenem + Gentamycin/Ciprofloxacin
  • 60. Step E: Empiric Therapy: Activated Protein C
    • Activated protein C modulates both inflammation and coagulation in severe sepsis, and reduces mortality
    • Activated protein C (drotrecogin alfa) is an endogenous protein that promotes fibrinolysis and inhibits thrombosis and inflammation. It is an important modulator of the coagulation and inflammation associated with severe sepsis Activated protein C is converted from its inactive precursor, protein C, by thrombin coupled to thrombomodulin.  The conversion of protein C to activated protein C may be impaired during sepsis as a result of the down-regulation of thrombomodulin by inflammatory cytokines. Reduced levels of protein C are found in the majority of patients with sepsis and are associated with an increased risk of death. This led to interest in therapeutic administration of activated protein C (and similar agents) in early sepsis.
    • A large randomized controlled trial has confirmed the efficacy of Activated Protein C (drotrecogin alfa). In patients with severe sepsis, an intravenous infusion of drotrecogin alfa activated at a dose of 24 µg per kilogram per hour for 96 hours is associated with a significant reduction in mortality (1). The use of this drug is indicated if the patient has a systemic inflammatory response, at least one organ dysfunction and known or suspected infection.
    • When using an infusion of activated protein C, it is important to monitor for signs of bleeding, an important side effect of therapy with this compound. The value of this agent in patients with multi-organ failure, or outside the first 24 hours of injury, is unknown.
    • References
    • (1)   Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344(10):699-709.
  • 61. Step F: Find the site and control the source
    • The systemic inflammatory response is driven along by persistent infection: you must find the source and remove it. This may involve extensive detective work.
  • 62. But, what if the patient is behaving as if he has sepsis, but there is no obvious source?
    • Respiratory
    • Abdominal:
    • Urinary tract
    • Sinuses
    • Heart
    • Central nervous system
    • What else?
    • Radiolabelled white cell scans (where do the white cells collect?) and bone marrow biopsies, but these tend to be very low yield in intensive care.
  • 63. Step G:  Feed the Gut
    • Prevention of gut mucosal villous atrophy and bacterial translocation involves restoration of splanchnic blood flow and of gut luminal nutrition.
    • There has been extensive discussion on the effects of vasoactive drugs on intestinal blood flow. The lining of the gut requires oxygen, from the blood, and nutrients, from the gut lumen, to stay intact. The presence of this lining is important as a barrier to bacterial translocation (1).
    • Early enteral nutrition maintains it. Thus an “inside-outside” gut protection strategy has emerged: combining splanchnic vasodilators, such as dobutamine, with feeding. Immunonutrition (2) is an advanced enteral strategy that combines glutamine, omega-3 fatty acids, arginine and ribonucleotides and conventional feeding substances. There is some evidence that these formulas reduce the risk of infection (3).
    • (1)   MacFie J. Enteral versus parenteral nutrition. Br J Surg 2000; 87(9):1121-1122.
    • (2)   Beale RJ, Bryg DJ, Bihari DJ. Immunonutrition in the critically ill: a systematic review of clinical outcome. Crit Care Med 1999; 27(12):2799-2805.
    • (3)   Barbul A. Immunonutrition comes of age. Crit Care Med 2000; 28(3):884-885.
  • 64. Step H - Hemodynamics: assess adequacy of resuscitation and prevention of organ failure.
    • blood pressure (using an arterial line) is essential to guide therapy, and there is a strong relationship between restoration of blood pressure and urinary output. The central venous pressure is useful for monitoring volume status, but of little value in terms of organ perfusion. In the blood gas, the pH, base deficit and serum lactate are useful guides of all body perfusion and anaerobic metabolism. During the resuscitation process, the patient should become gradually less acidotic and the base deficit and serum lactate should reduce.
    • mixed venous oxygen saturation
    • localize measurement of tissue perfusion – by looking at regional circulation. The most widely adopted tools are jugular venous oxygen saturation (SjO2), which is used in head injury, and gastric tonometery, which is sometimes used in sepsis. The most recent variant of tonometery, regional capnometery, measures gastric carbon dioxide (CO2)
  • 65. Step I – Iatrogenic injuries and complications
    • Critically ill patients are vulnerable: hiding within the intensive care unit is a variety of different injurious ambushes. Avoidance of hospital acquired injuries such as deep venous thrombosis (DVT), line sepsis, pressure sores is essential. In addition, the presence of an endotracheal tube provides a route for bowel organisms to infect the lungs. Prolonged use of neuromuscular blocking agents and steroids predispose to critical illness polymyopathy. Every intervention has a possible complication: the insertion of a central line can cause pneumothorax, air embolism, venous thrombosis, arterial dissection etc. You must weigh up the potential benefits and costs of each intervention.
  • 66. Step J - Justify your therapeutic plan
    • Finally you must look at all of the ongoing therapies and interventions and question: are they still necessary. If a patient is hemodynamically stable and the source controlled, it is unlikely that a pulmonary artery catheter will continue to be of any benefit, and certainly carries a risk. The spectrum of antimicrobial therapy should be narrowed, in accordance to laboratory results. Aggressive moves to wean vasopressor support and mechanical ventilation should be made. If the patient is not improving clinically, you must question if you have, in fact, affected source control.
  • 67. Step MN – Metabolic and Neuroendocrine Control
    • Sepsis is a multisystem disease modulated by the neuroendocrine response. The early response (the Ebb phase) is characterized by reduced metabolism and vasoconstriction. This is followed by a hypermetabolic phase, characterized by vasodilation, fluid sequestration, hyper-adrenergic activity, protein catabolism, hyperlactemia (not necessarily due to anerobic metabolism), and dysregulation of fat and lipoprotein metabolism. Hyperglycemia is inevitable and there is good evidence that control of blood sugar improves outcome in critical illness (1), due to a reduction in infectious complications.
    • Prolonged critical illness is characterized by derangement of the entire neuroendocrine response. There is dysfunction of the somatrophic and the hypothalmo-pituitary axis, sick euthyroid syndrome and loss of central endocrine control (2;3) . A relative adrenal insufficiency frequently manifests – the patient remains pressor dependent in spite of apparent source control (cortisol is required to facilitate the activity of norepinephrine and epinephrine at sympathetic nerve terminals).The diagnosis is made by ACTH stimulation test (4) (a 2 hour “bump” of less than 5mg/dl or a cortisol level of <20mg/dl is diagnostic) and the treatment is hydrocortisone. It is controversial whether other hormones should be replaced with similar physiologic doses (5).
    • (1)   Van den BG, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M et al. Intensive insulin therapy in the surgical intensive care unit. N Engl J Med 2001; 345(19):1359-1367.
    • (2)   Van den Berghe GH. Acute and prolonged critical illness are two distinct neuroendocrine paradigms. Verh K Acad Geneeskd Belg 1998; 60(6):487-518.
    • (3)   Van den Berghe GH. The neuroendocrine stress response and modern intensive care: the concept revisited. Burns 1999; 25(1):7-16.
    • (4)   Rivers EP, Gaspari M, Saad GA, Mlynarek M, Fath J, Horst HM et al. Adrenal insufficiency in high-risk surgical ICU patients. Chest 2001; 119(3):889-896.
    • (5)   Ligtenberg JJ, Girbes AR, Beentjes JA, Tulleken JE, van der Werf TS, Zijlstra JG. Hormones in the critically ill patient: to intervene or not to intervene? Intensive Care Med 2001; 27(10):1567-1577. page28.htm
  • 68. Conclusion
    • Initial management involves protection of the airway and delivery of oxygen into the blood, with restoration of circulating volume, initially with fluids and, if necessary, vasoactive agents. The splanchnic circulation appears to be a particularly important site for resuscitation, as the physiological response to hypotension causes reduction in blood flow to this area. The result is gut ischemia, bacterial translocation, worsened sepsis and renal failure. Gut resuscitation involves the use of beta-adrenergic agonists and early enteral nutrition, preferably with immunomodulatory supplements. There is increasing interest in the interaction between inflammation and coagulation in severe sepsis, with compelling data for the use of activated protein C in this patient population.
  • 69. Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock Dellinger, et al Crit Care Med 32:858-73, 2004. Recommendations (not based on expert opinion): Human activated protein C is recommended in patients with a high risk of death. After resolution of hypoperfusion and in the absence of CAD, acute hemorrhage or lactic acidosis, transfusion of rbc’s should only be done to maintain hemoglobin > 7 gm/dl.
  • 70. Vasopressors Volume Expansion Inotropes “ It’s déjà vu all over again!” Therapy of Shock
  • 71. Key Points
    • Immediate resuscitative efforts involve maintaining patency and adequacy of the airway, and ensuring oxygenation and ventilation. Initial management of hypotension is by aggressive volume resuscitation, either with isotonic crystalloids, or in combination with crystalloids. Do not interfere with the heart rate: tachycardia is a compensatory maneuver.
    • Take a history (or obtain a collateral one), examine the patient, and quantify the extent of sepsis: temperature, white cell count, acid-base status and cultures. The choice of antimicrobial is determined by the source of infection and a best guess of the organism involved.
    • Vasoactive therapy is commenced after other measures have failed. There is no simple solution. Vasoactive medication must be aimed at restoring tissue perfusion without causing ischemia. Persistent requirement for vasopressors requires investigation of adrenal function.
    • The systemic inflammatory response is driven along by persistent infection: you must find the source and remove it. This may involve extensive detective work.
    • The use of activated protein C at 24 µg per kilogram per hour for 96 hours is associated with a significant reduction in mortality.
    • Prevention of villous atrophy and bacterial translocation involves restoration of circulation and restoration of gut luminal nutrition. Secondary sources of sepsis (lines) and organ dysfunction (pulmonary embolism) must be avoided.
    • Adequacy of resuscitation is evaluated by looking at endorgan perfusion – using clinical examination and interpretation of monitored variables. There is no ideal method.
    • It is the second and subsequent hits that often kill patients: it is important that you prevent this from arising from an inatrogenic source. Minimize the amount of interventions involved and wean and remove therapies that are no longer beneficial.