How We Escalate Vasopressor and Corticosteroid Therapy in Patients With Septic Shock

Septic shock is defined by the need for vasopressor agents to correct hypotension and lactic acidosis resulting from infection, with 30%-40% case fatality rates. The care of patients with worsening septic shock involves multiple treatment decisions involving vasopressor choices and adjunctive treatments. In this edition of "How I Do It", we provide a case-based discussion of common clinical decisions regarding choice of first-line vasopressor, BP targets, route of vasopressor delivery, use of secondary vasopressors, and adjunctive medications. We also consider diagnostic approaches, treatment, and monitoring strategies for the patient with worsening shock, as well as approaches to difficult weaning of vasopressors. Septic shock is defined by the need for vasopressor agents to correct hypotension and lactic acidosis resulting from infection, with 30%-40% case fatality rates. The care of patients with worsening septic shock involves multiple treatment decisions involving vasopressor choices and adjunctive treatments. In this edition of "How I Do It", we provide a case-based discussion of common clinical decisions regarding choice of first-line vasopressor, BP targets, route of vasopressor delivery, use of secondary vasopressors, and adjunctive medications. We also consider diagnostic approaches, treatment, and monitoring strategies for the patient with worsening shock, as well as approaches to difficult weaning of vasopressors. A 65-year-old woman with atrial fibrillation sought treatment at the ED with fever and dysuria. Initial BP was 75/40 mm Hg (mean arterial pressure [MAP], 52 mm Hg), heart rate was 95 beats/min, and oxygen saturation was 92% on room air. Extremities were warm and well perfused. She received Ringer's lactate until she was no longer volume responsive by multiple measures and received antibiotics for community-acquired urosepsis. She remained hypotensive with a BP of 82/45 mm Hg (MAP, 57 mm Hg). Serum lactate was 2.5 g/L. Point-of-care echocardiography showed mildly reduced biventricular function and grade 1 diastolic dysfunction (unchanged from prior assessment). The ICU team was called for assistance, including to initiate vasopressor therapy. After discussion with the patient to determine if vasopressor therapy aligned with her goals, norepinephrine was started using a peripheral IV catheter and the patient was transferred to the ICU. We rarely start an alternative vasopressor to norepinephrine as first-line therapy in septic shock. Among patients at risk for, or who have, atrial fibrillation or other supraventricular arrhythmias and who are expected to tolerate rapid ventricular response poorly (eg, those with poor cardiac reserve), we consider vasopressin or phenylephrine instead of norepinephrine as the initial vasopressor. For more than a decade, guidelines have recommended norepinephrine as the first-line vasopressor in septic shock based on randomized clinical trials comparing norepinephrine (a primarily α1 agonist with additional β1 agonist) with other vasopressors with different mechanisms such as vasopressin, phenylephrine, dopamine, and epinephrine.1Evans L. Rhodes A. Alhazzani W. et al.Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.Intensive Care Med. 2021; 47: 1181-1247Crossref PubMed Scopus (1126) Google Scholar Although one randomized study found lower risk of arrhythmia with norepinephrine compared with dopamine,2De Backer D. Biston P. Devriendt J. et al.Comparison of dopamine and norepinephrine in the treatment of shock.N Engl J Med. 2010; 362: 779-789Crossref PubMed Scopus (1312) Google Scholar other randomized studies have not shown a difference in mortality or other patient-centered outcomes when comparing norepinephrine with alternative vasopressors outside of dopamine. Guidelines thus grade for superiority of norepinephrine as high only when compared with dopamine.1Evans L. Rhodes A. Alhazzani W. et al.Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.Intensive Care Med. 2021; 47: 1181-1247Crossref PubMed Scopus (1126) Google Scholar Although generally we initiate first-line norepinephrine, we occasionally consider agents without β1 agonist (vasopressin or phenylephrine) when adrenergic-related side effects of norepinephrine are expected to—or seem to—lead to clinical decompensation (eg, rapid ventricular rate resulting from atrial fibrillation), based on quasiexperimental observational evidence that initiation of phenylephrine leads to modestly improved heart rate control compared with norepinephrine3Law A.C. Bosch N.A. Peterson D. Walkey A.J. Comparison of heart rate after phenylephrine vs norepinephrine initiation in patients with septic shock and atrial fibrillation.Chest. 2022; 162: 796-803Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar among patients with sepsis and atrial fibrillation. We target an MAP of 60 to 65 mm Hg in most patients with septic shock. The history of targeting MAP of 65 mm Hg is based on evidence that cerebral autoregulation generally begins to drop precipitously less than a MAP of 60 mm Hg. Recent trials have clarified that MAP targets of > 65 mm Hg during shock potentially are harmful, with increased risk of supraventricular tachycardia and potentially death.4Lamontagne F. Day A.G. Meade M.O. et al.Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock.Intensive Care Med. 2018; 44: 12-21Crossref PubMed Scopus (81) Google Scholar,5Hylands M. Moller M.H. Asfar P. et al.A systematic review of vasopressor blood pressure targets in critically ill adults with hypotension.Can J Anaesth. 2017; 64: 703-715Crossref PubMed Scopus (32) Google Scholar The "65 Trial" randomized patients 65 years of age or older with vasodilatory shock to a MAP target of 60 to 65 mm Hg or usual care and found no difference in 90-day all-cause mortality and a possible signal for reduced mortality with the lower MAP target after adjustment for prespecified baseline variables.6Lamontagne F. Richards-Belle A. Thomas K. et al.Effect of reduced exposure to vasopressors on 90-day mortality in older critically ill patients with vasodilatory hypotension: a randomized clinical trial.JAMA. 2020; 323: 938-949Crossref PubMed Scopus (149) Google Scholar For patients initiated on low-dose norepinephrine (eg, < 15 μg/min or < 0.3 μg/kg/min), we typically start norepinephrine infusion via peripheral IV catheters and then assess whether another catheter type may be necessary. In patients expected to require norepinephrine for > 24 to 48 h, but who otherwise are hemodynamically stable and require low doses of norepinephrine, we typically switch to infusion via a midline catheter based on local institutional expertise and experience. In patients who persistently are unstable or require higher norepinephrine doses, additional vasopressors, or additional ports for other infusions, we rapidly transition to infusion via central venous catheter (CVC). Concern over vasopressor extravasation with subsequent tissue injury historically has limited infusion of vasopressors to CVCs. However, recent evidence suggests that delivery of vasopressors via peripheral lines has < 5% risk of extravasation when used for < 72 h,7Tian D.H. Smyth C. Keijzers G. et al.Safety of peripheral administration of vasopressor medications: a systematic review.Emerg Med Australas. 2020; 32: 220-227Crossref PubMed Scopus (71) Google Scholar,8Cardenas-Garcia J. Schaub K.F. Belchikov Y.G. Narasimhan M. Koenig S.J. Mayo P.H. Safety of peripheral intravenous administration of vasoactive medication.J Hosp Med. 2015; 10: 581-585Crossref PubMed Scopus (134) Google Scholar with no reported incidents of tissue necrosis or limb ischemia in a systematic review that included seven studies with 1,382 patients.7Tian D.H. Smyth C. Keijzers G. et al.Safety of peripheral administration of vasopressor medications: a systematic review.Emerg Med Australas. 2020; 32: 220-227Crossref PubMed Scopus (71) Google Scholar Additionally, vasopressor administration via peripheral vein may decrease time to vasopressor therapy compared with infusion via CVC.9Delaney A. Finnis M. Bellomo R. et al.Initiation of vasopressor infusions via peripheral versus central access in patients with early septic shock: a retrospective cohort study.Emerg Med Australas. 2020; 32: 210-219Crossref PubMed Scopus (32) Google Scholar These data have led to a weak recommendation in the Surviving Sepsis Campaign guidelines to start vasopressors peripherally to restore MAP rather than delaying initiation until a CVC is placed.1Evans L. Rhodes A. Alhazzani W. et al.Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.Intensive Care Med. 2021; 47: 1181-1247Crossref PubMed Scopus (1126) Google Scholar We start a second vasopressor for patients with septic shock and increasing vasopressor requirements, generally as doses of norepinephrine approach 15 μg/min (or 0.3 μg/kg/min), a practice that generally aligns with Surviving Sepsis Campaign guidelines and current evidence from trials. When perfusion goals are not met with moderate doses of the initial vasopressor, the decision to add another vasopressor or increase the current agent must take into consideration expected benefits (improved cardiac output, BP, perfusion) and risks (increased risk of arrhythmia, digital ischemia) of each approach. Little direct evidence guides decision-making regarding addition of secondary vasopressors. In septic shock, current guidelines provide a weak recommendation to add vasopressin to norepinephrine when norepinephrine doses approach 0.25 to 0.5 μg/kg/min.1Evans L. Rhodes A. Alhazzani W. et al.Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.Intensive Care Med. 2021; 47: 1181-1247Crossref PubMed Scopus (1126) Google Scholar The weak recommendation was driven by observed catecholamine vasopressor-sparing effects obtained with addition of vasopressin, with mixed clinical outcomes across meta-analyses. For example, a meta-analysis of 23 trials10McIntyre W.F. Um K.J. Alhazzani W. et al.Association of vasopressin plus catecholamine vasopressors vs catecholamines alone with atrial fibrillation in patients with distributive shock: a systematic review and meta-analysis.JAMA. 2018; 319: 1889-1900Crossref PubMed Scopus (118) Google Scholar showed a reduction in atrial fibrillation in arms adding vasopressin to norepinephrine, with inconsistent effects on mortality and renal replacement therapy. An individual patient-level meta-analysis of four trials11Nagendran M. Russell J.A. Walley K.R. et al.Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials.Intensive Care Med. 2019; 45: 844-855Crossref PubMed Scopus (74) Google Scholar showed no association with mortality, but a reduction in arrhythmia, increased digital ischemia, and inconsistent effects on need for dialysis with addition of vasopressin to catecholamines. In the absence of dose-response thresholds that show changes in BP and incidence of complications across norepinephrine doses, decisions about optimal timing of second vasopressor initiation can be informed by practical considerations and indirect evidence from trials. Practical considerations include the rate of required vasopressor escalation and availability of secondary vasopressors; escalation of primary vasopressor dose in rapidly decompensating patients should not be delayed awaiting a secondary vasopressor. However, clinicians should plan for addition of a second vasopressor early in shock for patients with increasing norepinephrine requirements. Rationale for early use of secondary vasopressors include subgroup analyses from the "Vasopressin in Septic Shock Trial" (VASST) comparing addition of vasopressin to norepinephrine with norepinephrine alone, showing lower mortality in patients receiving lower norepinephrine doses (< 15 μg/min) on enrollment who were randomized also to receive vasopressin. Similarly, the "Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock" (VANISH) trial12Gordon A.C. Mason A.J. Thirunavukkarasu N. et al.Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial.JAMA. 2016; 316: 509-518Crossref PubMed Scopus (392) Google Scholar of vasopressin vs norepinephrine enrolled patients within 6 h of shock onset and showed decreased need for dialysis with addition of vasopressin. Vasopressin is our choice of first-line second vasopressor. Decisions about choice of a second vasopressor should be guided by goals of vasopressor therapy. Generally, the goals of vasopressor therapy in distributive shock are to augment impaired vasoconstriction to meet hemodynamic goals without increasing complications, especially without evidence that perfusion goals are not met because of impaired cardiac output. Current guidelines suggest vasopressin as the preferred secondary vasopressor agent, mostly because of evidence that vasopressin reduces the need for dialysis and arrhythmias10McIntyre W.F. Um K.J. Alhazzani W. et al.Association of vasopressin plus catecholamine vasopressors vs catecholamines alone with atrial fibrillation in patients with distributive shock: a systematic review and meta-analysis.JAMA. 2018; 319: 1889-1900Crossref PubMed Scopus (118) Google Scholar and has been well studied as a secondary vasopressor that achieves hemodynamic goals. However, if arrhythmias are less likely (eg, younger patients), digital ischemia is a major concern (eg, history of Raynaud's syndrome or early signs of digital ischemia), or impaired cardiac output is thought to contribute to shock (eg, combined septic cardiomyopathy and distributive shock), then we prefer epinephrine as a second vasopressor. However, evidence supporting epinephrine as a secondary vasopressor is scant, and given that epinephrine works through most of the same adrenergic receptors as norepinephrine, hemodynamic goals may not be achieved as readily with combined norepinephrine and epinephrine as with agents that work through noncatecholamine mechanisms (eg, vasopressin or angiotensin II). Although we do not use angiotensin II routinely as a secondary vasopressor because of cost considerations and insufficient evidence of clinical outcome benefits, angiotensin II does expedite achievement of MAP goals.13Khanna A. English S.W. Wang X.S. et al.Angiotensin II for the treatment of vasodilatory shock.N Engl J Med. 2017; 377: 419-430Crossref PubMed Scopus (487) Google Scholar We add corticosteroids (hydrocortisone 50 mg IV q6h plus fludrocortisone 50 μg po daily for 7 days without tapering14Annane D. Renault A. Brun-Buisson C. et al.Hydrocortisone plus fludrocortisone for adults with septic shock.N Engl J Med. 2018; 378: 809-818Crossref PubMed Scopus (511) Google Scholar) for patients with escalating vasopressor requirements, generally when a second vasopressor is initiated. Multiple therapies have been evaluated to improve hemodynamics for patients with shock. These include corticosteroids, methylene blue, vitamins such as ascorbic acid or thiamine, or combinations of these agents. Corticosteroids—the most well-studied adjunct for shock—have multiple potential mechanisms of action including immunologic effects and direct effects on endothelial glucocorticoid receptors to reduce vasoplegia.15Goodwin J.E. Feng Y. Velazquez H. Sessa W.C. Endothelial glucocorticoid receptor is required for protection against sepsis.Proc Natl Acad Sci U S A. 2013; 110: 306-311Crossref PubMed Scopus (111) Google Scholar Evidence is strong for an effect of low- to moderate-dose (< 400 mg hydrocortisone equivalents/d) corticosteroids in increasing BP (mean increase in MAP, 5 mm Hg)16Venkatesh B. Finfer S. Cohen J. et al.Adjunctive glucocorticoid therapy in patients with septic shock.N Engl J Med. 2018; 378: 797-808Crossref PubMed Scopus (511) Google Scholar and shortening shock duration (mean, 1.5 fewer vasopressor days).17Rygård S.L. Butler E. Granholm A. et al.Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis.Intensive Care Med. 2018; 44: 1003-1016Crossref PubMed Scopus (123) Google Scholar However, corticosteroids may increase adverse events such as hyperglycemia, hypernatremia, and muscle weakness. A 2019 meta-analysis of 61 sepsis trials with > 12,000 patients showed a small benefit of corticosteroids for mortality reduction (relative risk, 0.91; 95% CI, 0.84-0.99).18Annane D. Bellissant E. Bollaert P.E. et al.Corticosteroids for treating sepsis in children and adults.Cochrane Database Syst Rev. 2019; 12: CD002243PubMed Google Scholar Thus, guidelines suggest use of corticosteroids for patients with septic shock and "ongoing requirement for vasopressors." Rationale for initiating corticosteroids for patients with higher vasopressor requirements (rather than lower requirements) include the concept that corticosteroids act potentially as vasopressor-sparing agents to reduce vasopressor-associated adverse effects generally seen at higher doses, a hypothesis supported by trials and modeling studies19Pirracchio R. Hubbard A. Sprung C.L. Chevret S. Annane D. Rapid Recognition of Corticosteroid Resistant or Sensitive Sepsis (RECORDS) Collaborators. Assessment of machine learning to estimate the individual treatment effect of corticosteroids in septic shock.JAMA Network Open. 2020; 3 (e2029050-e2029050)Crossref PubMed Scopus (26) Google Scholar that showed benefits of corticosteroids in shock14Annane D. Renault A. Brun-Buisson C. et al.Hydrocortisone plus fludrocortisone for adults with septic shock.N Engl J Med. 2018; 378: 809-818Crossref PubMed Scopus (511) Google Scholar,20Annane D. Sébille V. Charpentier C. et al.Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.JAMA. 2002; 288: 862-871Crossref PubMed Scopus (2609) Google Scholar only when enrolling patients with high baseline vasopressor requirements. The rationale for use of fludrocortisone with hydrocortisone is threefold. First, the two largest trials demonstrating clinical benefit of steroids used hydrocortisone and fludrocortisone together,14Annane D. Renault A. Brun-Buisson C. et al.Hydrocortisone plus fludrocortisone for adults with septic shock.N Engl J Med. 2018; 378: 809-818Crossref PubMed Scopus (511) Google Scholar,20Annane D. Sébille V. Charpentier C. et al.Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.JAMA. 2002; 288: 862-871Crossref PubMed Scopus (2609) Google Scholar whereas trials evaluating hydrocortisone alone did not show a mortality benefit12Gordon A.C. Mason A.J. Thirunavukkarasu N. et al.Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial.JAMA. 2016; 316: 509-518Crossref PubMed Scopus (392) Google Scholar,21Venkatesh B. Finfer S. Cohen J. et al.Adjunctive glucocorticoid therapy in patients with septic shock.N Engl J Med. 2018; 378: 797-808Crossref PubMed Scopus (584) Google Scholar,22Sprung C.L. Annane D. Keh D. et al.Hydrocortisone therapy for patients with septic shock.N Engl J Med. 2008; 358: 111-124Crossref PubMed Scopus (1717) Google Scholar; second, a trial directly comparing fludrocortisone plus hydrocortisone with hydrocortisone alone found a 3% absolute reduction in in-hospital mortality in patients who received fludrocortisone plus hydrocortisone, but was underpowered to detect a clinically feasible effect.23Annane D. Cariou A. Maxime V. et al.Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial.JAMA. 2010; 303: 341-348Crossref PubMed Scopus (258) Google Scholar Third, the main argument not to administer fludrocortisone is that hydrocortisone—at doses used clinically—has similar sodium-retaining activity24Louis S. Brunton L. Chabner B. Knollmann B. Goodman & Gilman's Pharmacological Basis of Therapeutics. McGraw-Hill, 2011Google Scholar to fludrocortisone; however, mineralocorticoids have several functions in addition to sodium retention, including a neural antiapoptotic role, alveolar fluid clearance by pulmonary epithelial cells, and innate immune system activation.25Heming N. Sivanandamoorthy S. Meng P. Bounab R. Annane D. Immune effects of corticosteroids in sepsis.Front Immunol. 2018; 9: 1736Crossref PubMed Scopus (66) Google Scholar Thus, pleiotropic effects beyond sodium retention may provide additional benefit from combining fludrocortisone with hydrocortisone.25Heming N. Sivanandamoorthy S. Meng P. Bounab R. Annane D. Immune effects of corticosteroids in sepsis.Front Immunol. 2018; 9: 1736Crossref PubMed Scopus (66) Google Scholar,26Annane D. Why my steroid trials in septic shock were "positive.Critical Care Med. 2019; 47: 1789-1793Crossref PubMed Scopus (15) Google Scholar Although we use 7 days without taper based on the "Activated Protein C and Corticosteroids for Human Septic Shock" (APROCCHSS) trial,14Annane D. Renault A. Brun-Buisson C. et al.Hydrocortisone plus fludrocortisone for adults with septic shock.N Engl J Med. 2018; 378: 809-818Crossref PubMed Scopus (511) Google Scholar optimal duration is uncertain and evidence is mixed regarding the risks and benefits of weaning steroids to prevent rebound hypotension.27Sobolewski K.A. Brophy A. Opsha Y. Zaid A. Mistry N. Abrupt versus gradual cessation of steroids in patients with septic shock.J Crit Care. 2018; 48: 198-202Crossref PubMed Scopus (5) Google Scholar,28Keh D. Boehnke T. Weber-Cartens S. et al.Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock.Am J Respir Crit Care Med. 2003; 167: 512-520Crossref PubMed Scopus (513) Google Scholar If shock recurs after cessation without taper, we consider restarting steroids and initiate further evaluation for causes of shock. Studies investigating methylene blue as a vasopressor adjunct are scant. Pilot trials of adjunctive methylene blue in septic shock showed improved MAP and heart rate compared with control participants, likely through inhibition of nitric oxide pathways.29Memis D. Karamanlioglu B. Yuksel M. Gemlik I. Pamukcu Z. The influence of methylene blue infusion on cytokine levels during severe sepsis.Anaesth Intensive Care. 2002; 30: 755-762Crossref PubMed Google Scholar,30Kirov M.Y. Evgenov O.V. Evgenov N.V. et al.Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study.Crit Care Med. 2001; 29: 1860-1867Crossref PubMed Scopus (192) Google Scholar Given the scant data for benefits to patient outcomes, we reserve use of methylene blue for patients with shock refractory to multiple vasopressors and corticosteroids, with the goal of temporarily increasing BP to allow initiation of other therapies (eg, infection source control measures) expected to improve longer-term outcomes. Based on potentially promising results of a small preimplementation vs postimplementation study,31Marik P.E. Khangoora V. Rivera R. Hooper M.H. Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study.Chest. 2017; 151: 1229-1238Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar multiple recent trials have investigated potential benefits of high-dose ascorbic acid (with or without corticosteroids or thiamine, often called metabolic resuscitation). However, multiple randomized trials failed to show benefits—or showed harms—with use of ascorbic acid during shock.32Fujii T. Salanti G. Belletti A. et al.Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis.Intensive Care Med. 2022; 48: 16-24Crossref PubMed Scopus (48) Google Scholar,33Lamontagne F. Masse M.H. Menard J. et al.Intravenous vitamin C in adults with sepsis in the intensive care unit.N Engl J Med. 2022; 386: 2387-2398Crossref PubMed Scopus (101) Google Scholar We do not use ascorbic acid- or thiamine-based metabolic resuscitation for the treatment of septic shock. After 24 h, the patient required norepinephrine increased to 0.5 μg/kg/min. A CVC was placed. Oxygen and vasopressor requirements improved. Antibiotics were narrowed to cover Escherichia coli urosepsis based on culture results. After gradual improvement, on hospital day 5, her condition worsened. She became intermittently hypotensive despite norepinephrine 0.5 μg/kg/min, addition of vasopressin 2.4 units/h (0.04 units/min), and subsequently epinephrine 0.3 μg/kg/min. BP was 95/40 mm Hg (MAP, 57 mm Hg) and heart rate was 110 beats/min. Hydrocortisone and fludrocortisone were started. Extremities were mottled and capillary refill was 4 s. Serum lactate level was 4.5 g/L. No evidence was found of hemorrhage, abdominal compartment syndrome, or pneumothorax, and point-of-care echocardiography findings were unchanged without evidence of tamponade, new right or left ventricular dysfunction, or outflow obstruction. Worsening or persistent shock despite initial source control and resuscitation should prompt consideration of additional diagnostic evaluation. Common causes and recommended evaluation of worsening shock after initial source control and stabilization during sepsis are shown in Table 1. Contributors to worsening shock often include worsening distributive shock resulting from nosocomial infections, obstructive shock resulting from pulmonary emboli or abdominal compartment syndrome, or cardiogenic shock resulting from septic cardiomyopathy or arrhythmia.Table 1Clinical Considerations for Patients With Worsening ShockConsiderationDiagnostic strategiesNew or concomitant causes of shock•Septic shock: Search for undiagnosed infection (eg, repeat culture tests, additional imaging), assess adequacy of treatment (antibiotic sensitivities, source control)•Cardiogenic shock: repeat echocardiography, central venous oxygen saturation•Hemorrhagic shock: fluid responsiveness assessment (recurrence of fluid responsiveness after resuscitation may be an early sign of occult bleeding), repeat CBC, evaluation for increased heart rate•Obstructive shock: echocardiography for tamponade, CT scan imaging to assess for pulmonary emboli, clinical assessment for abdominal compartment syndrome (eg, in patients with ascites and septic shock)•Adrenal insufficiency: review home medication list for corticosteroid use, consider potential causes of adrenal insufficiency (eg, etomidate use, pituitary disease)Possibility of MAP underestimation by peripheral arterial line•Begin by comparing noninvasive MAP with invasive MAP•Systolic pressure estimation by palpation•Assess other measures of perfusion (eg, changes in mental status, lactate, kidney function)•Consider placing central arterial catheter (eg, femoral or axillary)Acidosis contributing to reduced vasopressor effect•Assess acid and base status•Consider bicarbonate infusion or continuous renal replacement therapyInhibition of nitric oxide-induced vasodilation•Consider empiric trial of methylene blue as a temporizing measureMAP = mean arterial pressure. Open table in a new tab MAP = mean arterial pressure. We do not stop escalation of norepinephrine or epinephrine dosing at any particular dose. Without evidence of an asymptote of MAP response to norepinephrine or epinephrine across higher doses, we do not have an arbitrary dose limit for further escalation of these vasopressors; however, we generally do not titrate vasopressin to > 2.4 units/h (0.04 units/min) because of concerns of lower cardiac output and coronary or splanchnic perfusion at higher doses.34Demiselle J. Fage N. Radermacher P. Asfar P. Vasopressin and its analogues in shock states: a review.Ann Intensive Care. 2020; 10: 9Crossref PubMed Scopus (56) Google Scholar Studies evaluating patients receiving high-dose vasopressors for septic shock (> 1 μg/kg/min norepinephrine equivalents) have found survival rates ranging from 10% to 54%.14Annane D. Renault A. Brun-Buisson C. et al.Hydrocortisone plus fludrocortisone for adults with septic shock.N Engl J Med. 2018; 378: 809-818Crossref PubMed Scopus (511) Google Scholar,35Martin C. Medam S. Antonini F. et al.Norepinephrine: not too much, too long.Shock. 2015; 44: 305-309Crossref PubMed Scopus (84) Google Scholar, 36Brown S.M. Lanspa M.J. Jones J.P. et al.Survival after shock requiring high-dose vasopressor therapy.Chest. 2013; 143: 664-671Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 37Auchet T. Regnier M.A. Girerd N. Levy B. Outcome of patients with septic shock and high-dose vasopressor therapy.Ann Intensive Care. 2017; 7: 43Crossref PubMed Scopus (84) Google Scholar, 38Morelli A. Ertmer C. Lange M. et al.Effects of short-term simultaneous infusion of dobutamine and terlipressin in patients with septic shock: the DOBUPRESS study.Br J Anaesth. 2008; 100: 494-503Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar In the APROCCHSS trial, the mean norepinephrine dose on enrollment was 1.08 μg/kg/min for 1,086 patients receiving norepinephrine and 2.01 μg/kg/min for 111 patients receiving epinephrine. Ninety-day survival in this trial was 53.9%.14Annane D. Renault A. Brun-Buisson C. et al.Hydrocortisone plus fludrocortisone for adults with septic shock.N Engl J Med. 2018; 378: 809-818Crossref PubMed Scopus (511) Google Scholar Because central arterial pressure best describes perfusion pressure to vital organs, we often place central arterial catheters (femoral or axillary) in patients with seemingly refractory shock who seem to be deteriorating clinically despite increasing vasopressor doses. The Surviving Sepsis Campaign guidelines make a weak recommendation in favor of invasive monitoring of arterial pressure over noninvasive monitoring, but do not specify whether arterial pressure monitoring should be central or peripheral.1Evans L. Rhodes A. Alhazzani W. et al.Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.Intensive Care Med. 2021; 47: 1181-1247Crossref PubMed Scopus (1126) Google Scholar Hemodynamic management based on radial as opposed to central arterial pressure can lead to excess vasopressor administration.39Dorman T. Breslow M.J. Lipsett P.A. et al.Radial artery pressure monitoring underestimates central arterial pressure during vasopressor therapy in critically ill surgical patients.Crit Care Med. 1998; 26: 1646-1649Crossref PubMed Scopus (148) Google Scholar One study found that systolic arterial pressure and MAP were higher when measured from femoral vs radial sites, with immediate vasopressor dose reductions facilitated in 11 of 14 patients after change to central arterial catheters.39Dorman T. Breslow M.J. Lipsett P.A. et al.Radial artery pressure monitoring underestimates central arterial pressure during vasopressor therapy in critically ill surgical patients.Crit Care Med. 1998; 26: 1646-1649Crossref PubMed Scopus (148) Google Scholar For patients with severe acidemia, acute kidney injury, and refractory shock who have ventilation reserve, we administer sodium bicarbonate (HCO3−) targeting a pH of > 7.340Jaber S. Paugam C. Futier E. et al.Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial.Lancet. 2018; 392: 31-40Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar and initiate continuous renal replacement therapy if acidemia remains uncontrolled. Vascular reactivity and β-adrenergic receptor binding are impaired by acidosis.41Page I.H. Olmsted F. The influence of respiratory gas mixtures on arterial pressure and vascular reactivity in normal and hypertensive dogs.Circulation. 1951; 3: 801-819Crossref PubMed Scopus (8) Google Scholar,42Modest V.E. JFt Butterworth Effect of pH and lidocaine on beta-adrenergic receptor binding. Interaction during resuscitation?.Chest. 1995; 108: 1373-1379Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Sodium HCO3− and renal replacement therapy can correct acidosis temporarily.40Jaber S. Paugam C. Futier E. et al.Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial.Lancet. 2018; 392: 31-40Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar The "Sodium Bicarbonate to Treat Severe Acidosis in the Critically Ill" (BICAR-ICU) trial, which randomized critically ill adults with severe acidemia to sodium HCO3− infusion (4.2% [500 mEq/L], up to 1 L) or no sodium HCO3− infusion, found that among patients with acute kidney injury, those who received HCO3− infusion experienced lower mortality and more vasopressor-free days than those who did not.40Jaber S. Paugam C. Futier E. et al.Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial.Lancet. 2018; 392: 31-40Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar We require patients to have the ability to increase minute ventilation safely to compensate for increased CO2 production that may result after HCO3− administration. The patient's blood culture samples returned with positive results for methicillin-resistant Staphylococcus aureus. Appropriate antibiotics were started and the CVC was replaced. Serum lactate and vasoplegia improve; however, she continued to receive norepinephrine at a dose of 0.3 μg/kg/min and vasopressin. BP was 90/50 mm Hg (MAP, 63 mm Hg) and heart rate was 95 beats/min. Point-of-care echocardiography findings were unchanged and repeat culture findings were negative. We discontinue norepinephrine first, and then vasopressin last, for patients who are receiving both vasopressors but are improving clinically. Few data are available on the approach to weaning vasopressors. Several small, single-center observational studies among patients with septic shock receiving norepinephrine and vasopressin have found that discontinuing vasopressin first leads to increased incidence of hypotension,43Hammond D.A. McCain K. Painter J.T. et al.Discontinuation of vasopressin before norepinephrine in the recovery phase of septic shock.J Intensive Care Med. 2019; 34: 805-810Crossref PubMed Scopus (31) Google Scholar, 44Bissell B.D. Magee C. Moran P. Bastin M.L.T. Flannery A.H. Hemodynamic instability secondary to vasopressin withdrawal in septic shock.J Intensive Care Med. 2019; 34: 761-765Crossref PubMed Scopus (20) Google Scholar, 45Bauer S.R. Aloi J.J. Ahrens C.L. Yeh J.Y. Culver D.A. Reddy A.J. Discontinuation of vasopressin before norepinephrine increases the incidence of hypotension in patients recovering from septic shock: a retrospective cohort study.J Crit Care. 2010; 25 (362.e311): 362.e367Crossref Scopus (35) Google Scholar, 46Musallam N. Altshuler D. Merchan C. Zakhary B. Aberle C. Papadopoulos J. Evaluating vasopressor discontinuation strategies in patients with septic shock on concomitant norepinephrine and vasopressin infusions.Ann Pharmacother. 2018; 52: 733-739Crossref PubMed Scopus (28) Google Scholar suggesting that norepinephrine should be discontinued first. Her extremities were warm and well perfused and mental status and renal function were improving, but attempts to wean low-dose vasopressin (2.4 units/h [0.04 units/min]) resulted in MAP of 60 mm Hg. For patients who improve clinically (reversal of organ dysfunction), but have persistent, mild vasoplegia, we reduce the MAP target to 60 mm Hg to help with vasopressor weaning. Ongoing vasopressor-dependent hypotension without evidence of end-organ hypoperfusion can limit mobilization, physiotherapy and discharge from the ICU. Lowering the MAP target to 60 mm Hg is based on the 65 trial6Lamontagne F. Richards-Belle A. Thomas K. et al.Effect of reduced exposure to vasopressors on 90-day mortality in older critically ill patients with vasodilatory hypotension: a randomized clinical trial.JAMA. 2020; 323: 938-949Crossref PubMed Scopus (149) Google Scholar discussed in the section on MAP targets. Sometimes, sedatives also can contribute to hypotension, and we often adjust sedatives to reduce vasopressor requirements. We also consider repeating diagnostics (Table 1) to identify ongoing processes that may contribute to persistent vasopressor requirements (eg, intraabdominal abscess). Midodrine is an oral α1-adrenergic agonist that has received approval for use in the United States for symptomatic orthostatic hypotension. It has been used off-label to facilitate liberation from IV vasopressors; however, the recent "Midodrine as adjunctive support for treatment of refractory hypotension in the intensive care unit" (MIDAS) trial showed no benefit of midodrine in accelerating liberation from IV vasopressors.47Santer P. Anstey M.H. Patrocínio M.D. et al.Effect of midodrine versus placebo on time to vasopressor discontinuation in patients with persistent hypotension in the intensive care unit (MIDAS): an international randomised clinical trial.Intensive Care Med. 2020; 46: 1884-1893Crossref PubMed Scopus (32) Google Scholar Of note, this trial excluded patients with liver failure and chronic renal failure, and a beneficial effect was found in a post hoc subgroup analysis of patients with epidural analgesia. In patients for whom lowering MAP targets and minimizing sedation have not worked, particularly if patients have liver failure, renal failure, or a neurogenic component to hypotension, we try midodrine. One disadvantage to using midodrine is that it is often continued even after discharge from the hospital.48Rizvi M.S. Nei A.M. Gajic O. Mara K.C. Barreto E.F. Continuation of newly initiated midodrine therapy after intensive care and hospital discharge: a single-center retrospective study.Crit Care Med. 2019; 47: e648-e653Crossref PubMed Scopus (20) Google Scholar We typically prescribe midodrine 10 to 20 mg po every 8 h with a taper or stop date entered to avoid continuation after hospital discharge. If no improvement toward reaching MAP goals is achieved, we stop after 24 to 48 h. The care of patients with septic shock can be complex. Our suggested approach to treating hypotension in septic shock is summarized in Figure 1. In most patients, we initiate norepinephrine first, either through a peripheral IV or midline catheter, targeting a MAP of 60 to 65 mm Hg. If norepinephrine doses approach 15 μg/min (or 0.3 μg/kg/min), we initiate vasopressin for most patients, transition to infusion via CVC, and administer hydrocortisone and fludrocortisone for 7 days. We also assess for concomitant causes of shock (Table 1). For refractory shock, we consider central arterial pressure monitoring and correction of acidosis. When mild vasoplegia persists without evidence of end-organ ischemia, we reduce the MAP target to 60 mm Hg, modify or discontinue sedatives if possible, and often try midodrine.