PATHOPHYSIOLOGY MODULE #3: Inflammation (Sepsis & Shock)
Those who suffer an acute myocardial infarction are only ____ as likely to die from the MI as sepsis and in the stroke population; they are only ______ as likely to die. A. 1/4, half B. 1/3, half C. 1/4, 1/3 D. half, 1/3
B. 1/3, half This is a result of the advancements in treatment for MIs and strokes. Mortality rates from those whose illness advances to severe sepsis or septic shock is 39.4%, versus the 30% for sepsis alone.
True or False? Those of only one failed organ system had decreased rates of mortality.
TRUE! Cellular impairment from hypoxia, influx of water, and metabolic by product buildup instigate progression from sepsis to severe sepsis as organ systems begin to fail. Most patients with severe sepsis were affected by failure of only one organ system, but those who experienced multiple organ failure had greatly increased rates of mortality that rose with the number of system failures.
True or False? Co-morbidities are another factor leading to higher mortality in sepsis; the greater number of co-existing conditions, the higher mortality.
TRUE! Almost half of sepsis patients had at least one pre-existing condition, compared with slightly less than a quarter of patients in hospital for reasons other than sepsis. The most common comorbidities of sepsis patients in Canada were diabetes and different types of cancers.
In hypovolemic shock there is a reduction in...
total blood volume. This can be related to bleeding otherwise known as hemorrhage or excessive loss of body fluids as occurs during dehydration or with burns.
Activated protein C, or APC is the natural inhibitor of factors ____ and ____ of the coagulation cascade.
5A and 8A Thrombin is diminished through inhibition of the coagulation cascade by APC and so its anti-fibrinolytic effects are decreased.
Loss of blood of up to about ___ % which is the volume you would lose through blood donation is not problematic. Amounts above this begin to affect cardiac output and perfusion and losses between ____ and ____ % of blood volume abolish cardiac output and arterial pressure. A. 10%, 35 and 45% B. 15%, 35% and 45% C. 5%, 30% and 40% D. 5%, 35% and 45%
A. 10%, 35 and 45% Hypovolemic shock is caused by any event that reduces fluids such that there is insufficient blood to fill the vascular compartment. This condition may arise as a consequence of hemorrhage, plasma loss due to burns or massive shift of fluid from the vascular compartment to the extravascular space to replace lost fluids (such as from excessive vomiting or diuresis).
The first large-scale study of sepsis and its costs was reported in 2001. The mortality rate was reported to be ____%, although this number was __________ in children and _________ in the elderly. A. 28.6%, lower, higher B. 33.8%, higher, lower C. 29%, lower, higher D. 34.6%, lower, higher
A. 28.6%, lower, higher The cost at that time was an average of a little over $22,000 per case, totalling $16.7 billion annually nation-wide. A recent study in Canada looked at numbers of patients hospitalized for sepsis across the country, but excluded Quebec. A similar mortality rate to that reported 10 years ago in the US study was found, highlighting the lack of advances in the treatment of this syndrome.
Match em up! A. Cardiogenic B. Obstructive C. Hypovolemic D. Distributive 1. Reduced stroke volume (or HR) 2. Reduced preload 3. Low systemic vascular resistance 4. Impaired blood flow
A. Cardiogenic with 1. Reduced stroke volume B. Obstructive with 4. Impaired blood flow C. Hypovolemic with 2. Reduced preload D. Distributive with 3. Low systemic vascular resistance
For the very young who is hospitalized most often for sepsis? A. Neonates B. Children 2-4 C. Children 5-7
A. Neonates Especially among premature infants. Of children hospitalized for sepsis, >50% are neonates, while approx. 20% are infants under two months of age. Estimates of incidence are 1-2 per 1,000 live births in Canada, and may be as high as 4.6/1,000 in areas of the US.
Which toll-like receptor detects lipopolysaccharide? A. TLR-4 B. TLR-3
A. TLR-4 Toll-like receptor 4, or TLR-4, shown in purple at the top of the diagram in module detects lipopolysaccharide, also known as LPS or endotoxin, a component of the outer membrane of gram-negative bacteria. LPS is shown in pink at the top of the diagram, attached to the orange lipopolysaccharide binding protein or LBP. Another molecular pattern is double-stranded RNA, found in some viruses and detected by the pattern recognition receptor TLR-3. Once bound to a pattern recognition receptor, PAMPs cause an intracellular signalling cascade, such as the intricate one shown in the diagram, that results in the expression of inflammatory mediators such as cytokines. Nuclear factor KB, or NF-KB is a transcription factor that is activated by PAMPs through this pathway and can elicit the expression of inflammatory mediators.
Which of the following begin a cascade of inflammatory processes? A. Toll-like receptors B. White blood cells C. Cytokines
A. Toll-like receptors Toll-like receptors detect pathogen associated molecular patterns (PAMPs) such as lipopolysaccharides (LPS-a component of gram negative bacterial cell walls) and begin a cascade of inflammatory processes. Specialized detectors, or pattern recognition receptors called toll-like receptors are responsible for sensing invading organisms through pathogen-associated molecular patterns or PAMPs. There are several different toll-like receptors, each recognize a different PAMP.
The most common causes (75%) of pancreatitis are... A. gallstones and alcohol abuse B. kidney stones and alcohol abuse C. binge drinking and hypertriglyceridemia D. hypertriglyceridemia and gallstones
A. gallstones and alcohol abuse A procedure called endoscopic retrograde cholangiopancreatography or ERCP, can also irritate the pancreas. This can result in acute pancreatitis either from mechanical injury of the tissue or due to sensitivity or allergy to the dye. Drug reactions and abdominal trauma can also trigger the condition, as can hypertriglyceridemia. Due to the worldwide increase in the incidence of obesity, this may become an increasingly important factor in the prevalence of pancreatitis. Recent research has shown that severity is increased in obesity and a greater number of complications occur in these patients. Finally there are about 15% of cases that are idiopathic, that is they occur with no known cause.
What do selectins do?
APC also inhibits the production of cytokines by monocytes and down regulates expression of selectins on the surface of the endothelium; selectins attach to neutrophils and monocytes allowing them to roll along the vessel wall before adhering and extravasating into tissues. It is thought that exogenous APC needs to be administered in severe sepsis because its production is impaired.
Results of the original clinical trial for Early Goal Directed Therapy showed a ____ % absolute reduction risk of mortality with the early treatment protocol. A. 18% B. 16% C. 15% D. 20$
B. 16% Some of the subsequent studies showed even more dramatic results with some achieving a 50% or greater reduction in mortality when the treatment bundles were instituted. A recent meta-analyses conducted in 2014, looked at 13 RCTs conducted between 1992 and 2014, confirming the benefits of early goal directed therapy in reducing patient mortality from sepsis. A report of a local success with a bedside rapid response team on the wards that react as soon as the warning signs of sepsis appear. They describe how the work of this team has cut down on the number of patients who are put into the ICU (which is a greater cost and puts the patient at higher risk due to more severe illness and greater chance of nosocomial infections). The hospital also experienced fewer cardiac resuscitations in septic patients due to identification and treatment by this team.
It can be acute or chronic and may occur as a mild disease, although roughly ___ % of patients experience a severe disease course. A. 10% B. 20% C. 30% D. 15%
B. 20% In addition to its endocrine role releasing the hormones insulin and glucagon into the bloodstream, the primary role of the pancreas is as an exocrine gland delivering digestive enzymes produced in the acinar cells into the duodenum. It is damage to these cells that is thought to be the cause of pancreatitis. The acinar cells generate proteolytic enzymes, as well as amylase and lipases in nonactive forms that become activated once they reach the small intestine. Because the enzyme trypsin activates the other proteolytic enzymes once cleaved, the acinar cells also secrete a trypsin inhibitor. Acinar cell injury leads to activation of trypsin which prematurely activates other enzymes and causes autodigestion of the pancreatic tissues. The resulting tissue damage provokes inflammation with release of pro-inflammatory cytokines and complement system activation.
Which of the following patients would most likely have sepsis? A. John hospitalized for open heart surgery who has a temperature of 36.5, heart rate of 95 and a respiratory rate of 24. B. Ashley who had knee surgery with the wound displaying redness and puss. She also has a temperature of 39 and a respiratory rate of 22. C. Michael with a white blood cell count of 12,000, a temperature of 34 and a heart rate of 100. D. Victoria with a bloody scraped knee, a respiratory rate of 24 and a temperature of 39.
B. Ashley who had knee surgery with the wound displaying redness and puss. She also has a temperature of 39 and a respiratory rate of 22. Experts set out the criteria for systemic inflammatory response syndrome, or SIRS indicators. These symptoms indicate an inflammatory response that is systemic, rather than localized and include a higher or lower than normal body temperature, increased heart and respiratory rate and a high or low white blood cell count. Another marker is large proportion of 'bands' or immature white blood cells that indicate the body is ramping up production because of an inflammatory reaction. Greater than 10% band forms indicates body-wide inflammation and may be present instead of increased or decreased white blood cells. - Body temperature >38⁰C or <36⁰C - Heart rate > 90 beats/minute - Respiratory rate > 20/minute (or a PaCO₂ of <32 mm Hg) - White blood cell count > 12,000 mm3 or < 4,000 mm3 - Bands > 10% The identification of these symptoms when an infection is confirmed or suspected provides evidence for the diagnosis of sepsis.
What is the largest group hospitalized for sepsis in both the US and Canada? A. Children B. Elderly over 65 years of age C. Adults D. Teens
B. Elderly over 65 years of age The largest group hospitalized for sepsis in both countries is those over 65 years of age. Over 60% of sepsis patients in Canada in 2008-2009 were over 60 years of age, with the median age of 66. In the US about 2/3 of patients with sepsis were 65 or older. Sepsis rates are higher in the elderly and those who are immunocompromised. Since our populations are aging we expect to see greater incidence of these conditions in the future; this is one of the reasons that so many resources are being devoted to research in this area.
What is the first step in treating shock? A. Fluid resuscitation B. Investigation and discovery of the cause and correction or removal if possible. C. Antibiotics
B. Investigation and discovery of the cause and correction or removal if possible. Successful treatment of shock depends on prompt recognition and rapid intervention. Compensatory mechanisms, already examined that the body enlists to restore homeostasis are pictured and described in the figure. In most cases these processes are ineffective in reinstating cardiac and vascular balance so pharmacologic treatments must be administered as well. The first step in treatment of shock is investigation and discovery of the cause and correction or removal if possible. For example, if a patient is experiencing hypovolemic shock due to hemorrhage, further loss of blood would first be stopped. Similarly neurogenic shock would first be treated by stabilization of the spine if spinal cord trauma was the cause and removal or neutralization of the antigen would be attempted first in the case of anaphylactic shock. Treatment with fluids such as crystalloids, colloids or whole blood, if indicated are used to enhance blood volume. If vasopressors (to increase blood pressure) or inotropes (to increase myocardial contractility) are needed they would be administered in the ICU. Patients admitted to the ICU would undergo regular monitoring usually hourly to assess effectiveness of these treatments.
Inflammation is an attempt by the body to eliminate injurious stimuli and promote healing. Inflammation is ____________. A. Specific B. Non-specific
B. Non-specific Meaning that different types of insults will employ the same arsenal of protective cells and molecules. Inflammation is normally a helpful process but sometimes it overreacts (or under reacts which we will see can be the case late in causes harm in patients). This issue of dysregulation of defense processes and the consequences in the conditions of sepsis, shock and pancreatitis are the subject of the following.
Treatment for pancreatitis includes: A. pain relief and fluids by mouth B. pain relief and no food or fluids by mouth C. pain relief and pureed food by mouth
B. pain relief and no foods or fluids by mouth In addition, to meperidine or morphine, fentanyl is also used for pain relief, especially in mild cases of pancreatitis since it has less damaging effects on the kidneys than other drugs. Patients should receive no food or fluids by mouth, in order to allow the pancreas to rest, and a nasogastric tube may be employed to remove gastric fluids that irritate the condition. Resuscitation fluids are given intravenously in an attempt to restore blood volume and electrolyte balance may need to be re-established especially in cases of stomach acid removal.
Which of the following is an example of SIRS? A. Wound infection B. Viral meningitis C. Pancreatitis D. Urosepsis E. Ankle sprain
C. Pancreatitis Wound infection, viral meningitis and urosepsis are all examples of pathologies induced by infective agents. Ankle sprain involves inflammation with no infection but this would produce a local rather than systemic response. SIRS can and does occur without infection, an example of this is the case of pancreatitis.
Which system fails most often in severe sepsis? A. Kidneys B. Cardiovascular C. Respiratory D. CNS
C. Respiratory As shown in the chart (module), the respiratory system is that which falls most often. The kidneys have the next highest rate of failure, followed by the cardiovascular system, which results in septic shock. Of note is the fact that liver failure is the least common but has the highest rate of mortality, highlighting the vital role of this organ. The hepatic system is responsible for synthesis of most of the blood proteins, detoxification of ammonia via the urea cycle, and maintenance of blood sugar levels through glycogenolysis and gluconeogenesis.
Inflammatory mediators such as ____________ can cause the small vessels to dilate and become more permeable or "leaky".
Cytokines Cytokines released in response to binding of PAMPs to toll-like receptors lead to endothelial cell damage and increased permeability in the capillaries. Leakage of fluids from capillaries into the extravascular space results in less blood in the vasculature, leading to tissue hypoxia. Cytokines and damaged endothelial cells also initiate the coagulation cascade generating small fibrin clots within the microvasculature.
In ___ -___ % of cases, pancreatitis will recur within ___-___ weeks if the gallbladder is not removed. A. 25-35%, 6-18 weeks B. 20-30%, 5-16 weeks C. 15-30%, 6-17 weeks D. 25-30%, 6-18 weeks
D. 25-30%, 6-18 weeks Gallbladder or bile duct inflammation may occur as well if the gallbladder is not removed, even in mild cases of pancreatitis. If the attack is alcohol induced health teaching about the need to discontinue all alcohol use must occur as failure to eliminate alcohol consumption may lead to chronic pancreatitis. Nutritional support is indicated for patients who will need to be fasted for 7 days or longer. Enteral feeding of patients is preferred to parenteral because of lower risk of infection due to maintenance of the gut barrier. TPN, or total parenteral nutrition may need to be used if enteral feeding is not well tolerated. Those with mild pancreatitis that resolves in a few days don't need nutritional supplementation and can resume eating a soft food, low fat diet once pain has subsided. A cause of pancreatitis in the critically ill receiving parenteral nutrition may be the lipid suspension in the TPN. This may need to be removed and slowly re-introduced as the condition resolves.
What happens without oxygen? A. Hypoxia B. Anaerobic metabolism C. Increased pH D. Both A and B E. All of the above
D. Both A and B This describes the changes in cellular metabolism when there is hypoxia, or lack of oxygen. Without oxygen, glycolysis can proceed in the cytoplasm of the cell but its product, pyruvate, cannot enter the citric acid cycle within the mitochondrion. Pyruvate must then be converted to lactate to allow energy production to continue. Far fewer ATP molecules are produced this way and cellular processes such as the sodium/potassium pump are negatively impacted. Failure of this pump allows sodium to flow into the cell and potassium to leave the cell, upsetting the electrochemical gradient. This gradient is required for action potentials in cells such as neurons and muscle cells so the effects will be evident in the nervous system and myocardium fairly quickly. In addition to interference with chemical and ionic gradients, water flows into the cell leading to swelling, cellular membrane disruption, and release of lysosomal contents. These events initiate positive feedback loops that cause greater deterioration of the cell and impairment of perfusion. Meanwhile, the ongoing anaerobic metabolism results in a drop in pH due to lactic acid buildup and depletion of glycogen stores because of reduced nutrient delivery and increased metabolic demands. Protein synthesis is reduced and use of intracellular and plasma proteins for fuel may ensue as nutrient stores run out. The cellular response to this metabolic stress exacerbates the inflammatory response.
Septic shock falls under the subheading of what kind of shock?
Distributive, one of the three different forms of shock. All types of shock are potentially fatal and must be recognized and treated immediately.
True or False? More males are hospitalized for sepsis and the mortality rate is higher among males as well.
FALSE! In both Canada and the US more males were hospitalized for sepsis but the mortality rates for severe sepsis were higher in women. In Canada the difference was an 8% higher rate of mortality in females. The greater number of underlying illnesses, the greater the mortality in sepsis, but when sepsis occurs is also a contributing factor for mortality. Infections acquired while in the hospital, referred to as nosocomial infections that lead to sepsis, have a higher mortality rate than cases in which the patient was admitted with sepsis. Onset of sepsis- patient whose sepsis occurred after hospital admission had 56% higher odds of dying.
True or False? Sepsis is a complex syndrome that we fully understand now.
FALSE! Sepsis is a complex syndrome that we still don't completely understand. Originally thought to be due to the overzealous response of the inflammatory system, more recent research highlights an initial surge in pro-inflammatory activity, followed by a 'compensatory anti-inflammatory response system' or CARS. This phase is characterized by reduced expression of pro-inflammatory cytokines, an increased level of anti-inflammatory cytokines and cytokine inhibitors, and a high rate of apoptosis of lymphocytes, dendritic cells and epithelial cells. It is in this later stage of sepsis where the immune system is depressed that much of the mortality occurs. Reactivation of latent viruses can occur in this phase, as well as opportunistic infections. Roughly 80% of the population are infected with cytomegalovirus or CMV so in sepsis-induced immune suppression, it can reactivate and cause death. Studies have shown this to be true of the herpes simplex virus, which many people carry as well. It is for these reasons that many of the anti-inflammatory agents such as steroids and cytokine inhibitors tested in clinical trials for sepsis failed to show benefit.
True or False? Sepsis is only caused by gram-negative bacteria.
FALSE! Sepsis was previously thought to be only caused by gram-negative bacteria. It is now known to be caused not only by gram-positive organisms too but by fungi, viruses and parasites as well. Once any of these invaders is detected, inflammatory mediators are released by the innate immune system and impair the functioning of the microcirculation through vasodilation and an increase in capillary permeability. Systemic Inflammatory Response indicators become observable as the body tries to compensate for the falling circulatory volume and in the presence of a suspected or confirmed infection, if there are two or more SIRS symptoms, sepsis is diagnosed. If the patient is not treated and/or the compensatory measures fail, organs become dysfunctional and the patient progresses to severe sepsis. Continued leakage of fluids into the extravascular space and increased need for oxygen by the heart trying to compensate for lower blood volume may result in cardiovascular dysfunction and a progression to septic shock. Inability of the heart to deliver adequate blood to oxygenate tissues occurs in septic shock even once fluids are administered.
True or False? The RAAS does not aid hypovolemic shock.
FALSE! Similar to compensatory mechanisms in cardiogenic shock, the body retains fluid via the RAAS and release of ADH from the pituitary gland and the heart rate is increased. Further to these mechanisms, cardiac contractility is increased and vasoconstriction occurs in the extremities to keep vital organs perfused. Blood stored in the liver is released into the circulatory system and the hypothalamus stimulates thirst in an effort to increase fluid volume from external sources. Blood pressure can be maintained by these mechanisms for a short time but if the vascular volume is not restored adequate tissue perfusion cannot be maintained and organ dysfunction will occur with possible progression to organ failure.
True or False? Costs related to sepsis hospitalizations are much lower than other illnesses.
FALSE! They are much higher. This is partly because stays in hospital tend to be much longer for those admitted with sepsis (or those who develop sepsis while in hospital). The Canadian statistics highlight the greater average length of stay of 12 days for those with sepsis, versus 3 days of hospitalization for causes other than sepsis. The difference was even more dramatic for those with severe sepsis, whose hospital stay was about 11 days longer than those with sepsis that was not deemed severe. Similar results were seen in the US where hospital stays due to sepsis averaged 75% longer than hospitalizations for other reasons. In addition to the longer hospital stays, those with sepsis were more commonly admitted to costly intensive care units, or ICUs. Averaged stays in the ICU in the 2008-2009 period in Canada were 6.3 days, about 4 days longer than patients admitted for other causes. Age is one of the determining factors for incidence of sepsis with the very young and the very old being most susceptible.
How does the RAAS compensate for cardiogenic shock?
Failure of the heart to pump sufficient blood to adequately perfuse the tissues, despite ample blood volume can result in cardiogenic shock if not corrected. This condition often arises as a consequence of MI or severe myocardial ischemia and can also be a late-stage result of coronary artery disease. The renin-aldosterone-angiotensin system or RAAS, attempts to compensate through fluid retention and vasoconstriction. Anti-diuretic hormone or ADH is released as well which gives rise to further increase in blood volume. The adrenal glands react by releasing catecholamines that cause vasoconstriction and increased heart rate. This can worsen the problem by making the heart work harder, increasing systemic vascular resistance or SVR and preload due to the inability to completely empty the ventricles in addition to increased blood volume. Pulmonary and/or peripheral edema may occur due to fluid overload or mismatched ventricular pumping. In addition, myocardial oxygen demands go up because of the increase in heart rate and perfusion is impaired due to decreased oxygen delivery to the myocardium. Blood pressure falls because of reduced cardiac output and proper cellular metabolism cannot continue with delivery of insufficient quantities of oxygen and nutrients. This leads to dysfunction not only in the heart but other oxygen systems as well.
______________ and ________________ are interconnected processes in sepsis.
Inflammation and coagulation
How is the metabolic acidosis measured?
Lack of adequate perfusion to organs can result in septic shock. The metabolic acidosis due to anaerobic respiration can be measured via blood lactate. Studies have shown that patients with improvements in microvasculature perfusion, even with similar hemodynamic values are more likely to survive.
Shock is a condition that may be arrived at several different ways and may manifest with different symptoms but the underlying impairment to cellular metabolism caused by inadequate perfusion is the same. This figure (in module) illustrates this common pathway and the mechanisms that occur and lead to organ dysfunction. The switch to anaerobic metabolism was mentioned previously, along with the reduction in efficiency of ATP production and the intracellular consequences of this scarcity in energy. The increase in lactate levels and ensuing metabolic acidosis due to anaerobic glycolysis was discussed as well. The drop in pH in the blood due to lactic acidosis decreases hemoglobin's affinity for oxygen, further aggravating the hypoxic situation.
OU DAMN!
The 4 types of shock include...
Other types of shock exist provoked by different types of trauma other than infection. There are four types of shock and they are as follows; cardiogenic, obstructive, hypovolemic and distributive.
What are DAMPs?
Pathogen associated molecular patterns from invading microorganisms or parasites along with molecules released by injured tissues are called 'damage associated molecular patterns' or DAMPs. Both of the types of ligands referred to as DAMPs are recognized by the pattern recognition receptors or 'PRRs' which cause over-expression of pro-inflammatory mediators and activate the compliment and coagulation systems. Cells of the innate immune system recruited by cytokines, release harmful agents such as reactive oxygen species and enzymes in their attempts to destroy the invading organisms. These agents damage the endothelial cells of the vasculature creating a pro-coagulant environment. Activation of the coagulation system as well as endothelial cell damage inhibits fibrinolysis and leads to disseminated intravascular coagulation or DIC which is commonly seen in sepsis and further imbalances coagulation and inflammation. Loss of homeostasis in the autonomic nervous system intensifies the pro-inflammatory response of the innate immune cells aggravating the situation. The prolonged pro-inflammatory state leads to apoptosis and dysfunction in immune cells and finally immunosuppression. It is during this late stage in sepsis that immune paralysis can allow reactivation of latent viruses or infection by normally non-pathogenic organisms and lead to death.
Other potential treatments
Recent novel therapies under investigation include several TLR antagonists (mainly targeting TLR-4) and antibody therapies (otherwise known as biologics) that target pro-inflammatory cytokines such as TNF-alpha and IL-18. TLR antagonists mainly act to modulate inflammation by inhibiting innate immune response. While two TLR-4 antagonists have gone through phase 3 clinical trials, the timing, dosage, safety and efficacy are still being investigated. Biologics that inhibit pro-inflammatory cytokines are thought to have an action on both innate and adaptive immune cells. A 2013 meta-analysis of 15 RCTs employing anti-TNF-alpha antibodies or soluble TNF-alpha receptors used to block TNF-alpha signalling suggests that there is a modest benefit for patients suffering from sepsis. Conflicting evidence came out of a recent RCT involving ICUs across 7 countries including Australia, Belgium, Canada, Czech Republic, Finland, France, and Spain. This RCT evaluated the effectiveness of two different doses of anti-TNF-alpha therapy for treating severe sepsis and/or septic shock. While circulating TNF-alpha levels were reduced in the patients in the study, there was no observable clinical benefit i.e. patients suffering from severe sepsis or shock fared no better than those receiving usual care. It is obvious from these results that sepsis is a complex syndrome that still remains poorly understood. The progression from a pro-inflammatory to compensatory anti-inflammatory state - coupled with the dynamic cross-talk between the complement, coagulation and inflammatory systems - likely contributes to the variation in study outcomes.
And to end this lame journey...
Remember that overall mortalities from sepsis are higher than those for MIs and even higher for patients with severe sepsis. At present, there are no good biomarkers or tests for detecting sepsis. As such it is important for the healthcare team to closely observe a patient with a suspected or confirmed infection for signs of shock; realizing that changes in blood pressure may occur much later in sepsis. Early intervention in sepsis and shock results in better outcomes. In both sepsis and shock it is important to identify and treat (if possible) the underlying cause. Module also discussed the pathophysiology of pancreatitis - an inflammation of the pancreas which can quickly become systemic leading to SIRS and potentially shock. If not treated promptly both sepsis and shock can quickly lead to multiple organ dysfunction syndrome or MODS.
A study at McMaster found that survivors with severe sepsis had higher baseline levels of APC than did non-survivors. Recent research on APC at McMaster has also noted an anti-apoptotic activity for monocytes of APC as well as the anti-coagulant, anti-inflammatory and pro-fibrinolytic capabilities. While early clinical trials using human recombinant Activated Protein C (hrAPC) marketed as Xigris seemed promising it was quickly pulled from the world market in 2011 when a large clinical trial failed to show a significant reduction in 28-day all-cause mortality amongst study participants suffering from septic shock. At the time, Xigris was very costly at $10,000 per dose. It was reserved for the sickest of the sick and unfortunately caused increased bleeding episodes as it is a naturally occurring anticoagulant.
SO COOL!
When the symptoms worsens such that hypotension occurs despite the administration of resuscitation fluids, the patient is considered to be suffering from... and what organ system malfunctions?
Septic shock and the heart and entire cardiovascular system The organ system that malfunctions in septic shock is the heart and entire cardiovascular system. The heart fails to pump sufficient blood to supply organs and tissues with oxygen and nutrients. The oxygen that is delivered is not transferred to cells efficiently due to decreased systemic vascular resistance that results in a lack of adequate pressure to drive the oxygen across the cell membranes. This gives rise to anaerobic metabolism, which is not only inefficient in ATP production, but also leads lactic acidosis. ATP is required to fuel the sodium-potassium pump and maintain the correct ion distribution inside and outside the cell. With insufficient energy to maintain the electrochemical gradient, sodium and chloride build up in the cell and cause swelling as water flows in to dilute these ions. Water moving from the extracellular space or interstitium and into cells causes water to flow out of the vasculature volume and further impairs organ and tissue perfusion. In addition to the definitions decided upon for SIRS, the group of experts also came to consensus on the definition of sepsis, severe sepsis and septic shock. These syndromes exist as a continuum and it is easy for a patient to progress from one condition to the next unless they are treated aggressively to prevent the physiological downward spiral that occurs when the inflammatory response damages endothelial cells and dilates the vessels so that it interferes with proper tissue perfusion.
Progression of the condition such that organ systems start to fail due to lack of perfusion causes a deterioration to what?
Severe sepsis Organ dysfunction can be detected by signs of altered mentation such as confusion or agitation, oliguria or decreased urine production, or increased lactate levels which are evidence of insufficient oxygen delivery to cells.
Which medication is given to limit pancreatic secretions helping the pancreas rest thus aiding healing?
Somatostatin (Octreotide) givne IV or SUBCUT
True or False? Pancreatitis can cause ARDS and ATN.
TRUE! In the more severe cases of pancreatitis the damage is widespread enough to incite systemic inflammation and the appearance of SIRS. Shock or other forms of organ dysfunction such as Acute Respiratory Distress syndrome, ARDS, in the lungs or Acute Tubular necrosis, ATN, in the kidneys may occur depending on the severity of the disease process. A large quantity of fluid may migrate to the abdominal cavity and cause a reduction in blood volume with the accompanying hypoperfusion. In addition, the lining of the gut becomes dysfunctional due to damage and allows translocation of intestinal bacteria into the bloodstream, resulting in sepsis. The most common symptom in pancreatitis is severe epigastric or mid-abdominal pain, which can radiate to the back as well and may require narcotics to control. The preferred drug for pain relief is meperidine hydrochloride or Demerol rather than morphine due to a reduced incidence of spasm in the pancreatic duct sphincter.
True or False? There are a spectrum of symptoms that appear with shock, although the body's compensatory mechanisms may mask many of them temporarily.
TRUE! Low blood pressure, decreased urine production, and poor perfusion leading to acidosis are characteristic of all types of shock, but some of the other symptoms are dependent on the cause of the physiological disturbance. Body temperature is decreased in many types of shock but may be increased at the onset of septic shock. In this case the skin may be warm and flushed, rather than cool and clammy as described in the figure. Skin is also warm and dry in neurogenic shock and this is the one type of shock that usually involves bradycardia rather than tachycardia. The ability to spot the warning signs of shock, especially anaphylactic shock, where apprehension, abdominal cramping, coughing, wheezing and the appearance of hives come on quickly, could contribute to the rapid institution of lifesaving interventions.
True or False? Rates for hospitalization for severe sepsis have risen.
TRUE! Rates for hospitalization for severe sepsis have risen from the 2004-2005 time period, although overall sepsis hospitalizations are about the same. It was also noted that some patients about 4% were even hospitalized for sepsis more than once during a year.
True or False? Early recognition and treatment are the most effective ways to deal with the sepsis syndrome.
TRUE! The earlier treatment begins the better the chances of restoring homeostasis and halting the progression to septic shock, organ failure and death. A protocol was devised to administer treatments such as fluid resuscitation and monitor the patient for results, treating until goals have been attained for central venous pressure or CVP, mean arterial pressure or MAP and, central venous oxygen saturation or ScvO₂. The most effective treatment for severe sepsis is a protocol called 'Early Goal Directed Therapy'.
Hypoperfusion is a consequence of what?
The effects of sepsis and septic shock are due to dysfunction at the cellular level. Hypoperfusion is a consequence of vasodilation and capillary leak due to inflammatory mediators in sepsis and severe sepsis and additionally, failure to deliver sufficient blood by the cardiovascular system in septic shock. You may remember that aerobic metabolism requires oxygen. Without oxygen cells must produce energy anaerobically. Aerobic metabolism is about 19 times more efficient than anaerobic, producing close to 38 molecules of ATP per molecule of glucose, versus only 2 produced by glycolysis, which does not require oxygen. The reduced amount of energy produced anaerobically is not enough to sustain all of the cellular processes. As metabolic impairment in cells continues, organ dysfunction occurs. As the number of failing organ systems increases, so does the risk for mortality.
What happens with when the pulmonary system begins to fail?
The most common organ system to fail in severe sepsis is the pulmonary system. Endothelial dysfunction in the capillaries of the lungs, along with extravasation of fluid, causes edema in the lungs and impairs gas exchange. Less surfactant is produced and immune cells infiltrate lung tissue and cause further damage. Loss of aeration leads to hypoxia and impaired perfusion in other organs as well as the lungs where Acute Respiratory Distress syndrome, or ARDS may occur necessitating mechanical ventilation.
What is the most specific and sensitive diagnostic marker for pancreatitis?
The most specific and sensitive diagnostic marker for pancreatitis is an elevated serum lipase level. Serum amylase may be elevated as well but this marker is more transient, disappearing upon late presentation. Other inflammatory markers may be assessed such as C-reactive protein or CRP, this indicator is also used to evaluate disease severity.
Describe the Early Goal Directed Therapy.
The need for fluids and antibiotics within an hour of recognition is highlighted along with cultures to ensure administration of the correct antibiotic as well as control of the source of the infection. Constant monitoring is necessary to confirm that the target blood pressures and oxygen saturation are achieved and maintained. If vasopressors or inotropes such as epinephrine, norepinephrine, dobutamine, dopamine or milrinone are required to increase blood pressure or heart contractility, these would be administered in the ICU, IV and preferably through a central line. See chart in module. To be completed within 3 hours: 1) Measure lactate level 2) Obtain blood cultures prior to administration of antibiotics 3) Administer broad spectrum antibiotics 4) Administer 30mL/kg crystalloid for hypotension or lactate > or equal to 4 mmol/L To be completed within 6 hours: 5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure > or equal to 65mm Hg. 6) In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate > or equal to 4 mmol/L (36 mg/dL): - Measure central venous pressure - Measure central venous oxygen saturation 7) Remeasure lactate if initial lactate was elevated Targets for quantitative resuscitation included in the guidelines are CVP of > or equal to 8 mm Hg. Scvo2 > or qual to 70% of normalization of lactate.
"Cross-talk" in sepsis...
Within sepsis there is interaction between a number of systems. This 'cross talk' between the complement, coagulation and inflammatory systems, as well as the autonomic nervous system can lead to the life-threatening state of immunosuppression.
See chart in module for hospitalizations for sepsis, severe sepsis and non-severe sepsis.
These Canadian results show the small differences between 2004 and 2009, but recently released US data showed a much greater increase in sepsis hospitalizations.
Thrombin does what?
Thrombin is produced during the coagulation cascade and activates inhibitors of fibrinolysis such as Thrombin-Activatable Fibrinolysis Inhibitor, or TAFI, and Plasminogen Activator Inhibitor, or PAI-1 as well as cleaving fibrinogen to form fibrin clots.
What is the initiator of coagulation and how is it activated?
Tissue factor is activated by cytokines such as Tumor Necrosis Factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), expressed by immune cells in response to the detection of infective agents.
In distributive shock there is a profound...
vasodilation that increases the capacity of the vascular system, such that one's normal blood volume may no longer be sufficient to fill this space and maintain a blood pressure. Often times the vasodilation is accompanied by an increase in capillary permeability- that is to say that the capillaries become leaky - which makes the situation even worse as fluids begin to leak from the blood vessels into the tissues. Common causes of excessive vasodilation include systemic inflammation (as in sepsis), allergic reactions (as in anaphylaxis) and loss of sympathetic input to blood vessels as in acute spinal cord injury.
Why might an ultrasound be done?
Ultrasound may be used to investigate the cause of the condition when gallstones are suspected and CT is often used to scan for the extent of tissue necrosis and accumulation of fluid. Removal of gallstones and/or necrotic tissue may help resolve the illness. Cholecystectomy, or gallbladder removal is indicated for all patients who have had acute pancreatitis due to gallstones. When possible this should be done after recovery but before discharge from hospital.
In obstructive shock, there is an obstruction of...
blood flow, which either impedes the filling or emptying of the heart. Common causes include pulmonary embolism (which obstructs blood flow through the pulmonary circuit), cardiac tamponade (which obstructs proper filling of the heart) and tension pneumothorax, otherwise known as a collapsed lung (which obstructs filling of the heart by causing collapse of the vena cava and right atrium).
The delivery of glucose is ____________ by ______________.
decreased, hypoperfusion The effect of impaired glucose utilization has not yet been considered. Delivery of glucose is decreased by hypoperfusion in the same way as delivery of oxygen to the cells. Uptake of glucose may also be reduced due to the release of hormones, vasoactive substances and steroids into the blood. This lack of glucose in the cells increases the use of other fuels so that lipolysis, glycogenolysis and gluconeogenesis are all enlisted for energy production. Due to the extremely limited supply of glycogen in most cells other than liver and muscle, energy stores are quickly reduced. Utilization of lipolysis for energy increases the quantity of free fatty acids and triglycerides in serum, free fatty acids have been found to be cytotoxic, especially to pancreatic beta cells. These dysregulation of cellular metabolism can lead to cell death but gluconeogenesis is the process that can lead to organ failure. Use of protein for energy not only increases the amount of urea and toxic ammonia produced, but also depletes plasma protein levels allowing the movement of more fluid out of the vasculature in response to lower oncotic pressure. Alanine is also generated and once converted to pyruvate for energy production worsens the state of lactic acidosis. Use of protein from muscles can lead to wasting of both skeletal and cardiac fibres and depletion of immunoglobulin proteins can impair immune function, which is especially problematic in septic shock.
Cardiogenic shock, as it implies is shock that comes to failure of the "pump". Some common causes of pump failure include...
heart attack (MI), cardiac conduction problems (such as arrhythmias or blocks) and diseases of the heart muscle collectively referred to as cardiomyopathies. In essence there is an inability of the heart to contract (or to contract in a coordinated manner) which prevents it from functioning as an effect pump.
Anaphylactic shock results form an overwhelming...
systemic allergic response and can vary in severity according to the amount of antigen the patient is exposed to as well as their sensitivity to the antigen. Vasodilatory substances, such as histamine are released in large quantities and increase the capillary permeability as well as dilating the vessels. In addition, to the circulatory effects, anaphylactic reactions can include laryngeal and angio-edemas, gastrointestinal cramps, hives and bronchoconstriction that causes difficulty with breathing. Common antigens that cause anaphylactic shock re nuts, shellfish, bee stings and drugs such as penicillin. This form of shock comes on very suddenly and treatment must be administered immediately. The rapid drop in blood pressure diminishes tissue perfusion and quickly leads to altered mentation. Individuals with known sensitivities should wear a Medic Alert bracelet to warn healthcare providers; they should also carry a single-dose Epipen. Epinephrine is administered quickly via IM injection or IV to cause vascular constriction, reverse airway constriction and curtail mast cell and basophil degranulation, minimizing release of histamine and other vasodilatory substances. Because of the short half-life of epinephrine multiple doses may be required. In addition to regular resuscitation, antihistamines, both short and long-acting may also be required.
Neurogenic shock is also known as...
vasogenic shock which occurs when the balance between parasympathetic and sympathetic nervous systems is lost. In addition, to the spinal cord and brain trauma, this can be caused by depressant drugs and anaesthetics and insufficient delivery of glucose to the brain, possibly due to the action of excess insulin. Widespread vasodilation occurs and although there is sufficient fluid volume, the vascular compartment had expanded so this volume is no longer adequate. Due to the suppression of the sympathetic system, this is the one type of shock in which the heart rate slows instead of escalating and the skin remains warm and dry instead of cold and clammy as in other forms of shock. Neurogenic shock is categorized as a type of distributive shock along with septic shock and anaphylactic shock, since there is no loss of fluid, rather a redistribution that impairs tissue perfusion. This is the rarest form of shock and tends to be transitory.
