Critical Care Medicine 978-1-4963-0291-5 chapter 27

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Critical Care Medicine FIFTH EDITION Publishing October 2018

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When you have to be right

Critical Care Medicine FIFTH EDITION By JJohn J Marini and David J Dries

ISBN 9781496302915 Pages 720 Price £54.00

Publishing October 2018 Sample Chapter Preview

When you have to be right

Brief description With a full-color design and concise, easy-to-read chapters, Critical Care Medicine: The Essentials and a Bit More covers the core elements of critical care, with a unique focus on the pathophysiology underlying clinical disorders and how pathophysiologic concerns affect treatment options. There is much here that’s new: brand-new content, expanded discussions, and more graphical elements than ever before. Chapters follow a consistent structural template, with discussions of diagnosis, instrumentation, treatment and management techniques, and more. Expertly and succinctly captures all the fundamentals of the field!

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Designed primarily for use by students and residents, but also helpful for anyone already in practice. Now with updated drug info and more substantial coverage of interventional radiology, pregnancy care, and organization of critical care. Emphasizes the pathophysiologic elements and treatments of illness and injury. NEW NEW

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Topics range from intubation, ventilation, and pharmacotherapy, as well as drug overdoses, sepsis, gastrointestinal bleeding, and other crisis care scenarios.

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CHAPTER

Sepsis and Septic Shock

syndrome (SIRS), a term in use for decades, is no longer thought well suited for practice by the most recent consensus of international experts (Fig. 27-1). Instead, “sepsis” is now defined as a life-threatening organ dysfunction caused by a dysregulated response to infection. “Septic shock” is the subset of sepsis with circulatory and/or cellular/metabolic dysfunc- tion and higher risk of mortality (Fig. 27-2). The shock state is identified by the need for a vasopressor (e.g., norepinephrine) to maintain a mean arterial pressure greater than 65 mm Hg in the absence of hypovolemia, accompanied by a lac- tate level greater than 2 mmol/L. Moreover, as more has been learned about the pathobiology of the syn- dromes associated with systemic infection, it was thought wise to dissociate the potentially homeo- static responses to infection (e.g., fever, leukocytosis, and tachycardia) from those that reflect the adverse organ response. Prominent among the latter are altered mental status, hypotension, and tachypnea. Whether the shock physiology of sepsis is driven pri- marily by impaired perfusion or by abnormalities of cellular energetics has not been settled. It is likely that causative primacy may depend not only on the individual but on the time point of observation. An operational definition of sepsis is outlined in Table 27-1. EPIDEMIOLOGY The millions of cases of severe sepsis that occur each year across the world present huge medical, social, and economic problems. Severe systemic infections have no age or gender boundaries. With the excep- tion of a spike in frequency in the first year of life, septic shock has a low incidence throughout early adulthood and then an exponentially rising inci- dence, mortality rate, and cost after the age of 50. Although sepsis can develop in perfectly healthy persons, most patients have been hospitalized for several days before recognition of the condition.

• Key Points 1. Sepsis is defined as life-threatening organ dysfunc- tion caused by dysregulated (as opposed to homeo- static) host response to infection. Septic shock is a subset of this condition, with circulatory and/or cel- lular/metabolic dysfunction and higher mortality risk. 2. Septic shock is a common condition that overall car- ries a 30% to 40% risk of death. Outcome is influ- enced strongly by the number and severity of organ system failures that occur. 3. Whereas disordered mental functioning and tran- sient oliguria are almost universal, the lung and circulatory system are the two organ systems that overtly fail with highest frequency. Both manifest dysfunction early in the septic process. Circulatory failure usually reverses within days or proves fatal, whereas respiratory failure often requires 1 to 2 weeks of ventilatory support. Frank renal failure requiring dialysis is unusual. Cognitive function may remain abnormal for months after recovery. 4. Early fluid replacement and vasopressor therapy aimed at restoring adequate perfusion pressure are keystones of circulatory support. Glucocorticoids are a reasonable therapeutic option for patients with shock refractory to vasopressor support. 5. Infection source control, directed cultures, initial broad-spectrum coverage, and targeted antimicro- bial therapy during deescalation phase are essential elements of treating septic shock. TERMINOLOGY Criteria for early recognition of sepsis and septic shock as well as guidelines for best therapeutic approach continue to undergo revision and refinement, perhaps because systemic infection occurs so commonly and with life-threatening consequences unless treated effectively. The term systemic inflammatory response

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SECTION II • Medical and Surgical Crises

SYSTEMIC INFLAMMATORY

RESPONSE SYNDROME (SIRS)

SEPSIS

INFECTION

eventually regain premorbid levels of function in most organs; however, there is a growing aware- ness that a significant proportion of patients are left with long-lasting cognitive and neuromuscular impairments (see Chapter 18). The average survivor requires 7 to 14 days of intensive care support, with much of this time spent receiving mechanical ven- tilation. After intensive care unit (ICU) discharge, an additional 10- to 14-day hospital stay is typical. Thus, the hospital length of stay for survivors aver- ages 3 to 5 weeks. Massive hospital bills are often generated during the care of septic shock even when the course of treatment and recovery are relatively uncomplicated. After hospital discharge, long-term skilled inpatient care or challenging home care and rehabilitation are often required. Most survivors of septic shock are discharged on numerous medica- tions, require office visits to physicians frequently during the year after discharge, and are readmitted one or more times for treatment of complications. RELATIONSHIP OF INFECTION TO SEPSIS Recovery of a pure growth of a pathogen from a normally sterile site (e.g., blood or joint or cerebro- spinal fluid [CSF]) diagnoses infection ; however, most infected patients do not develop overt sepsis. This fact suggests that it is not infection per se that is etiologic but rather the combination of infection and host response that determines if an individual will develop organ dysfunction. Interestingly, a clear microbiologic explanation is absent in many patients, even though cultures grow some organism 60% to 80% of the time. Many of these “positive” cultures are obtained long after symptomatic sepsis or septic shock is established and represent insignifi- cant colonization, contamination, or superinfection. FIGURE 27-1. Formerly prevailing classification of systemic inflammatory states. In this nosology, SIRS is defined by a specific pattern of vital sign abnormali- ties. Infection is the presence of a microbe within the host at a normally sterile site. When infection causes SIRS, the resulting syndrome is called sepsis (central overlap). If an organ failure results from sepsis, the syndrome is called severe sepsis.

SEVERE SEPSIS

SEVERE SIRS

Victims of trauma, immunosuppressed patients, and patients with chronic debilitating medical conditions (e.g., diabetes, chronic obstructive lung disease) or those undergoing complicated surgical procedures are most at risk. Overall, approximately 30% of patients with sep- tic shock die despite receiving “standard therapy” consisting of antimicrobial therapy and organ system support with fluids, vasoactive drugs, mechanical ventilation, dialysis, and nutrition. Such statistics motivate continuing efforts to recognize and optimally treat this high-risk patient group, as exemplified by the recurring Surviving Sepsis campaigns. Elderly and hypothermic patients have a substantially worse prognosis than those without these factors; however, the best practical clinical predictor of outcome is the number of dysfunctional organ systems. Among the possible organ failures, circulatory failure (shock) has a disproportionately negative prognostic value. Morbidity and mortality from septic shock remain unacceptably high, and billions of dollars are spent caring for this desperately ill group of patients. Fortunately, survivors usually

INFECTION

SEPSIS

SEPTIC SHOCK

FIGURE 27-2. Suggested revision of the classification scheme for septic conditions.

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Table 27-1. Sepsis Syndrome Criteria I. Clinical evidence of infection (required) II. Major criteria (two of four required) Fever or hypothermia (temperature >100.4°F or <96°F) Tachypnea or high minute ventilation (respiratory rate >20 or minute ventilation >10 L)

Tachycardia (pulse >90 in the absence of intrinsic heart disease or drug therapy inhibiting tachycardia) Leukocytosis or leukopenia (WBC >10,000/mm 3 or <4,000/mm 3 ) or greater than 10% band forms on differential III. Acute impairment of organ system function (one required) Altered mental status (reduction in Glasgow coma score >2 points) Hypotension (SBP < 90 mm Hg or fall in BP > 40 mm Hg refractory to fluid challenge) Impaired gas exchange or acute respiratory distress syndrome (PaO 2 /FiO 2 ratio <300) Metabolic acidosis/lactic acidosis Oliguria or renal failure (urine output <0.5 mL/kg/h) Hyperbilirubinemia Coagulopathy (platelet count <80,000/mm 3 or a 50% decline within 48 hours; INR > 2.0; PTT > 1.5 × control with elevated fibrin degradation products)

Common examples include growth of skin flora in one of several blood culture bottles, the recovery of a light growth of Staphylococcus aureus from sputum of a ventilated patient, or demonstration of a few colonies of Candida albicans in the urine of a patient with an indwelling urinary catheter. Perhaps the most convincing evidence of infection comes when several blood cultures obtained at the onset of the episode grow an identical pathogen consistent with the patient’s clinical situation, for example, recovery of Escherichia coli in multiple blood cultures from an elderly man with bladder outlet obstruction and pyuria. Unfortunately, positive blood cultures are recovered in the minority of patients with advanced sepsis, and blood cultures are seldom positive if obtained after antimicrobial therapy is started. Despite historical teaching, there is little prognostic import of having positive blood cultures, unless bac- teremia cannot be eradicated. Inability to clear the circulation of organisms is often associated with an unresolved focus of infection (e.g., endocarditis or an infected foreign object) and portends a worse prognosis. Remarkably, host responses that mimic sepsis are encountered in noninfected patients with severe pancreatitis, trauma, or burns, as these conditions produce similar biochemical changes, disordered physiology, clinical presentation, and outcome. This observation suggests that infection is not essen- tial but rather that microbiologic stimulation acts merely as one disease trigger. The lung is the most common site of infection leading to life-threatening sepsis, accounting for

roughly half of all cases. Intra-abdominal infections (20% to 25%) and urinary tract infections (approx. 10%) are the next most common, with all other sites comprising the remaining 15% of infections. MICROBIOLOGY Bacteria, fungi, parasites, and viruses all can incite the sepsis syndrome. Because of the relatively high incidence of bacterial infections and relative ease in recovery of these organisms, bacteria are most com- monly implicated. Limitations of diagnostic tech- niques make causative viruses difficult to identify. Historically, fungal infections were rarely etiologic in immunocompetent hosts, but with improved antibacterial agents and support techniques, increased numbers of immunocompetent patients now survive long enough to acquire a fungal infec- tion. Distressingly, the frequency of fungal, particu- larly Candida infection, has risen dramatically over the past decades and now accounts for almost 10% of all sepsis-related episodes. When a bacterial pathogen is identified, the fre- quency of gram-positive versus gram-negative bac- teria is roughly 50:50. Discussions of the likelihood of gram-positive versus gram-negative infection are of limited value; the prevalence of organisms varies by location and over time, “cycling” under antibiotic pressure. Furthermore, knowing the frequency of each type of bacteria across a population is not partic- ularly helpful in designing the initial treatment plan for an individual patient, except that such informa- tion can highlight unusual local resistance patterns.

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For example, in some parts of the Southeastern United States, half of all Pneumococcus isolates are at least of intermediate resistance to penicillin. In addition, now in many ICUs, the single most com- mon organism causing severe episodes of sepsis is a highly resistant nosocomial pathogen, typically methicillin-resistant S. aureus (MRSA) or vanco- mycin-resistant Enterococcus (VRE). Regardless, in most circumstances, critically ill patients require prompt empiric therapy for all reasonably likely organisms until culture data are available. PATHOPHYSIOLOGY The severity of sepsis is determined more by the specificity and ferocity of the host response than by the inciting organism. Ironically, the same inflam- matory and coagulopathic mechanisms that are detrimental when intense, unrestrained, and undi- rected in the septic patient usually act as beneficial and effective defenses. Certainly, both confined inflammation and accelerated coagulation limit spread of local infection or injury. It is only when rogue, diffuse, unbridled inflammation, or coagu- lation occurs that they are counterproductive and organ damaging. Adverse host responses impair car-

diovascular, neuronal, autonomic, hormonal, bioen- ergetic metabolic, and coagulation functions. Historically, excessive inflammation was con- sidered the major, if not sole, pathogenetic factor in severe sepsis. This paradigm envisioned a multistage inflammatory “cascade” in which an initial trigger caused production of a few “early” mediators, followed over hours by a larger number of secondary media- tors (Table 27-2). Moreover, a linear progression from health to septic shock was envisioned, based primarily on the intensity of inflammation. It is now clear that inflammation, though extremely important and cen- tral to the sepsis syndrome, is but one of at least three important pathophysiologic pathways that includes enhanced coagulation and impaired thrombolysis. The trigger for severe sepsis is often a protein, lipid, or carbohydrate toxin shed from a microbe but may be activated complement, a clotting cas- cade component, or dead host tissue. The most notorious inciting factor is endotoxin, the integral cell wall lipopolysaccharide component of gram- negative bacteria. However, it is far from being the only important toxin; staphylococcal toxic shock syndrome toxin (TSST-1) and group B streptococ- cal (GBS) toxin are other well-recognized triggers. The triggering compound usually is only present

Table 27-2. Common Mediators of Sepsis and Their Actions Agent Action CELLULAR ELEMENTS Monocytes and macrophages Neutrophils Cytokine production, tissue factor expression Tissue destruction via oxidant and protease mechanisms

EICOSANOIDS Prostaglandins Prostacyclin Thromboxane E-series prostaglandins Leukotrienes

Vasodilation, inhibition of platelet aggregation Vasoconstriction, platelet aggregation Renal vasodilation, inhibition of cytokine generation Vasodilation, increased vascular permeability, leukocyte chemotaxis

CYTOKINES Tumor necrosis factor

Interleukin-1 Interleukin-6 Interleukin-8 OXIDANTS H 2 O 2 , HOCl 2 PROTEASES

Neutrophil chemoattractant

2 −

− , O

Direct injury of lipids, nucleotides, and proteins

Destruction of vital cellular proteins, including antioxidants

CLOTTING PROTEINS Thrombin

Microvascular thrombosis, leukocyte activation, inhibition of fibrinolysis

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CHAPTER 27 • Sepsis and Septic Shock

transiently in the circulation and commonly escapes detection, even when sophisticated monitoring is performed. For example, less than one half of patients exhibiting septic shock ever have detect- able endotoxin in plasma. This fact may help to explain the failure of antidotes developed to bind and neutralize circulating toxins. Development of sepsis does not require bacteremia or endovascular infection; toxic products may be released into the bloodstream from localized sites (e.g., abscesses) or directly from the colon (gut translocation), even when viable organisms do not circulate. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) have received the most attention as targets for modifying the septic response because they are potent, rapidly produced inflammatory compounds found in the tissues and circulation of many septic patients (Table 27-3). However, controversy exists regarding the significance of these circulating cyto- kines, and clinical trials designed to lessen levels of these compounds have not reduced mortality. That controversy notwithstanding, these cytokines are major stimulants for generation and release of other mediators, including IL-6, IL-8, enzymes,

prostaglandins, leukotrienes, oxidant radicals, plate- let-activating factor, and nitric oxide. Some activate coagulation (Fig. 27-3). Simultaneously with the dominant proinflammatory agents, anti-inflammatory mediators ramp up their activity. There is growing appreciation that abnormal coagulation is nearly universal in severe sepsis and that a complex interplay exists between clot- ting and inflammation. At the outset of the syn- drome, tissue factor expressed by leukocytes and endothelium and cytokines lead to the production of thrombin by stimulating clotting factors V and VIII. Initially, the natural anticlotting systems (e.g., protein C, protein S, antithrombin) counteract the accelerated clotting. In this process, clotting proteins are consumed forming thrombi, and anti- clotting proteins are depleted trying to inhibit clot formation. Because sepsis also impairs the host’s ability to convert inactive anticlotting precursors to functioning proteins, clotting proceeds unopposed. As a second line of defense, endogenous fibrino- lytic systems (e.g., plasminogen) are activated to dissolve the microvessel clogging thrombi, increas- ing plasma levels of clot degradation products.

Table 27-3. Experimental and Unverified Therapies for Sepsis Category Proposed Action Result Corticosteroids Nonspecific anti-inflammatory

Multiple failed human trials, possibly increases infection risk Inconsistent data from clinical trials

Replacement of relative adrenal insufficiency

Naloxone

Opioid receptor antagonist

May transiently raise blood pressure, no effect on survival

Cyclooxygenase inhibitors

Reduce thromboxane and prostacyclin Improved vital signs, no effect on survival, overall safe

Antiendotoxins

Inactivate gram-negative toxins

Several failed trials, possible harm suspected from one agent; trials ongoing

IL-1 receptor antagonist

Block IL-1 action Inactivate TNF Block TNF action

No improvement in physiology or survival

TNF receptor antagonists

Dose-dependent increase in mortality

Antioxidants Prevent oxidant-mediated cellular injury Trials ongoing Toll-like receptor antagonists Block inflammatory signal transduction Positive phase II human trails, studies ongoing Tissue factor pathway inhibitor Inhibit tissue factor activation of coagulation Studies ongoing Activated protein C Antithrombotic, anti-inflammatory serine protease No benefit in several trials. Possible harm

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TRIGGER

IL-8

TNF

RADICALS

O 2

IL-1

TNF IL-1

PAF

IL-6

MONONUCLEAR CELLS

ENZYMES

PROSTAGLANDINS

ADHESION

FIGURE 27-3. Simplified representation of the early biochemical events in sepsis syndrome. In most cases, an inflammatory stimulus ( upper left ) activates tissue-based and circulating mononuclear cells. The resulting production of tumor necrosis factor (TNF) and interleukin-1 (IL-1) can activate diverse nucleated cells. In response to TNF, other cells, especially neutrophils ( upper right ), release additional interleukins, more TNF, oxidant radicals, prostaglandins, leukotrienes, and proteases. TNF and IL-1 also activate adhesion molecules on neutrophils and vascular endothelium, resulting in cellular binding and vessel injury ( bottom ). Simultaneously, activation of tissue factor on white blood cells and endothelial cells results in accelerated clotting and inhibition of fibrinolysis.

Although routine clotting assays (e.g., prothrombin and activated partial thromboplastin times) may be near normal, abnormalities of clotting and anticlot- ting systems can be detected using more sensitive laboratory tests. The complex interrelationship among the three major pathways that mediate sep- sis (inflammation, coagulation, and fibrinolysis) is still being elucidated by ongoing research. It is also clear, however, that counterregulating immunosup- pressive activity begins from the very first stages of the proinflammatory response. One highly simpli- fied schema depicting these interactions is illus- trated in Figure 27-4. CLINICAL DIAGNOSIS Sepsis has many classic presentations: Group B Streptococcal sepsis in newborns, meningococ- cemia in young children, and staphylococcal toxic shock syndrome of adults. Unfortunately, such “classic presentations,” which include recovery of a

specific organism, are exceptional. Sepsis is a clini- cal diagnosis, not one made by noting a single spe- cific laboratory value or positive culture. Because a central tenet of improving the response to sepsis is early identification and intervention, detection of organ dysfunction at the earliest possible stage is a high priority. To this end, the quick qSOFA score, an abbreviated and user-friendly version of the well validated but more difficult to use sequential organ failure assessment (SOFA) score, has been devel- oped, tested and advocated. Three clinically observ- able elements comprise qSOFA: (1) alteration of mental status (e.g., obtundation or confusion); (2) respiratory rate >22/min; and (3) systolic blood pressure less than 100 mm Hg. If two of these three elements are present, sepsis is likely or imminent. Although the qSOFA may not be infallible, more traditional clinical signs and measures are less spe- cific or less reliable for organ dysfunction. For example, although fever is present in more than 90% of diagnosed cases, it may reflect

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CHAPTER 27 • Sepsis and Septic Shock

Leukocytes

Inflammation

Endothelial cells

 Increased cytokine production  Adhesion molecule exposure

 Adhesion molecule ligand exposure  Chemokine receptors

Mediators

DIC initiation

 Chemotaxis  Release of TNF- a and IL-10  Phagocytic activity

 Tissue factor exposure  Activation of coagulation system  Thrombin generation

Platelets

Immune cells

Coagulation Immunosuppression

FIGURE 27-4. Interactive inflammation, coagulation, and immunosuppressive sectors of the septic response.

a normal homeostatic response or conversely, be minimal or absent in the elderly, in patients with chronic renal failure, or in those receiving steroids or other anti-inflammatory drugs. Indeed, hypo- thermia occurs in approximately 10% of cases of overt sepsis and is a particularly poor prognostic sign, with mortality rates in hypothermic patients approaching 80%. This high mortality rate is not due to the reduced temperature itself but rather the close linkage of hypothermia with chronic underly- ing disease, shock, gram-negative bacteremia, and/ or a more ferocious host inflammatory response. Tachycardia, too, is an unreliable marker; it may be a sign of homeostatic behavior, rather than a sign associated with sepsis-defining organ dysfunction. Yet, unless patients have intrinsic cardiac conduc- tion system disease or are receiving medications to prevent tachycardia (e.g., β -blockers, calcium chan- nel blockers), tachycardia almost invariably accom- panies sepsis. Oliguria (urine output <0.5 mL/kg/h

for >2 hours), though a key clinical observation, may indicate an adaptive homeostatic response to hypovolemia, rather than organ injury by sepsis. Respiratory rate, on the other hand, is a key vital sign, because newly developed tachypnea is an early harbinger of advancing sepsis. Although it is pos- sible to have near-normal lung function with sep- sis, the diagnosis should be questioned in patients without tachypnea or abnormalities of gas exchange; more than 90% of patients develop hypoxemia suf- ficient to require supplemental oxygen (usually a PaO 2 /FiO 2 ratio below 300), and nearly 75% of life-threatening sepsis victims require noninvasive or invasive forms of mechanical ventilation. New abnormalities in circulating leukocyte (WBC) count (>10,000 cells/mm 3 or <4,000 cells/mm 3 ) occur fre- quently enough to be considered an important but highly nonspecific diagnostic criterion for sepsis. Among ICU patients, such leukocyte abnormalities are nearly universal.

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20 Mortality Rate (%)

FIGURE 27-5. Relationship between mortality and the number of organ systems failing because of sepsis. Each additional failing organ system raises the overall mortality rate by 15% to 20%.

Number of Organ Failures

ORGAN SYSTEM FAILURES In fatal cases of sepsis, it is the cumulative effects of organ system failures that cause patients to suc- cumb. Therefore, understanding the usual onset, duration, and resolution of organ failure and meth- ods of support assumes paramount importance. A clear relationship exists between the number of organ failures and mortality. Each new organ system failure adds roughly 15% to 20% to the baseline risk of death for all ICU residents (Fig. 27-5). Septic patients in the ICU typically average two to three failing organ systems at the time of diagnosis. The frequency of various organ failures noted at the time of diagnosis is shown in Figure 27-6. The most com- mon constellation is the development of pulmonary dysfunction and shock. (Most patients develop-

ing shock also will be oliguric at least transiently.) Despite the multiplicity of causes, the pattern of organ failures in sepsis is remarkably similar among patients, with lung and circulatory failure devel- oping rapidly (usually within 72 hours). Advanced central nervous system (CNS) dysfunction tends to develop later, although confusion is often the predominant manifestation of severe sepsis in the elderly. Oliguria is extremely common in the early stages of sepsis of whatever severity and does not always signal advancing kidney injury before resus- citation has been completed. Even though coagu- lation abnormalities exist in almost all victims of life-threatening sepsis, overt disseminated intra- vascular coagulation (DIC) occurs in only 10% to 15%, and its timing and its clinical recognition are unpredictable.

Percent with Organ Failure

FIGURE 27-6. Prevalence of organ system failures at the time of diagnosis of severe sepsis. ARDS, acute respiratory distress syndrome; CNS, central nervous system.

Oliguria

Shock

PaO 2

/FiO 2

ARDS

CNS Dysfunction

< 300

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