Hello, my name is John Ceransky and I have the privilege of spending a few moments as part of the multi-professional critical care review course for the Society of Critical Care Medicine to talk about evidence-based management of sepsis and septic shock. We see listed here my intellectual and grant support disclosures. During the next few moments, we are going to discuss the definition of sepsis and septic shock, the management of sepsis, and the management of patients with septic shock. Let's start with a question. What is sepsis? Is it bacteria circulating in the bloodstream, systemic inflammatory response syndrome, or SIRS, a host immune response to infection, or a complex syndrome related to infection that is difficult to diagnose and maybe even more difficult to treat? The answer is that it involves parts of all of these options to varying degrees. Under the current sepsis 3 definition, sepsis is a life-threatening organ dysfunction caused by dysregulated host response to an infection. Let's focus on organ dysfunction and its role in making a diagnosis of sepsis. Perhaps the easiest way to define organ dysfunction is by looking at the Serial Organ Failure Assessment or SOFA score. Organ dysfunction can be identified as an acute change in the SOFA score of 2 or more points. For patients without pre-existing organ dysfunction, we can assume a baseline value of 0, and so a SOFA score of 2 would qualify them as having organ dysfunction, and therefore possibly sepsis as well. Septic shock is then defined as hypotension despite adequate fluid resuscitation requiring the use of vasopressors to maintain a mean arterial pressure or MAP of 65 or greater and having a lactate of greater than 2. A patient with septic shock then can be identified as someone who has persistent hypotension requiring vasopressors to maintain a mean arterial pressure of 65 or greater with an elevated serum lactate of 2 or more despite adequate volume resuscitation. These criteria were derived and validated from roughly 3 million patient charts. As you can see from this slide, the risk of mortality was highest for those patients who had all three criteria that we just mentioned, hypotension requiring vasopressors with an elevated lactate level. From an epidemiological perspective, we know that gram-positive bacteria are the most common cause of sepsis, with gram-negative bacteria a close second, followed by fungal infections. In the U.S. each year, nearly 2 million people develop sepsis and more than a quarter million people die as a result of sepsis. That makes sepsis the third most common cause of death in the U.S. In fact, it's estimated that 1 out of every 3 patients who die in the hospital, 1 die as a result of sepsis. Worldwide, every year there are roughly 50 million cases of sepsis and 11 million deaths due to sepsis. In fact, sepsis is the leading cause of death worldwide. Although both the incidence and mortality from sepsis have declined over time, sepsis contributes roughly one-fifth of all global deaths year after year, with more than 20 deaths every minute on average. Not surprisingly, the burden of sepsis is associated with a country's income and development, with the vast majority of sepsis-related deaths occurring in lower and middle-income countries. Why is sepsis so difficult to diagnose? One of the challenges of diagnosing sepsis is that its presentation can be heterogeneous. It looks different in every patient. It can entail different types of infections—respiratory, skin, brain infections, and so on. There are different sources of infection. Different organisms can be involved. Organ dysfunction can also occur in different ways, and different organs may be affected from one patient to another. Sepsis can additionally occur in patients of all ages, affecting patients of different ages at different ways. At its earliest stages, when sepsis is easier to treat, it tends to be more difficult to diagnose. But as sepsis progresses and causes more and more problems, the diagnosis may become easier. However, at later stages, the treatment is more difficult. Of note, sepsis is a syndrome, not a disease. We don't have a single diagnostic test that lets us know that sepsis is present. Because we don't have a diagnostic test or biomarker to diagnose sepsis, we need to rely on the definition of sepsis to diagnose it. That definition includes organ dysfunction as one of its components. There are two important components of organ dysfunction that are important to remember. First, sepsis-induced organ dysfunction may be a cult. If you have a patient who presents with an infection, you should screen them to look for organ dysfunction, because otherwise it may not be evident on its own. Second, a patient with organ dysfunction may have an underlying and unrecognized infection. If you have a patient with organ dysfunction, especially one who is critically ill, you should evaluate the patient for an infection that could be cause of the organ dysfunction. Sepsis management relies on sepsis identification, and early identification is the key to providing optimal care. Differentiating sepsis from septic shock determines the type of care that's needed, as well as the urgency of care. Several key strategies for managing sepsis were spelled out in the Surviving Sepsis Campaign, which was launched in 2002 as a collaboration between the Society of Critical Care Medicine and the European Society of Intensive Care Medicine with the goals of reducing mortality and morbidity from sepsis and septic shock worldwide. An important principle from the campaign is to recognize that sepsis and septic shock are medical emergencies, and that treatment and resuscitation should begin immediately. Antimicrobial therapy is critically important for treating the underlying infection. Therefore, the Surviving Sepsis Guidelines recommend beginning IV administration of antimicrobials as soon as possible after recognition of sepsis, and ideally within one hour of recognition for both sepsis and septic shock. Empiric broad-spectrum antimicrobial therapy is recommended with at least one antimicrobial to cover all likely pathogens for infection. This includes MRSA and, in some cases, multidrug-resistant organisms. The Surviving Sepsis Campaign also recommends that a specific anatomic diagnosis of infection requiring source control be identified or excluded as quickly as possible, and that any source control intervention be initiated as soon as it is medically possible and logistically practical. That is because while antibiotics are important, they by themselves may not be sufficient to treat the sepsis. Source control, including drainage, catheter removal, or surgical interventions, may play an essential role in treating these patients. Fluid resuscitation is another cornerstone of sepsis therapy. The Surviving Sepsis Guidelines recommend that resuscitation of patients with sepsis-induced hyperperfusion be accomplished with at least 30 milliliters per kilogram of intravenous crystalloid fluid administered within the first three hours, ideally initiated within the first hour. More recent studies, including the CLASSIC study and the CLOVERS trial, that I'll talk about in just a moment, suggest that fluid-limited resuscitation is at least as good as more aggressive volume resuscitation. After the initial volume resuscitation, the recommendation is to administer additional fluids as needed based on the patient's hemodynamic status, which should be monitored and reassessed frequently. There are a number of potential options to do so, including using dynamic measures, targeting capillary refill, or targeting lactate levels in patients whose lactate is elevated. Balancing the need for adequate resuscitation with an avoidance of excess volume resuscitation requires careful attention to the patient. As mentioned, there is increasing evidence that limited fluids may be appropriate in patients with sepsis and septic shock. There are two recent large trials that include patients with septic shock that were not considered in the 2021 Surviving Sepsis Guidelines. These include the CLASSIC trial, which enrolled patients with septic shock of under 12 hours duration and were randomized to either restrictive fluids or usual fluids. In the ICU, those treated with restrictive fluids received a median of 800 cc less IV fluids after 24 hours and 1.6 liters less after 5 days, with similar amounts of acute kidney injury, limb ischemia, 90-day mortality, and days alive without organ support. In the CLOVERS trial, patients with sepsis-induced hypotension who had received at least 1 liter of IV fluids were randomized to restrictive fluids versus liberal fluids. Those patients randomized to restrictive fluids received more vasopressors, while those randomized to liberal fluids, not surprisingly, received more fluids. There was no difference between the groups in 90-day mortality, need for renal replacement therapy, or days of organ failure free days between the groups. Crystalloids are the fluid of choice because they're readily available and there is no evidence that other fluids are superior. Albumin is recommended for sepsis patients only in patients where crystalloids are becoming ineffective or who require substantial administration of crystalloids. The surviving sepsis guidelines also recommend against the use of starches for IV volume replacement because these have been shown to be harmful in patients with sepsis and septic shock. One change from the previous guidelines is the suggestion to use balanced salt solutions rather than normal saline. Given the potential concerns about the possibility of normal saline worsening acute kidney injury, there have been a number of recent large clinical trials examining the role of balanced salt solutions in sepsis and other forms of critical illness. While the larger multi-center clinical trials have individually not shown a clear benefit to the use of balanced salt solutions, which include lactated ringers or plasmalite, however, a recent meta-analysis suggests a potential benefit to balanced salt solutions in all critically ill patients. When the authors of this meta-analysis looked separately at the sepsis patients enrolled into trials with a low risk of bias, they concluded there was a high probability that there is an effect of using balanced crystalloids is to reduce mortality. For patients with persistent hypotension and septic shock, norepinephrine is the first choice vasopressor over other vasopressors. After adding norepinephrine, for patients who remain hypotensive despite the norepinephrine, the addition of vasopressin may be useful for raising the mean arterial pressure to its target. If the patient is on norepinephrine and vasopressin and still remains hypotensive, it is reasonable to consider adding epinephrine. The blood pressure target for patients with septic shock should be 65. Of note, the 65 trial, which compared usual care with aiming for a mean arterial pressure between 60 to 65 in adults greater than 65, showed no difference in outcomes between the two treatment groups. Of note, in the intervention arm, which aimed for a mean arterial pressure between 60 to 65, the median mean arterial pressure in this intervention arm was 67, while in the usual care arm was 73. Thus, people did not, as sometimes happens in the ICU, reach the targeted goal, but there was separation between the two groups. In patients with septic shock, it is important that hemodynamic assessments be continued to be performed so that fluids and vasopressors can be titrated as needed. The surviving sepsis guidelines also suggest that, to predict fluid responsiveness in patients, dynamic variables should be used over static variables when that capability is present. Several other measures that you can use to guide resuscitation include to normalize lactate levels in patients with an elevated lactate or to follow capillary refill. Increased lactate levels can result from an imbalance between oxygen demand and delivery, so one way of thinking about managing lactate levels is to seek ways to address this imbalance. Similarly, impaired capillary refill can also be an imbalance between oxygen demand and delivery. You can consider what can be done to decrease oxygen demand, such as reducing workload, providing sedation, or you can potentially increase oxygen delivery through improved cardiac output or improved oxygen content, for example. If after these inventions the lactate is decreasing or the capillary refill is improving, you can consider resuscitation efforts to be effective in that patient. However, if there is no change, you may need to rethink the intervention and reassess the underlying problem to make sure that you're not missing potential causes of the derangement. There are several adjunctive therapies that are sometimes used in the treatment of sepsis and septic shock. In patients with septic shock, IV hydrocortisone is often used at a dose of about 200 mg per day, which can be added for patients who are persistently hypotensive, despite fluid resuscitation and the use of at least one vasopressor. For patients who are anemic, RBC transfusion is appropriate if the hemoglobin is less than 7. Otherwise, RBC transfusion is generally not indicated for patients with septic or septic shock. Acute respiratory failure is another complication of sepsis, and mechanical ventilation is therefore an important supportive therapy. Use the same strategies that are used for other critically ill patients, such as those with the acute respiratory distress syndrome, or ARDS. We use a target tidal volume of 6 mL per kg of predicted body weight, along with an upper limit of the plateau pressure goal of 30 cm of water in patients with sepsis-induced ARDS. The surviving sepsis guidelines suggest using lower tidal volumes in patients with sepsis-induced respiratory failure and those patients with respiratory failure who do not have ARDS, because in these patients, low tidal volume may prevent the development of ARDS. For some patients with sepsis-induced respiratory failure, there are other components of supportive therapy that you should think about. In patients with moderate to severe ARDS caused by sepsis, use prone ventilation for more than 12 hours a day. In patients with moderate to severe sepsis-induced ARDS, do not use incremental peep titration along with recruitment maneuvers in these patients, for this has been shown to increase mortality. I should note that the surviving sepsis guidelines no longer comment on things that will happen after the initial presentation of patients with sepsis. These will be discussed in the next slide. Similar to other critically ill patients, one should use the ICU Liberation Bundle, which combines several elements, such as doing daily spontaneous breathing trials, avoiding excessive use of sedatives and analgesics, mobilization, and other parts that are important to treat patients with sepsis-induced respiratory failure. This slide shows data from the ICU Liberation ABCDEF Bundle, showing that patients in whom the bundle was used had more days alive and free of delirium and coma in a dose-response fashion to bundle compliance. There are some other supportive therapies that should be used similarly to other types of patients with life-threatening illness. These include protocolized glucose management to prevent severe hyperglycemia and hypoglycemia, venous thromboembolism prophylaxis, early initial of enteral nutrition in patients who can tolerate it. Please don't use IV vitamin C in patients with sepsis and septic shock, and finally, early discussion of goals of care and prognosis with patients and their family, and please incorporate these goals from the discussion into treatment planning. To summarize what we've talked about in this presentation, sepsis and septic shock are medical emergencies for which treatment must begin immediately. Treatment goals include obtaining cultures, administer antibiotics, and consider the need for source control, all of which ideally should be done within the first hour or few hours. Appropriate IV fluids and vasopressors should be administered early and according to patient needs, and please use appropriate hemodynamic assessments aimed at individualizing therapy. Finally, as with all critically ill patients, please pay close attention to ancillary supportive therapies and use the ICU Liberation Bundle to liberate patients from invasive mechanical ventilation and to accelerate recovery. Now, let's review some cases. The first is a 58-year-old white male with COPD who presents to the emergency department with a two-day history of fever, cough with purulent sputum, dyspnea, and right-sided chest pain. On exam, his vital signs show fever and an oxygen saturation of 94%. He's noted to be dyspneic and has rails in the right lower chest. His labs show an elevated white count, a creatinine of 2.1, a lactate of 2.2, blood gases that you can see on the slide, and a rapid gram stain of sputum that shows gram-positive diplococci. The first question in this case is, what criteria allow you to make the diagnosis of sepsis in this patient? The patient has sepsis because, one, he has evidence of an infection with fever and leukocytosis. Two, he has infection with a lactate greater than two. Three, his primary care doctor called the ED and told the clerk he was coming with sepsis. Four, he has an infection with a creatinine elevation that counts for two SOFA points. And five, he doesn't have sepsis. In this case, the patient does have sepsis. Recall sepsis is an infection causing new organ dysfunction, most often measured by the SOFA score. This patient had an elevated creatinine that qualified for an elevated SOFA score in the presence of infection, thereby meeting the criteria for sepsis. While SIRS criteria may be relevant for sepsis screening and may be early markers for sepsis, they are not part of the sepsis diagnosis. And finally, elevated lactate is only part of the septic shock definition and does not count towards the SOFA score. The second case is a 59-year-old female who is eight days postoperative from a bowel resection with priming anastomosis at an outside hospital. She's admitted to your ICU from the emergency room with worsening abdominal pain, nausea, and vomiting. Looking at her vitals, we see tachycardia, hypotension, tachypnea, an oxygen saturation of 94% on four liters, and fever. Her labs revealed leukocytosis, anemia, elevated creatinine, elevated aspartate, aminotransferase, and a lactate of 3.1. She has a CT scan of her abdomen showing an anastomotic leap. She has cultures taken. She's given antibiotics and three liters of lactated ringers. Here's the question. This patient has septic shock because she's got infection, hypotension, and an elevated lactate greater than two. She has an infection with a QSOFA greater than two. The outside hospital called you to tell you that she was coming with septic shock. She has an infection with organ dysfunction that counts for greater than two SOFA points, or she doesn't have septic shock. The answer to this question is the last one. She does not have septic shock. As you may recall, septic shock is now defined as sepsis causing hypotension sufficient to require vasopressors to maintain a mean arterial pressure greater than 65 despite fluid administration and with a lactate greater than three. You need to have all three of these criteria. Although she was hypotensive, had an elevated lactate level, and received fluids, the information provided did not include blood pressure and did not indicate she was on a vasopressor. On its own, hypotension with an elevated lactate does not constitute septic shock. Please also recall that the QSOFA score is only used as a screening tool for sepsis and is typically used outside the ICU. It is not used and should not be used to diagnose sepsis or septic shock. Finally, SOFA is not used to diagnose septic shock. Septic shock is the combination of hypotension despite vasopressors in patients who have been adequately resuscitated along with an elevated lactate. In conclusion, the sepsis 3 definition allows methods to screen and diagnose for sepsis focusing on organ dysfunction and illness severity. Early patient identification and rapid treatment improve the likelihood of a patient surviving sepsis. Because the definition of sepsis is not simple, you should screen for organ dysfunction when suspecting sepsis when unexplained organ dysfunction is present. I thank you for your attention and hope that this has proved useful. I appreciate your taking some time to listen to this review of the diagnosis and treatment of patients with sepsis and septic shock. And I hope that this has proven useful to you. For suggestions, please do not hesitate to reach out to me personally, jsevran at emory.edu. Thank you.

sepsis

septic shock

SOFA score

antimicrobial therapy

fluid resuscitation

vasopressors

Surviving Sepsis Campaign