Initial Management of Sepsis

Reviewed and revised 17 September 2019

OVERVIEW

Initial management of sepsis and septic shock involves consideration of:

• resuscitation
• early administration of appropriate antibiotics following blood cultures
• early source control
• judicious fluid resuscitation, avoiding excess fluids
• noradrenaline for refractory hypotension (septic shock)
• inotropes for septic cardiomyopathy
• therapies for refractory hypotension
• other experimental and rescue therapies
• ongoing supportive care and monitoring

Surviving Sepsis Guidelines (SSG) (Dellinger et al, 2013), appear to be religiously followed in some parts of the world, however they are not usually explicitly followed in Australia and New Zealand (see Surviving Sepsis Campaign Guidelines 2012)

• The approach below is adapted from the examination committee’s answer guide to a FCICM Second Part exam question
• Use of local guidelines and/or national guidelines (e.g. Australian Therapeutic Guidelines) is recommended

Effective management of sepsis/ septic shock depends on early recognition (see Sepsis Definitions and Diagnosis)

RESUSCITATION

Address life threats

• coordinated team approach in an appropriately equipped and staffed resuscitation area is ideal
• manage ABCs (airway, breathing, and circulation) appropriately
• attach monitoring (HR, ECG, NIBP, RR, SpO2)
• large bore IV access (e.g. 2 X 16G peripheral IV lines) and obtain blood cultures if suspected sepsis

Initial fluid resuscitation

• Most patients need no more than 2-3 L (30 ml/kg IBW) IV in total (see Fluid bolus therapy)
  • physiological reasoning: treat relative volume depletion due to vasodilation in sepsis
  • consistent with SSG
  • consistent with recent early goal directed therapy (EGDT) studies (ARISE, PROMISE, PROCESS) showing no additional benefit for protocolized care as described by Rivers et al, 2001 (see Early Goal Directed Therapy in Septic Shock) (Angus et al, 2015)
  • a spanner in the works: fluid bolus therapy increased mortality in African children with septic shock (FEAST) (see FEAST and Paediatric Fluid Resuscitation)
  • current trends are for restricted volumes of fluid management tailored to clinical context (e.g. a septic patient presenting with severe diarrhoea and dehydration likely requires larger amounts of fluid therapy)
• Use crystalloid (0.9% NaCl or balanced salt solutions such as Hartmanns or Plasmalyte)
  • Consider 4% Albumin
    • recommendation by SSG for refractory hypotension in septic shock
    • SAFE trial showed no difference between 0.9% NaCl and 4% albumin in ICU patients overall and there was a “trend” towards mortality benefit for 4% albumin (post hoc subgroup analysis) (Finfer et al, 2004)
    • ALBIOS trial showed no difference from saline in patients with severe sepsis or septic shock (Caironi et al, 2014)
  • Avoid starch solutions (6S and CHEST studies) (Perner et al, 2012; Myburgh et al, 2012)
  • balanced salt solutions, compared to 0.9% NaCl, are associated with improved mortality in sepsis admitted to ICU, however this is largely based on observational data that is subject to confounders (Raghunathan et al, 2014) and secondary analysis of a pragmatic, cluster-randomized, multiple-crossover trial (Brown et al, 2019)
• Consider blood transfusion if bleeding or anaemic
  • in non-bleeding patients target Hb >70g/L
    • transfusion trigger of Hb <70 g/L supported by TRICC (Hébert et al, 1999), TRISS (Holst et al, 2014) and Australian Patient Blood Management Guidelines
    • Hb 70-90g/L supported by SSG (Dellinger et al, 2013)
    • Note that Rivers et al (2001) recommended target haematocrit 30%, which results in more blood transfusions compared to usual care with no demonstrable benefit (ARISE, PROMISE and PROCESS) (Angus et al, 2015)

Consider early vasopressors (see below)

• if critically ill and hypotensive do not delay vasopressor administration pending central line insertion
• it is acceptable to give vasopressors (e.g. noradrenaline infusion) via a proximal peripheral venous line (e.g. large bore cannula in antecubital fossa) in the short-term (e.g. first 6 hours) with close observation for extravasation (Loubani and Green, 2015; Cardenas-Garcia et al, 2015))
• low dose dilute noradrenaline via a perpheral route led to improved control of shock at 6 hours in a phase II trial (CENSER) (Permpikul et al, 2019)
• use intraosseous (IO) access if anticipated delay in obtaining peripheral IV access

Consider early intubation and mechanical ventilation if critically ill (to facilitate procedures and decreased work of breathing/ oxygen consumption)

• “resuscitate before you intubate” (e.g. fluids, vasopressors) and avoid exacerbation of acidaemia due to apnoea (see Intubation, Hypotension and Shock)
• use protective lung ventilation (VT 6 mL/kg PBW, Pplat <30 cmH20) (see Protective Lung Ventilation)

ANTIBIOTICS AND SOURCE CONTROL

Antibiotics

• investigate first, start early and aggressively, and streamline quickly to reduce resistance
• appropriate broad spectrum antibiotics should be administered as soon as possible
  • Australian Therapeutic Guidelines recommends: “For the greatest survival benefit, give antibiotics as early as possible and always within one hour of emergency department presentation or, for ward-based patients, recognition of severe sepsis or septic shock”
  • the SSG 2015 update differs, it states that broad spectrum antibiotics should be administered within 3 hours of the time of presentation
  • supported by numerous observational studies (Kumar et al, 2006; Seymour et al, 2017) (see Antibiotic timing)
• blood cultures must be taken prior to antibiotic administration (2 sets; i.e. 4 bottles)
• initial empiric antibiotic choice should be based on syndromic approach according to local guidelines
  • see Antibiotic Guidelines in ICU, Neutropaenic sepsis and Specific Infections, Causative Organisms & Treatment
• modify dose appropriately to achieve adequate drug exposure in critically ill patients with (‘severe’) sepsis or septic shock (see Antimicrobial dosing and kill characteristics)

Source control

• aggressive early identification and treatment of source of infection
  • e.g. septic screen, swab and culture potentially infected sites, advanced imaging (e.g. CT)
  • operative interventions such as laparotomy, incision and drainage of abscesses
  • may require minimally invasive approaches initially  (e.g. cholecystostomy) followed by later definitive therapy (e.g. cholecystectomy)
  • consider removal of pre-existing in situ devices
  • should occur within 6 hours if septic shock associated with a perforated viscus (Azuhata et al, 2010)

ASSESS FOR FURTHER FLUID THERAPY

This is a highly controversial area of sepsis management!

Target mean arterial pressure (MAP) >65 mmHg initially in most patients

• early insertion of intra-arterial line for continuous monitoring
• consider modifying MAP target according to clinical response (patient may be well perfusion at lower targets) and pre-existing blood pressure (e.g. consider higher target if previous hypertension)
• SEPSISPAM found no benefit of targeting MAP 80-85 mmHg versus MAP 65-70 mmHg, however those with pre-existing hypertension had less renal replacement therapy but more atrial fibrillation with the higher MAP target (Asfar et al, 2014)

Perform frequent assessment of response to therapy and target appropriate end-points

• SSG recommends ongoing fluid resuscitation according to response using dynamic or static variables
• Frequent clinical reassessment (especially after fluid bolus therapy)
  • Assess heart rate, blood pressure, peripheral perfusion, urine output, and mental state (if unintubated)
  • e.g. SSG recommends a target urine output of > 1 mL/kg/h
• Consider monitoring lactate clearance (see Lactate Clearance vs ScvO2 Monitoring in Sepsis)
  • e.g. >10% clearance over 2 hours
  • lactate screening may help detect occult septic shock
  • lactate is an independent predictor of mortality in sepsis
  • remember that lactate is a non-specific marker of a stress response affected by many factors and does not necessarily imply impaired oxygen delivery/ utilisation
  • Jones et al JAMA 2010 found that lactate clearance is non-inferior to ScvO2 monitoring for guiding resuscitation in sepsis (see
• No need to specifically target CVP >8-12 mmHg
  • CVP monitoring is a widespread convention for assessing fluid status but its use is lacking in evidence
  • SSG recommends CVP >8-12 based on arbitrarily chosen target from Rivers et al, 2001
  • static CVP measurements are not useful for determining fluid responsiveness and ‘delta CVP’ is also unreliable (see Marik’s 2013 meta-analysis) (see CVP Measurement)
• Use dynamic measure to assess fluid responsiveness (see Fluid Responsiveness)
  • e.g. mini-fluid challenge, passive leg raise, expiratory occlusion test and ultrasound/ echocardiography
  • supported by many small physiological studies but there are no large RCTs with patient-oriented outcomes to guide practice
  • remember that just because a patient is fluid responsive, fluid administration may not improve their overall outcome
• Consider monitoring central (ScvO2) or mixed (SvO2) venous oxygen saturation
  • continuous monitoring is not typically used in Australasia for sepsis and septic shock
  • ARISE, PROMISE and PROCESS found no benefit of EGDT using ScvO2 monitoring versus ‘usual care” (Angus et al, 2015)
  • ScvO2 monitoring (ScvO₂ > 70%) is recommended by SSG based on Rivers et al ,2001 (see Central venous oxygen saturation (ScvO2) monitoring)
  • SvO2 requires PA catheters, which also allows PAOP monitoring, but is not commonly used in septic patients (PAC-Man and SUPPORT showed no benefit/ harm for PACs; see Mixed venous oxygen saturation (SvO2) monitoring)
• Consider monitoring the “PCO2 gap” (see pCO2 gap)
  • PCO2 gap is the arteriovenous CO₂ difference (PcvO2 – PaCO2)
  • target PCO2 gap <6mmHg as an index of adequate tissue perfusion
  • this approach is not widely used in current Australasian practice
  • supported by observational data suggesting a role in identifying patients with ScvO2 >70% who are still inadequately resuscitated (Vallee et al, 2008) and predicts lactate clearance (Mesquida et al, 2015 and Mallat et al, 2014)

NORADRENALINE FOR REFRACTORY HYPOTENSION

If hypotensive and not responsive to fluid boluses will need vasopressor support (see Inotropes, vasopressors and other vasoactive agents)

• e.g. following 2L IV crystalloid (20-30 mL/kg)
• noradrenaline is first line agent (SSG recommendation) (see Noradrenaline)
  • maintains coronary perfusion by increasing diastolic blood pressure through systemic arterial vasoconstriction
  • increases preload by venoconstriction
• adrenaline is an acceptable alternative (SSG recommendation; CAT study showed no difference between adrenaline and noradrenaline) (see Adrenaline)
• avoid dopamine (increased dysrhythmias and worse mortality in De Backer et al’s 2012 meta-analysis) (see Dopamine)
• generally avoid phenylephrine (though no worse than noradrenaline according to Morelli et al, 2008) and metaraminol (although

INOTROPES FOR SEPTIC CARDIOMYOPATHY

• Low cardiac output (absolute or relative) is common in sepsis due to septic cardiomyopathy (or other coexistent causes) (see Septic cardiomyopathy)
• Consider Echo, ScvO2, SvO2, PiCCO or other measure of cardiac output
  • No benefit from PAC (PAC-man and SUPPORT)
  • ARISE, PROMISE, PROCESS suggested no benefit of the EGDT with protocolised use of ScvO2 to guide initiation of dobutamine (Angus et al, 2015)
• If low cardiac output consider an inotrope in addition to noradrenaline (e.g. dobutamine or adrenaline) (see (see Inotropes, vasopressors and other vasoactive agents)
  • inotropic support (dobutamine) recommended by SSG based on Rivers et al, 2001 EGDT resuscitation algorithm (see Dobutamine)
  • ARISE, PROMISE, PROCESS suggested no benefit of the EGDT with protocolised use of dobutamine to treat apparent inadequate oxygen delivery refractory to other therapies (Angus et al, 2015)
  • unclear role for milrinone and levosimendan (both are inodilators, may exacerbate vasodilation in sepsis)
• Unclear role for VA-ECMO to support cardiogenic circulatory failure in septic shock

TREAT REFRACTORY HYPOTENSION

Consider adding vasopressin (see Vasopressin)

• Usual rate of ~ 0.03 U/min (e.g. 2 U/h)
• Supported by SSG guidelines as an option for refractory hypotension but not recommended as first line vasopressor (Dellinger et al, 2012)
• No mortality benefit with additional vasopressin in patients receiving low dose noradrenaline (up to 5 mcg/min) (VASST) (Russell et al, 2008)
• Less use of renal replacement therapy (RRT) in the VANISH trial, but no diffierence in mortality compared with noradrenaline (Gordon et al, 2016)
• Relative vasopressin deficiency is seen in approximately one-third of late septic shock patients (Sharshar et al, 2013)

If hypotensive following fluid resuscitation and vasopressors, consider hydrocortisone 200mg IV daily (see Corticosteroids in Refractory Shock)

• SSG allows consideration of corticosteroids
• mixed evidence on the role of glucocorticoids steroids (e.g. Annane et al, JAMA 2002  versus CORTICUS NEJM 2008)
• no need to perform synACTHen test
• Awaiting results of the ADRENAL study…

OTHER EXPERIMENTAL AND RESCUE THERAPIES

Consider:

• Angiotensin-II (FDA approved in 2019)
  • noradrenaline sparing in the ATHOS trial (Chawla et al, 2014)
  • improves blood pressure (MAP) in vasodilatory shock refractory to other vasopressors (ATHOS-3) (Khanna et al, 2017)
  • improved mortality, blood pressure, and renal replacement therapy (RRT) duration in vasodilatory shock patients on RRT (ATHOS-3) (Tumlin et al, 2018)
• agents to reduce toxin production (e.g. toxic shock syndrome, necrotizing fasciitis) (see Intravenous Immunoglobulin and Necrotising Fasciitis)
• Ensure corrected ionised calcium (for intropy and vasopressive effects)
• Methylene blue (consider for refractory vasoplegic shock) (see Methylene Blue)
• Correction of severe acidosis (pH <7.15) with bicarbonate or THAM (SSG) (Dellinger et al, 2013)
• Esmolol to improve diastolic filling and ameliorate catecholamine toxicity (Morelli et al, 2013) (see Catecholamine excess, Beta Blockade and Critical Illness)
• High volume haemofiltration to remove inflammatory mediators (however, no benefit apparent in a cohort study by Bourquin et al, 2012)

These interventions either lack evidence supporting current use in clinical practice and/or are likely to only be of use in highly select circumstances. The exception, perhaps, is angiotensin-II which is likely to be used

ONGOING SUPPORTIVE CARE AND MONITORING

• admission to HDU/ICU if sepsis/ septic shock for active management
•  monitoring
  • invasive arterial blood pressure monitoring
  • T,P,R, SpO2
  • ETCO2
  • CVP is often monitored
• seek and treat complications of underlying disease and therapies
• supportive care (comprehensive mnemonic “FASTHUGS IN BED Please“)
  • invasive arterial BP monitoring
  • Venous Thromboembolism (VTE) Prophylaxis
  • Stress Ulcer Prophylaxis
  • glucose control (e.g. insulin infusion to target glucose 6-10 mmol/L) (see Glucose Control in ICU)
  • delirium management (see Delirium and Septic encephalopathy)
  • protocolised sedation for intubated patients (Sedation in ICU)
• seek and treat complications of underlying disease and therapies

References and links

LITFL

• CCC — Sepsis Overview (collates links to other CCC entries on Sepsis and Septic Shock)

FOAM and web resources

• EMCrit IBCC — Septic Shock (2017)
• EMCrit —Podcast 154 – Preemptive Sepsis Panel SmaccBack (2015)
• EMCrit — Podcast 161 – The New Fluid Assessment in Sepsis (2015)
• EMCrit — Podcast 111 – Fluids in Sepsis, A New Paradigm – Paul Marik (2014)
• EMCrit — Podcast 054 to 056 – Dr. Rivers on Severe Sepsis – Part I, Part II and Part III (2011)
• EMCrit — Podcast 37 – Lactate in Sepsis (2010)
• EMCrit — Sepsis Evidence Page (2015)
• SMACC — Sepsis SMACCdown (2015)

Journal articles

• Angus DC, Barnato AE, Bell D. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive care medicine. 41(9):1549-60. 2015. [pubmed]
• Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51. doi: 10.1056/NEJMra1208623. PubMed PMID: 23984731. [Free Full Text]
• Annane D, Vignon P, Renault A. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet (London, England). 370(9588):676-84. 2007. [pubmed]
• Annane 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 Aug 21;288(7):862-71. [pubmed] [free full text]
• Asfar P, Meziani F, Hamel JF. High versus low blood-pressure target in patients with septic shock (SEPSISPAM). The New England journal of medicine. 370(17):1583-93. 2014. [pubmed]
• Azuhata T, Kinoshita K, Kawano D. Time from admission to initiation of surgery for source control is a critical determinant of survival in patients with gastrointestinal perforation with associated septic shock. Critical care (London, England). 18(3):R87. 2014. [pubmed]
• Bourquin V, Ponte B, Pugin J, Martin P, Saudan P. Use of high-volume haemodiafiltration in patients with refractory septic shock and acute kidney injury. Clinical Kidney Journal. 6(1):40-44. 2012. [article]
• Brown RM, Wang L, Coston TD, et al. Balanced Crystalloids Versus Saline in Sepsis: A Secondary Analysis of the SMART Trial. Am J Respir Crit Care Med. 2019; doi: 10.1164/rccm.201903-0557OC. [Epub ahead of print] [pubmed]
• Cardenas-garcia J, Schaub KF, Belchikov YG, Narasimhan M, Koenig SJ, Mayo PH. Safety of peripheral intravenous administration of vasoactive medication. J Hosp Med. 2015;10(9):581-5. [pubmed]
• Cariou A, Vinsonneau C, Dhainaut JF. Adjunctive therapies in sepsis: an evidence-based review. Critical care medicine. 32(11 Suppl):S562-70. 2004. [pubmed]
• Caironi P, Tognoni G, Masson S. Albumin replacement in patients with severe sepsis or septic shock (ALBIOS). The New England journal of medicine. 370(15):1412-21. 2014. [pubmed]
• Chawla LS, Busse L, Brasha-Mitchell E. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Critical care (London, England). 18(5):534. 2014. [pubmed] [free full text]
• De Backer D, Aldecoa C, Njimi H, Vincent JL. Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis*. Critical care medicine. 40(3):725-30. 2012. [pubmed]
• De Backer D, Biston P, Devriendt J. Comparison of dopamine and norepinephrine in the treatment of shock. The New England journal of medicine. 362(9):779-89. 2010. [pubmed]
• Dellinger RP, et al; Surviving Sepsis Campaign Guidelines (SSG) Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af. PubMed PMID: 23353941. [free full text]
• Finfer S, Bellomo R, Boyce N. A comparison of albumin and saline for fluid resuscitation in the intensive care unit (SAFE). The New England journal of medicine. 350(22):2247-56. 2004. [pubmed]
• Gordon AC, Mason AJ, 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(5):509-18. [pubmed]
• Hébert PC, Wells G, Blajchman MA. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care (TRICC) Investigators, Canadian Critical Care Trials Group. The New England journal of medicine. 340(6):409-17. 1999. [pubmed]
• Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock (TRISS). N Engl J Med. 2014;371(15):1381-91. [pubmed]
• Jang DH, Nelson LS, Hoffman RS. Methylene blue for distributive shock: a potential new use of an old antidote. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 9(3):242-9. 2013. [pubmed]
• Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24;303(8):739-46. PubMed PMID: 20179283; PubMed Central PMCID: PMC2918907.
• Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3). N Engl J Med. 2017;377(5):419-430. [pubmed]
• Kumar A, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006 Jun;34(6):1589-96. PubMed PMID: 16625125.
• Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care. 2015;30(3):653.e9-17. [pubmed]
• Mallat J, Pepy F, Lemyze M. Central venous-to-arterial carbon dioxide partial pressure difference in early resuscitation from septic shock: a prospective observational study. European journal of anaesthesiology. 31(7):371-80. 2014. [pubmed]
• Marik PE, Bellomo R. Lactate clearance as a target of therapy in sepsis: A flawed paradigm. OA Critical Care 2013 Mar 01;1(1):3. [Free Full Text]
• Mesquida J, Saludes P, Gruartmoner G. Central venous-to-arterial carbon dioxide difference combined with arterial-to-venous oxygen content difference is associated with lactate evolution in the hemodynamic resuscitation process in early septic shock. Critical care. 19:126. 2015. [pubmed]
• Morelli A, Ertmer C, Westphal M. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 310(16):1683-91. 2013. [pubmed]
• Morelli A, Ertmer C, Rehberg S. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial. Critical care (London, England). 12(6):R143. 2008. [pubmed] [free full text]
• Mouncey PR, Osborn TM, Power GS. Trial of early, goal-directed resuscitation for septic shock (PROMISE). The New England journal of medicine. 372(14):1301-11. 2015. [pubmed]
• Myburgh JA, Finfer S, Bellomo R. Hydroxyethyl starch or saline for fluid resuscitation in intensive care (CHEST). The New England journal of medicine. 367(20):1901-11. 2012. [pubmed]
• Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367(2):124-34. [pubmed]
• Russell JA. Bench-to-bedside review: Vasopressin in the management of septic shock. Critical care . 15(4):226. 2011. [pubmed]
• Patel GP, Balk RA. Systemic steroids in severe sepsis and septic shock. American journal of respiratory and critical care medicine. 185(2):133-9. 2012. [pubmed] [free full text]
• Peake SL, et al. Goal-directed resuscitation for patients with early septic shock (ARISE). The New England journal of medicine. 371(16):1496-506. 2014. [pubmed]
• Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med. 2019;199(9):1097-1105. [pubmed]
• Seymour CW, Gesten F, Prescott HC, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med. 2017;376(23):2235-2244. [pubmed]
• Sharshar T, Blanchard A, Paillard M, Raphael JC, Gajdos P, Annane D. Circulating vasopressin levels in septic shock. Crit Care Med. 2003;31(6):1752-8. [pubmed]
• Sprung CL, et al; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366. [pubmed] [Free full text]
• Tumlin JA, Murugan R, Deane AM, et al. Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II (ATHOS3). Crit Care Med. 2018;46(6):949-957. [pubmed]
• Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy (EGDT) Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. PubMed PMID:11794169. [Fulltext]
• Russell JA, Walley KR, Singer J. Vasopressin versus norepinephrine infusion in patients with septic shock (VASST). The New England journal of medicine. 358(9):877-87. 2008. [pubmed]
• Vallée F, Vallet B, Mathe O. Central venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock? Intensive care medicine. 34(12):2218-25. 2008. [pubmed]
• Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock (PROCESS). The New England journal of medicine. 370(18):1683-93. 2014. [pubmed]