Critical Care PDF - Hemodynamic Parameters & Shock Treatment

Critical Care I. INTERPRETATION OF HEMODYNAMIC PARAMETERS A. Hemodynamics (Table 1) 1. A rterial blood pressure is the product of cardiac output and resistance to flow (systemic vascular resistance [SVR]). a. Cardiac output (milliliters of blood pumped per minute) is calculated by stroke volume...

Critical Care I. INTERPRETATION OF HEMODYNAMIC PARAMETERS A. Hemodynamics (Table 1) 1. A rterial blood pressure is the product of cardiac output and resistance to flow (systemic vascular resistance [SVR]). a. Cardiac output (milliliters of blood pumped per minute) is calculated by stroke volume (milliliters of blood ejected from the left ventricle per beat) times heart rate. b. Stroke volume is determined by preload (amount of blood available to eject), afterload (resistance to ejection), and contractility (amount of force generated by the heart). These will be discussed in more detail later. 2. A rterial blood pressure can be described by systolic blood pressure (SBP), diastolic blood pressure (DBP), or mean arterial pressure (MAP). This is the driving pressure for organ perfusion and oxygen delivery. MAP = [SBP + (2 × DBP)]/3. Note that MAP is based largely on DBP because most of the cardiac cycle is spent in diastole. a. Normal MAP is 70–100 mm Hg. b. M AP is an indication of global perfusion pressure; a MAP of at least 65 mm Hg is necessary for adequate cerebral perfusion in most patients. c. M AP can be calculated using the above equation, but direct measurement from an arterial line provides more timely and accurate measurements. 3. Preload is defined as ventricular end-diastolic volume, and it increases proportionally with stroke volume (Frank-Starling mechanism). Commonly used measures of preload include central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), or pulmonary artery occlusion pressure (PAOP), and newer measures such as stroke volume variation (SVV) and pulse pressure variation (PPV). a. CVP is the pressure in the vena cava at the point of blood returning to the right atrium and may reflect volume status, although its utility in assessing volume responsiveness (i.e., whether a patient’s low blood pressure will improve with an increase in intravascular volume) is poor. A CVP of 8–12 mm Hg (12–16 mm Hg if mechanically ventilated because of increases in thoracic pressure) has been suggested as being optimal for a patient with hypoperfusion from sepsis, but data on the use of CVP are lacking. CVP values at the extremes usually reflect hypovolemia (less than 2 mm Hg) and hypervolemia (greater than 18 mm Hg). b. PCWP or PAOP is the pressure when a balloon is inflated (wedged) in one of the pulmonary artery branches. Because the measurement is taken closer to the left ventricle than CVP, it may be a more accurate marker of volume status, but controversy remains. Its utility is diminished because the use of pulmonary artery catheters has severely declined. c. Dynamic markers (SVV, PPV) are increasingly used to determine a patient’s volume responsiveness to a fluid challenge. These measurements consider other variables and provide a better assessment of an individual patient’s position on the Starling curve. Further information about dynamic markers can be found in the references. (Curr Opin Crit Care 2013;19:234-41) B. Indicators of oxygen delivery 1. Assessment of end organ function is perhaps the simplest measurement of adequate oxygen delivery. Changes in mental status, decreased urine output (less than 0.5 mL/kg/hour), and cold extremities may be the first markers of organ hypoperfusion. 2. Blood pressure is the driving force behind oxygen delivery. Every organ is able to autoregulate blood flow, but this ability is generally lost at MAP values less than 65 mm Hg. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-301 Critical Care 3. 4. Lactic acid a. Lactic acid is formed during anaerobic metabolism. b. During states of hypoperfusion, the tissues receive less blood and therefore less oxygen. c. If there is less oxygen for the tissues, they will convert to anaerobic metabolism, with the subsequent production of lactic acid. d. Lactate clearance can be used as a therapeutic end point in shock states. Venous oxygen saturation a. The oxyhemoglobin saturation of venous blood returning to the right atrium is normally 70%– 75% (with a normal [99%–100%] arterial oxygen saturation), indicating that the normal oxygen extraction ratio is around 25%–30%. b. In times of decreased oxygen delivery (caused by anemia, a decrease in Sao2, CO, or tissue perfusion), more oxygen is extracted from the blood that is being perfused to tissues, causing an increased extraction ratio and thus a decrease in venous oxygen saturation. c. Central venous oxygen saturation (Scvo2) and mixed venous oxygen saturation (Svo2) are measurements of venous oxygen saturation. These values are similar, but Scvo2 is slightly higher than Svo2 because it has not mixed with venous blood from the coronary sinus. Scvo2 is measured in the superior vena cava, and Svo2 is measured from the pulmonary artery; therefore, Svo2 is about 5% lower than Scvo2. d. A normal Svo2 does not rule out hypoperfusion in patients with impaired extraction (e.g., sepsis). An elevated lactate concentration may indicate hypoperfusion in this scenario. Table 1. Hemodynamic Parameters and Normal Values Parameter Systolic blood pressure (SBP) Diastolic blood pressure (DBP) Mean arterial blood pressure (MAP) Systemic vascular resistance (SVR) Heart rate (HR) Cardiac output (CO) Cardiac index (CI) Stroke volume (SV) Pulmonary capillary wedge pressure (PCWP) or pulmonary arterial occlusion pressure (PAOP) Central venous pressure (CVP) Lactic acid Central venous oxygen saturation (Scvo2) Calculation (If Applicable) [SBP + (2 × DBP)]/3 80 [(MAP – CVP)/CO] HR × SV CO/BSA CO/HR Normal Range 90–140 mm Hg 60–90 mm Hg 70–100 mm Hg 800–1200 dynes/s/cm5 60–80 beats/min 4–7 L/min 2.5–4.2 L/min/m2 60–130 mL/beat 5–12 mm Hg 2–6 mm Hg <1 mmol/L 70%–75% BSA = body surface area. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-302 Critical Care II. TREATMENT OF SHOCK A. D  iagnosis of shock is based on hemodynamic parameters. Many patients have more than one type of shock (Table 2). Table 2. Definitions of Shock Hemodynamic Subset CI Hypovolemic Low CVP/PCWP Low SVR High Description Patients with hypovolemic shock have a low CI because the Starling curve shows reduced cardiac function as intravascular volume is reduced The reduced intravascular volume is indicated by a low PCWP, with a reflex increase in SVR to maintain tissue perfusion Cardiogenic Low High High SVR is inversely related to flow (CI) Patients with cardiogenic shock have acute heart failure (low CI) The insufficient forward flow of blood causes venous congestion (high PCWP) and an underfilled arterial blood volume Obstructive Low Low (impaired ejection) High High (impaired filling) Distributive or vasodilatory High (early) Low (early) Low (late) Normal to high (late) Low (early and late) The subsequent reduced tissue perfusion causes a reflex vasoconstriction (which, although it can improve blood flow to vital organs, can worsen heart function by increasing afterload) and reduced renal excretion of Na+ and water Impairment in diastolic filling (caused by tamponade) or systolic contraction (massive pulmonary embolus, aortic stenosis) Differentiation can usually be made by patient history Patients with distributive shock are typically hyperdynamic (high CI), with vasodilation (low SVR) and increased vascular permeability (“leaky capillaries”), causing intravascular fluid to shift into the interstitial spaces (thus, low PCWP) The vasodilation and vascular permeability are attributable to cytokines and inflammatory mediators CI = cardiac index; CVP = central venous pressure; Na+ = sodium; PCWP = pulmonary capillary wedge pressure; SVR = systemic vascular resistance. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-303 Critical Care B. Treatment of hypovolemic shock 1. Treatment focuses on restoring intravascular volume and oxygen-carrying capacity. Crystalloids and colloids are discussed in the “Fluids, Electrolytes, and Nutrition” chapter. 2. Blood products (packed red blood cells and coagulation factors) should be administered in hypovolemic shock, if clinically indicated. a. A hemoglobin less than 7 g/dL is defined as a transfusion threshold in patients in the general ICU. It is reasonable to have higher hemoglobin targets in selected patients (e.g., patients with symptomatic cardiovascular disease may need a hemoglobin greater than 10 g/dL). b. Actively bleeding patients should have blood products administered regardless of hemoglobin concentration in conjunction with interventions to stop the source of bleeding. 3. Patients may need vasopressors if hypotension is not rapidly reversed with fluid resuscitation. a. The efficacy of vasopressors is reduced in patients who have not received adequate intravascular volume resuscitation. b. Adverse events associated with vasopressors (e.g., arrhythmias, ischemia) may occur more often or at greater severity in patients who have not received adequate fluid resuscitation. C. Treatment of cardiogenic shock 1. Cardiogenic shock involves injury to the left or right ventricle, resulting in reduced cardiac output and perfusion. Causes of myocardial injury are extensive and can be ischemic (e.g., myocardial infarction) and non-ischemic (e.g., myocarditis, valvular disease, medication nonadherence). Injury can be multifactorial and be present with other types of shock. 2. Management depends on the underlying chronic or acute cardiovascular diseases, and treatment considerations vary depending on the hemodynamic indices. Details are discussed in the “Acute Care in Cardiology” chapter. D. Treatment of obstructive shock 1. Fluids and vasopressors can be used temporarily to improve end organ perfusion, but may not improve outcomes. 2. Treatment of the actual obstruction is the only way to reverse the shock state. a. Massive pulmonary embolism: Thrombectomy or administration of systemic or catheter-directed thrombolytics may be indicated if the patient has a high risk of death. b. Cardiac tamponade: Removal of fluid in the pericardial sac is the only definitive treatment. E. Treatment of vasodilatory and distributive shock 1. Septic shock is the most common cause of vasodilatory shock (Table 3). Other causes such as anaphylaxis, vasoplegia, intoxication, pancreatitis, and neurogenic and endocrine causes will not be discussed in this section. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-304 Critical Care Table 3. Classifications of Sepsis Definition Life-threatening organ dysfunction caused by a dysregulated host response to infection Sepsis Septic shock Criteria Sepsis screening tools have a wide variation in diagnostic accuracy, but they are important components of the early identification and treatment of patients with sepsis; a variety of clinical variables (signs of infection, vital signs) and tools may be used for screening, (e.g., SIRS, NEWS, or MEWS); notably, the 2021 guidelines recommend against the use of qSOFA as a single screening tool for sepsis Lactate concentrations can also be used as a sepsis screening tool for patients with suspected sepsis Septic shock is a subset of sepsis in Need for vasopressors to maintain MAP ≥ 65 mm Hg and which profound circulatory, cellular, lactate > 2 mmol/L despite adequate fluid resuscitation and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone MAP = mean arterial pressure; MEWS = Modified Early Warning Score; NEWS = National Early Warning Score; qSOFA = quick Sequential Organ Failure Assessment; SIRS = systemic inflammatory response syndrome. 2.  he hallmark treatments of septic shock are rapid antibiotic administration and fluid resuscitation, T ideally within the first hour of hypotension. 3. The Surviving Sepsis Campaign (SSC) is an initiative to reduce mortality from sepsis and septic shock. 4. SSC hour-1 bundle a. The SSC bundle is a group of selected elements of care taken from evidence-based practice guidelines that, when implemented as a group, have a greater effect on outcomes than any individual element. b. The SSC recommends the following bundle to be completed within 1 hour for patients presenting with sepsis or septic shock. i. Measure baseline lactate concentration. (a) Guide resuscitation to normalize lactate in patients with elevated lactate concentrations as a marker of tissue hypoperfusion. ii. Obtain blood cultures before administering antibiotics. iii. Administer appropriate broad-spectrum antibiotics depending on the suspected source of infection and likely pathogens. iv. Begin administering 30 mL/kg balanced crystalloid for hypotension or lactate 4 mmol/L or greater. (a) Albumin can be considered when patients need a substantial amount of crystalloids. There is no evidence that colloids are superior to crystalloids in improving outcomes, and they are more expensive. (b) Hydroxyethyl starches (e.g., hetastarch) are not recommended for fluid resuscitation because of an increased risk of acute kidney injury and mortality. (c) A  dministration of large volumes of chloride-rich solutions leads to metabolic acidosis and acute kidney injury. The use of “balanced crystalloids” (solutions with electrolyte concentrations similar to those of extracellular fluid, such as lactated Ringer solution and Plasmalyte) for volume replacement can lead to less acute kidney injury than the use of other fluids (0.9% sodium chloride). This is probably a dose-dependent phenomenon. A recent systematic review and meta-analysis found balanced crystalloids were associated with a lower 28or 30-day mortality than saline in critically ill patients. Specifically, patients with sepsis had similar mortality rates but lower odds of major adverse kidney events within 30 days. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-305 Critical Care v. Increasing evidence suggests that balanced crystalloids are preferred to saline for fluid resuscitation in critically ill patients (Ann Pharmacother 2020;54:5-13). The 2021 guidelines suggest using balanced crystalloids instead of normal saline for resuscitation. Initiate vasopressors if the patient is hypotensive during or after fluid resuscitation to maintain MAP 65 mm Hg or greater (Table 4). (a) The goal MAP of 65 mm Hg may be modified depending on patient-specific factors. A higher goal may be appropriate in patients with atherosclerosis or a history of hypertension. The individualized target MAP should correlate with improvement in other clinical parameters (e.g., lactate concentration, mental status, urine output, capillary refill). (b) Ideally, vasopressors should be used after restoration of intravascular volume, but in patients with septic shock and hypoperfusion, vasopressors may be necessary during fluid resuscitation to optimize perfusion of vital organs. Once intravascular volume is optimized with fluid resuscitation, vasopressors should be weaned if possible. (c) Vasopressors improve tissue perfusion by increasing blood pressure and/or CO. Few studies have evaluated an improvement in clinical outcomes, but differences in safety profile have been observed. Therefore, drug selection is based largely on expert opinion, practitioner experience, and patient response. (d) Norepinephrine is the initial vasopressor of choice. The SOAP II trial is a multicenter randomized trial of patients requiring vasopressors because of any type of shock. Enrolled patients received either blinded norepinephrine or dopamine. There was no difference in 28-day mortality, but patients receiving dopamine more commonly developed an arrhythmia, required open-label norepinephrine, and required more days with vasopressor support. The study results suggest although norepinephrine does not improve mortality compared with dopamine, it is safer and more effective. (e) Vasopressin can be added to norepinephrine if needed. It is usually administered at a fixed dose of 0.03 units/minute. Splanchnic, digital, and cardiac ischemia have been reported at higher doses. The efficacy of vasopressin when added to norepinephrine is similar to that of norepinephrine alone. Vasopressin can have a vasopressor-sparing effect, although mortality is not improved with the combination. The addition of vasopressin earlier (at norepinephrine doses of less than 15 mcg/minute) may be associated with an improvement in outcomes. The exact threshold of when to add vasopressin varies in the literature and remains unclear. The 2021 guidelines suggest initiating vasopressin with a norepinephrine dose range of 0.25–0.5 mcg/kg/minute. Refer to Table 4 for additional vasopressor dosing. (f) Epinephrine can be added in patients with inadequate MAP levels despite norepinephrine and vasopressin. (g) Dopamine is an alternative to norepinephrine, but it is associated with a higher incidence of tachyarrhythmias compared with norepinephrine. Dopamine use should be limited to patients with a low risk of tachyarrhythmias and absolute or relative bradycardia. Lowdose dopamine should not be used for renal protection because evidence does not support this practice. Use of dopamine is also associated with neuroendocrine abnormalities. (h) Phenylephrine is an alternative to consider in patients with vasopressor-induced tachyarrhythmias or persistent hypotension refractory to other vasopressors. (i) Use of an arterial catheter for blood pressure measurements is preferred in patients needing vasopressors, because it is a more accurate measurement of arterial pressure (compared with a blood pressure cuff) and allows continuous monitoring. (j) The 2021 guidelines suggest starting vasopressors peripherally rather than delaying initiation until a central line is secured. If vasopressor therapy is needed beyond a short period (> 6 hours), efforts should be made to obtain central venous access for administration. This helps reduce the risk of extravasation and subsequent tissue ischemia. If ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-306 Critical Care extravasation occurs, stop the vasopressor immediately and switch to another site if necessary. Phentolamine (an α-receptor antagonist) can be injected around the site as soon as possible to reduce tissue necrosis. In a phentolamine shortage, other options include nitroglycerin ointment (applied around the site of extravasation every 6 hours) or subcutaneous terbutaline (peripheral vasodilation is mediated through β2-receptors). (k) Angiotensin II is a novel vasoactive agent that increases blood pressure in adults with septic or other distributive shock. It is a peptide hormone of the renin-angiotensin-aldosterone system, causing vasoconstriction and increasing aldosterone release, which increases blood pressure. The 2021 guidelines state angiotensin II may be used as an adjunct vasopressor therapy, and acknowledge the limited evidence and clinical experience currently available. Additional studies are needed to confirm the exact role and benefit in septic shock. vi. If persistent arterial hypotension occurs despite volume resuscitation or initial lactate 4 mmol/L or more, volume status and tissue perfusion should be reassessed by either of the following: (a) Repeated focused examination including vital signs, cardiopulmonary examination, capillary refill, pulse, and skin findings assess source control. (b) Two of the following: (1) CVP measurement (2) Scvo2 measurement (3) Bedside cardiovascular ultrasound (4) Dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge Table 4. Vasopressors and Inotropesa Drug Dose Norepinephrine 0.01–3 mcg/ kg/min α1 ++++ β1 ++ β2 0 DA 0 Notes Epinephrine 0.04–1 mcg/ kg/min +++ ++ ++ 0 Positive inotropic and chronotropic effects can induce tachyarrhythmias and myocardial ischemia Low doses primarily β-adrenergic; escalating doses primarily α-adrenergic Some evidence of reduced splanchnic circulation, which can lead to gut ischemia Increases blood glucose and lactate concentrations (type B lactic acidosis)b May be used for refractory hypotension Vasopressin 0.03–0.04 unit/min 0 0 0 0 Direct stimulation of smooth muscle V1 vasopressin receptors; peripheral vasoconstriction, no adrenergic activity Theoretically beneficial because of an apparent relative vasopressin deficiency in septic shock, but no evidence of efficacy over other vasopressors (see text) Effective during acidosis and hypoxia because it does not rely on adrenergic receptors Doses ≥ 0.04 unit/min are associated with coronary vasoconstriction and peripheral necrosis Not titrated like traditional vasopressors Prone to dosing errors because of “unit/min” ↓ Renal perfusion ↑ SVR, ↑ MAP ↔ to ↑ CO (at high doses) Peripheral ischemia Can induce tachyarrhythmias and myocardial ischemia ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-307 Critical Care Table 4. Vasopressors and Inotropes (Cont’d) Drug Phenylephrine Dose 0.5–8 mcg/kg/ min α1 ++++ β1 0 β2 0 DA 0 Angiotensin II Initial (during first 3 hr of treatment): 10–80 ng/kg/ min Maintenance: 1.25–40 ng/ kg/min 0 0 0 0 Binds to the G protein-coupled angiotensin receptor type 1 on vascular smooth muscle cells resulting in smooth muscle contraction, and vasoconstriction Increased risk of thrombotic events (mechanical and pharmacologic thromboprophylaxis is recommended) May cause increased heart rate, lactic acidosis, infections (e.g., fungal), and delirium Recent exposure to angiotensin-converting enzyme (ACE) inhibitors may cause an exaggerated response to angiotensin II Recent exposure to angiotensin II receptor blockers (ARBs) may cause a reduced response to angiotensin II Dopamine 1–3 mcg/kg/ min +/− + +/– ++++ + ++ 0 ++ +++ ++ 0 + Lower doses cause renal, coronary, mesenteric, and cerebral arterial vasodilation and a natriuretic response Do not use low-dose dopamine for renal protection because evidence does not support this practice Lower inotropic doses can complement the vasoconstrictive effects of norepinephrine Moderate doses can ↑ contractility and SVR Effects on renal blood flow may be lost at higher doses because of predominant α1-vasoconstrictive effects Any dose can induce arrhythmias Any dose can cause endocrine changes (e.g., decreased prolactin, growth hormone, thyroid hormone); however, the clinical significance is unknown Immediate precursor of norepinephrine Prolonged infusions can deplete endogenous norepinephrine stores, resulting in a loss of vasopressor response 3–10 mcg/kg/ min 10–20 mcg/kg/ min Notes ↓ Renal perfusion ↑ SVR, ↑ MAP Pure α-adrenergic agonist with minimal cardiac activity Rapid ↑ SBP and DBP can cause a reflex bradycardia and reduction in CO Can be administered as a rapid bolus for acute hypotension (e.g., intraoperative) or as a continuous infusion. Dobutamine 2–20 mcg/kg/ min + +++ + 0 Positive inotrope (↑ CO) Can cause hypotension because of β2-stimulation Higher doses can cause tachyarrhythmias and changes in BP, which can lead to myocardial ischemia Milrinone 50-mcg/kg load over 10 min, followed by 0.375–0.75 mcg/kg/min 0 0 0 0 Noncatecholamine, phosphodiesterase type 3 inhibitor Positive inotrope (↑ CO) Vasodilation leading to hypotension, arrhythmias possible Excreted as mostly unchanged drug in urine; renal dose adjustments necessary Loading doses often omitted especially because of increased risk of vasodilation Some vasopressors may be administered using weight-based dosing or non-weight-based dosing (e.g., norepinephrine, epinephrine, phenylephrine). As opposed to type A lactic acidosis caused by tissue hypoperfusion, epinephrine may cause increased lactate concentrations because of accelerated aerobic glycolysis through β-adrenergic stimulation. BP = blood pressure; CO = cardiac output; DA = dopamine; DBP = diastolic blood pressure; MAP = mean arterial pressure; SBP = systolic blood pressure; SVR = systemic vascular resistance. 0 = no effect +/− = may have some effect + = mild effect ++ = moderate effect +++ = strong effect ++++ = strongest effect ↓ = decreases; ↑ = increases; ↔ = no change a b ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-308 Critical Care 5. 6. Appropriate use of antimicrobials in patients with sepsis a. Empiric antimicrobials should cover likely pathogens according to suspected location of infection and risk of multidrug-resistant pathogens. Common sources of infection are lung, abdomen, blood, and urinary tract. Please refer to the “Infectious Diseases” chapter for discussion of specific agents. b. Consider empiric fungal therapy with either triazoles such as fluconazole, an echinocandin, or a lipid formulation of amphotericin B if patients have several risk factors, including recent abdominal surgery, long-term PN, indwelling central venous catheters, or recent treatment with broad-spectrum antibiotics or if patients are immunocompromised (e.g., chronic corticosteroids or other immunosuppressants, neutropenia, malignancy, organ transplant). An echinocandin is preferred in patients with septic shock, recently treated with antifungal agents, or if Candida glabrata or Candida krusei infection is suspected. c. Other considerations when choosing appropriate antimicrobials include the patient’s history of drug allergy or intolerance, recent antibiotic use, comorbidities, and antimicrobial susceptibility patterns in the community and hospital. d. Consider empiric antiviral therapy with oseltamivir for patients presenting with flu-like symptoms during flu season. e. For patients with probable sepsis or shock with a high likelihood from sepsis, antimicrobials should be administered immediately, and ideally within one hour of recognition. For patients with possible sepsis without shock, rapid assessment should be completed to assess for infectious or noninfectious illness. This should be completed within 3 hours of presentation, and antimicrobials should be administered within this time if concern for infection persists. Antimicrobials should be administered preferably after at least two sets of blood cultures (one obtained percutaneously) are obtained. Quantitative cultures of other potential sites of infection (e.g., urine, sputum) should also be obtained before antimicrobials are administered, if possible. f. If several antibiotics are prescribed, administer the broadest coverage first and infuse as quickly as possible. g. Mortality increases by 7.6% for each 1-hour delay in administering appropriate antimicrobials at appropriate doses which obtain therapeutic serum concentrations at the suspected infection site. h. Appropriate antimicrobials do not reduce the importance of emergency source control by drainage, debridement, or device removal as needed. i. De-escalation should occur with respect to culture data or clinical judgment. Empiric use of combination therapy should not be administered for longer than 3–5 days if de-escalation to a single agent is appropriate. j. Consider discontinuing antimicrobials after 7-10 days for most serious infections. A longer course may be necessary if the patient has slow response, an undrainable foci, deep seated infections, immunologic deficiencies, bacteremia with S. aureus, or some fungal or viral infections. k. Procalcitonin, a serum biomarker for bacterial infections, can be used as a guide for antibiotic therapy. Protocols that encourage or discourage the use of antibiotics depending on procalcitonin concentrations decrease unnecessary antibiotic use without increasing harm to patients. l. Discontinue antimicrobials if no infectious cause is found. Indication for and use of corticosteroids a. Adrenal function in critically ill patients can be suppressed by endotoxins produced by bacteria and by the body’s immune response to stress. b. Early studies showed a relationship between vasopressor responsiveness and glucocorticoid administration. c. To determine a patient’s adrenal function during critical illness, a corticotropin stimulation test (“stim test”) may be performed, although it is no longer recommended. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-309 AL GRAWANY Critical Care i. The corticotropin stimulation test has come under criticism because of the high dose of cosyntropin administered, the inability to measure free (active) cortisol, and lack of data on outcomes of responders versus nonresponders. It is not indicated for evaluation of immune response in the general ICU septic population. d. Clinical trials of steroids in septic shock i. In a study published in 2002, adult patients with septic shock were given a corticotropin stimulation test and then randomly assigned to intravenous hydrocortisone combined with oral fludrocortisone or placebo, regardless of stimulation test results. In the entire patient population, steroid therapy improved 28-day survival; however, this result was driven primarily by a mortality benefit in patients who were unresponsive to the corticotropin stimulation test.. Responders showed no improvement with steroid therapy (JAMA 2002;288:862-70). ii. The CORTICUS trial, published in 2008, had a similar method to the study above but omitted fludrocortisone. In this study, corticosteroids were not associated with a mortality benefit regardless of the results from a corticotropin stimulation test; however, they were associated with a higher risk of hyperglycemia, new sepsis, or septic shock. For this reason, corticosteroids are not recommended in patients with septic shock who have been stabilized with fluid and vasopressor therapy. iii. In the ADRENAL trial, published in 2018, adult patients with septic shock were randomized to receive an intravenous infusion of hydrocortisone or placebo. There was no difference in 90-day all cause mortality, but hydrocortisone infusion decreased duration of septic shock and blood transfusions. This is the largest randomized controlled trial assessing steroids in septic shock. iv. The APROCCHSS Trial, also published in 2018, had similar methods as the study from 2002 described above with intravenous hydrocortisone and oral fludrocortisone or placebo. There was a decrease in 90-day all cause mortality and duration of septic shock in patients treated with hydrocortisone and fludrocortisone. v. The mixed results from numerous studies leaves uncertainty as to the mortality benefit of steroids in septic shock. However, there seems to be consistency as to the short-term benefits including decreased time to resolution of shock especially relative to start of supplementation. e. Evidence-based guidelines i. SSC guidelines (a) The SSC suggests the use of intravenous corticosteroids for adult patients with septic shock and ongoing requirement for vasopressor therapy. Hydrocortisone 200 mg per day is recommended based on multiple studies, and it may be administered either as a continuous infusion or 50 mg intravenously every 6 hours. Although the optimal timing of initiation is uncertain, the 2021 guidelines define ongoing requirement of vasopressor therapy as norepinephrine greater than 0.25 mcg/kg/min for at least 4 hours. There is growing literature that early initiation of hydrocortisone in this patient population may be associated with improved outcomes such as shorter duration of vasopressor therapy. (b) The SSC recommends against using the corticotropin stimulation test to identify the subset of adults with septic shock who should receive hydrocortisone. (c) Although fludrocortisone was a component of the treatment regimen in some studies, the SSC only includes hydrocortisone in recommendations for septic shock. ii. American College of Critical Care Medicine corticosteroid insufficiency guidelines recognize that although hypothalamic-pituitary-adrenal axis dysfunction is common in some critically ill patients (sepsis), diagnosis and management of this disorder are complicated. (a) The expert panel’s recommendations for septic shock are similar to the SSC guidelines, that hydrocortisone should be considered in the management strategy for patients with septic shock, particularly those who have responded poorly to fluid resuscitation and vasopressor agents. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-310