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Assessment and Management of Hypoperfusion in Sepsis and Septic Shock

Written By

Zohair Al Aseri

Submitted: 26 February 2021 Reviewed: 14 June 2021 Published: 30 July 2021

DOI: 10.5772/intechopen.98876

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Diagnosis of organ hypoperfusion in patient with sepsis is not always straightforward which makes septic shock definition, diagnosis, and early treatment are major challenges that emergency physicians and intensivist must deal with in their daily practice. Normal blood pressure does not always mean good organ perfusion, which means patient might develop septic shock, yet they are not hypotensive. There are several indices that could be used in combination to diagnose and manage hypoperfusion in patients with septic shock. Fluid resuscitation and vasopressor administration along with infection sources control are the cornerstones in septic shock management. This chapter will cover indices that can be used to diagnose hypoperfusion, type and amount of fluid and vasopressor that can be used in resuscitating septic shock patients.


  • septic shock
  • hypoperfusion
  • fluid resuscitation
  • vasopressor

1. Introduction

Sepsis is defined as life-threatening condition caused by a dysregulated host response to infection, resulting in organ dysfunction while septic shock is circulatory, cellular, and metabolic abnormalities in septic patients, presenting as fluid-refractory hypotension requiring vasopressor therapy with associated tissue hypoperfusion [1]. Septic shock has high mortality rate and constitutes 20% of all global deaths [2]. Mortality associated with septic shock range from 24–41% [3, 4, 5, 6]. Increased morbidities and decreased functional status of septic shock patients after hospital discharge are major concerns and related to poor management [7]. Management of Septic shock include early recognition, source control with antibiotic and surgical intervention if needed, adequate perfusion and vital organ support including renal and respiratory support [8]. Patient in the early stage of septic shock required individualized fluid resuscitation and early administration of vasopressor to ensure tissue perfusion.


2. Indices of Hypoperfusion

Progression of sepsis to septic shock occur very quickly and leads to hypoperfusion, end organ failure and death. Figure 1 summaries the pathophysiology of sepsis and septic shock [9, 10, 11]. Hemodynamic, clinical and laboratory indices could be used to determine the level of hypoperfusion and its response to resuscitation. Table 1 summaries the perfusion indices of and their targets during resuscitation.

Figure 1.

Pathophysiology of sepsis and septic shock.

Heart Rate60–90 Beats per minute
Mean arterial pressure MAP≥65 mmHg
Diastolic arterial pressure (DAP)≥50 mmHg
Skin examinationNormal color worminess
Temperature≥ 36oC
Capillary Refill Time (CRT)< 3 seconds
Urine Output (OUP)≥ 0.5 ml/kg/hour
Central Venous Pressure (CVP)< 6–8 mmHg in spontaneous breathing
> 12–15 mmHg in ventilated patient
Serum Lactate< 2.2 mmol/L

Table 1.

Indices of hypoperfusion and their targets.

2.1 Heart rate

Tachycardia is common sign of septic shock, and it predicts poor prognosis of septic shock patient. It is caused by stimulation of α- and β-adrenergic receptors increases in response to venodilattion and could be also related high temperature. Tachycardia is a sign impaired arterial tone [12]. It increases oxygen consumption, decreases diastolic filling and coronary perfusion, and increases arrhythmia [13]. Patients with septic shock and persistent tachycardia despite resuscitation measures has high mortality and morbidity rate [14].

2.2 Blood pressure

Blood pressure is easy to measure and monitor. Blood pressure is determined by cardiac output, systemic vascular resistance, and arterioles pressure and coronary perfusion and heart flow depend upon diastolic arterial pressure (DAP) [15].

Hypotension reflects decrease cardiac output, but it could be a delayed sign of hypoperfusion, and its absence does not necessarily rule out hypoperfusion. Hypotension triggers resuscitation. Low diastolic arterial pressure, in septic shock indicates impaired arterial tone. Optimizing blood pressure is one of the goals of fluid resuscitation and associated with better outcome [16]. Prolonged hypotension, low mean arterial pressure (MAP) and DAP associated with high mortality in septic shock patient [17, 18]. Normal MAP and DAP should be targeted to improve survival of septic shock patients [15]. No evidence what the best target level of DBP is but common approach is to titrate vasopressors in septic shock to keep DAP ≥50 mmHg [19]. Resuscitation should target MAP of 65 mmHg per the septic shock guidelines [20]. Hypoperfusion may persist even when pressure is restored so personalization approach to target blood pressure should consider other indices of perfusion [21].

2.3 Skin changes

Skin examination including its color, blanching and worminess is one of the most important physical examination to determine level of skin perfusion which reflect vital organ perfusion. Anterior aspect of the knee is one body area that commonly examined for skin perfusion Mottling score is one of indices of hypoperfusion and associated with worse outcome regardless of vasopressor use [2223]. Normalization of skin color and disappearance of mottled skin are targets of resuscitation and related to higher survival rate of septic shock patient [24, 25].

2.4 Skin temperature

Skin temperature is one of the most accessible markers of skin perfusion and hence tissue perfusion [26]. Hypothermia in circulatory shock is associated with impaired outcome [27].

2.5 Capillary refill time (CRT)

CRT is the time taken to regain distal capillary bed color after blanching by pressure. Normally should be less than 3 seconds. It has been shown in in study of 783 critically ill patients that CRT is sensitive sign of decrease cardiac output measured by echocardiogram [28]. Capillary refill time is one of the best indices of adequate perfusion [29, 30]. And could be used as screening tool to predict sick patient that might need admission to critical care area. In one study, CRT and lactate are similar in predict survival [31]. In other study prolonged CRT associated with decrease perfusion of the liver, kidneys, gut and spleen [32]. CRT more than 4 seconds associated with higher mortality rate of septic shock patients [33]. In a randomized controlled study of septic shock patients with high lactate level but with a normal CRT had lower day-28 mortality when compared to prolonged CRT and high lactate level and survival of patients is higher with when resuscitation is guided by capillary refill time but not lactate levels [34]. When CRT used as index as optimal resuscitation it led to decrease mortality rate and should be used to guide fluid resuscitation in septic shock patient [34, 35, 36]. Septic shock patients failing to normalize their CRT after the first fluid bolus in ED had high mortality [37].

2.6 Passive leg raise

Passive Leg Raise (PLR) Can assist in identifying preload dependence. Utilization of the passive leg raise as index of resuscitation lead to reduce net fluid balance, acute kidney injury and pulmonary edema and may improve outcomes [38].

PLR became more popular and easier to use in different sitting including emergency department sitting [39].

By moving the patient from a semi-recumbent position, lowering the trunk and raising the patient’s legs to 45°, an amount of ~300 mL of blood is transferred to the ventricles, thereby increasing the cardiac preload. If CO increases of at least 10% compared to baseline, the patient is considered preload responsive, thus capable of displaying a CO increase following administration of fluid. The change in cardiac output changes in is measured by thermodilution, echocardiography, pulse contour analysis or pulse pressure variation. Passive leg rising is shifts venous blood from the legs to the intrathoracic compartment. This response can predict the response to a fluid challenge. Passive leg-raise test is accurate and has excellent sensitivity and specificity, for that it is recommended to determine fluid responsiveness [20, 40]. A meta-analysis of 21 studies and 991 adult patients showed that a 10% 2% increase in cardiac output with PLR predicted fluid responsiveness [41].

2.7 Urine output

Oliguria which is urine output less than 0.5 ml/kg/hour is one of the main triggers for fluid challenges in septic shock patient [16]. Oliguria is one of signs of acute renal failure which is an independent risk factor associated with increased mortality during sepsis. Low UOP may reflect low renal perfusion pressure. UOP 30–50 mL/h in adult patient with septic shock should prompt further fluid resuscitation or other measures to increase cardiac output in a non–fluid-responsive patient [42]. UOP should not be taken alone as fluid resuscitation may not increase urinary output and cause positive fluid balance in patients with septic shock [20].

2.8 Central venous pressure (CVP)

Venodilation and hypovolemia cause decrease in ventricular preload which is signaled by decrease in central venous pressure. CVP reflect the right atrial pressure [43]. CVP alone is a poor variable to predict fluid responsiveness [44, 45]. The target CVP is < 6–8 mmHg in spontaneous breathing patient and > 12–15 mmHg in mechanically ventilated patient [46].

2.9 Lactate

Lactates reflect the onset of anaerobic metabolism. In experimental conditions, lactate increases when oxygen consumption increased and oxygen delivery decreased. Lactate also elevated in beta-adrenergic stimulation, leading to an accelerated glycolysis and liver failure. Lactate >2 mmol/L associated tissue hypoperfusion (lactate >2 mmol/L) [47]. Clinical studies show high lactate levels are associated with a high mortality, independently of its cause [48]. Lactate is easy to measure and can be used in emergency department triage and as a goal of early sepsis therapy [49]. Repeating lactate measurements is a trigger of resuscitation [20]. Lactate-guided resuscitation has emerged after the observation that the higher the decrease in lactate levels, the best the outcome [50].

Indices of hypoperfusion are combinations of pressure and flow measurements and clinical markers. They should be taken together and not to rely only on one index to diagnose and mange hypoperfusion [51].


3. Fluid resuscitation of septic shock patient

Crystalloid intravenous fluid either ringer lactate or 0.9% normal saline is the first and the main step in restoring hemodynamic instability. Septic shock patient in the initial stage should be considered fluid responsive and receive fluid bolus [52]. Not all septic shock patient will respond to the initial fluid resuscitation, hence additional pharmaceutics intervention is needed to augment of fluid resuscitation to restore the hemodynamic and improve organ perfusion [53, 54]. Fast intravenous (IV) crystalloid infusion has a slower redistribution rate. Interstitial distribution is hypothesized to be greater in sepsis than in healthy volunteers due to sepsis pathophysiology [55] (Figure 1). The maximal effect of IV crystalloid bolus achieves at one minute and return to baseline after 30 minutes. Only one third of septic shock patient will have risen in MAP after fluid challenge [56, 57]. Amount of IV fluid resuscitation in patients with septic shock is not known. In one retrospective study found large amount of fluid more than 5 liter per day associated with increase mortality rate and need of ventilatory support [58, 59]. 50% 0f septic shock patients will be non-fluid responsive, where a condition where the administration of more fluid bolus may lead to fluid accumulation, impaired oxygen delivery, and worsening hypoperfusion [60]. How fast fluid should be administered in septic shock resuscitation is not known. Mainly retrospective studies shows failure to complete 30 mL/kg of IV crystalloid over 3 hours was associated with increased mortality [61]. In multi-center study found IV fluid administration within six hours was associated with decreased mortality [62]. regarding type of fluid in resuscitating septic shock patient, the current guideline recommends both sodium chloride and balanced crystalloids [20]. Studies within the critically ill have shown lower risk of in-hospital or 30-day mortality, AKI, or major adverse kidney event in the first 30 days with the use of balanced crystalloids over sodium chloride solutions [63, 64]. SMART trial, compared the two solutions in 15,802 critically ill patients, reported a lower rate of death from any cause, renal-replacement therapy, or renal failure with using balanced crystalloids versus normal saline [63]. In secondary analysis of SMART study among 1,641 patients were admitted to the medical ICU with a diagnosis of sepsis, balanced crystalloids was associated with a lower 30-day in-hospital mortality rate, renal failure, and a higher number of vasopressor free days compared with use of saline [64]. Amount of fluids resuscitation should be decided to minimize the complication of over resuscitation as pulmonary edema, brain edema, abdominal compartment syndrome and third space edema which will lead resulting in end-organ hypoperfusion by decrease oxygen delivery, capillary blood flow and lymphatic drainage. Which explain worse outcomes in shock with a positive fluid balance [55, 65, 66]. Collapsible inferior vena cava can along with other hypoperfusion indices can be used to monitor fluid and resuscitation of septic shock patient [67]. Resuscitation of septic shock patient with high volume of normal saline is associated with hyperchloremia, AKI, multiorgan dysfunction, and high mortality [68, 69]. Fixed amount of fluid hardly suitable for all septic shock patients, Teboul and Monnet proposed to administer crystalloid about 10 mL/kg within the first 30 to 60 min and monitor patient [52]. If patient develop any signs of respiratory failure stop further boluses. In case CRT is still prolonged, tachycardia or low blood pressure reading, skin mottling increase in the infusion rate [70].

Perfusion indices should be used to individualize fluid administration approach in balanced crystalloid is recommended over normal slain in septic shock resuscitation.


4. Vasopressors in septic shock management

Vasopressor increases systemic vascular resistance (SVR), cardiac output CO, and heart rate (HR) and rapidly restore organ perfusion [71]. Vasopressors either catecholamine- or non-catecholamine-based agents. Dopamine, norepinephrine, epinephrine, and phenylephrine are catecholamine-based vasopressors while vasopressin is a non-catecholamine-based vasopressors [72]. Norepinephrine is the first-line vasopressor for patients with septic shock [20]. Early vasopressors administration in septic shock patients revert the severely impaired arterial tone and associated with lowest mortality rate occurred when vasoactive agents were started 1 to 6 hours of septic shock identification [20, 73, 74, 75, 76]. CENSER trial shows early NE administration is associated with increased shock control over the first 6 hours [76]. Addition of vasopressin to norepinephrine in the few hours of shock when doses of norepinephrine dose is ≥1 μg/Kg/min, may decrease mortality, arrhythmia, hypotension and need for renal replacement therapy [77, 78]. Addition of vasopressin to norepinephrine is more effective in early septic shock management and reach MAP target faster and lower incidence of atrial fibrillation [79, 80]. Possible complication of vasopressor includes dysrhythmias tachycardia or atrial fibrillation. Hyperlactatemia and hyperglycemia [80, 81]. Peripheral administration of vasopressors includes extravasation and peripheral ischemia given their potent vasoconstrictive properties [82]. Extravasation was uncommon if vasopressors are administered peripherally for less than 22 hours. Peripheral administration of vasopressors in upper arm using 20 gauge or larger is safe and feasible in the initial hours of resuscitation [82, 83, 84]. Vasopressor treatment can be initiated on a peripheral venous line with non-invasive BP monitoring, and shifted, as soon as possible, to central venous catheter with arterial pressure monitoring [85].

Early norepinephrine administration should be started in septic shock patient with slow response to fluid resuscitation. Vasopressin is recommended in when norepinephrine dose is ≥1 μg/Kg/min.


5. Conclusion

Septic shock is life threatening condition complicated with hypoperfusion, Indices of hypoperfusion are combinations of pressure and flow measurements and clinical markers. Indices should be taken together and not to rely only on one index to diagnose and mange hypoperfusion. Perfusion indices should be used to individualize fluid administration approach in balanced crystalloid is recommended over normal slain in septic shock resuscitation. Early norepinephrine administration should be started in septic shock patient with slow response to fluid resuscitation. Vasopressin is recommended in when norepinephrine dose is ≥1 μg/Kg/min.


  1. 1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Defi nitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315(8):801-810. doi:10.1001/jama.2016.0287
  2. 2. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020 Jan 18;395(10219):200-211. doi: 10.1016/S0140-6736(19)32989-7
  3. 3. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10. 358(2):111-124
  4. 4. Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012 May 31. 366(22):2055-2064
  5. 5. Levy MM, Artigas A, Phillips GS, Rhodes A, Beale R, Osborn T, et al. Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis. 2012 Dec. 12(12):919-924
  6. 6. Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013 Mar 20. 309(11):1154-1162
  7. 7. Meyer N, Harhay MO, Small DS, Prescott HC, Bowles KH, Gaieski DF, Mikkelsen ME. Temporal Trends in Incidence, Sepsis-Related Mortality, and Hospital-Based Acute Care After Sepsis. Crit Care Med. 2018 Mar;46(3):354-360. doi: 10.1097/CCM.0000000000002872
  8. 8. De Backer D, Dorman T. Surviving Sepsis Guidelines: a continuous move toward better care of patients with sepsis. Journal of the American Medical Association 2017;317:807-808
  9. 9. Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management. BMJ. 2016 May 23;353:i1585. doi: 10.1136/bmj.i1585
  10. 10. Angus DC, van der Poll T. Severe Sepsis and Septic Shock. N Engl J Med 369(9):840- 851, 2013
  11. 11. Russell JA, Rush B, Boyd J. Pathophysiology of Septic Shock. Crit Care Clin 34(1):43-61, 2018
  12. 12. Magder S. The meaning of blood pressure. Crit Care. 2018 Oct 11;22(1):257. doi: 10.1186/s13054-018-2171-1
  13. 13. Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med. 2007 Jun;35(6):1599-1608. doi: 10.1097/01.CCM.0000266683.64081.02
  14. 14. Domizi R, Calcinaro S, Harris S, Beilstein C, Boerma C, Chiche JD, D'Egidio A, et al. Relationship between norepinephrine dose, tachycardia and outcome in septic shock: A multicentre evaluation. J Crit Care. 2020 Jun;57:185-190. doi: 10.1016/j.jcrc.2020.02.014. Epub 2020 Feb 28
  15. 15. Magder SA. The highs and lows of blood pressure: toward meaningful clinical targets in patients with shock. Crit Care Med 2014;42(5):1241-1251
  16. 16. Cecconi M, Hofer C, Teboul JL, etal. Fluid challenges in intensive care:the FENICE study: a global inception cohort study. Intensive Care Med 2015; 41:1529 – 1537
  17. 17. Varpula M, Tallgren M, Saukkonen K, Voipio-Pulkki LM, Pettilä V. Hemodynamic variables related to outcome in septic shock. Intensive Care Med 2005;31:1066-1071
  18. 18. Vincent JL, Nielsen ND, Shapiro NI, Gerbasi ME, Grossman A, Doroff R, et al. Mean arterial pressure and mortality in patients with distributive shock: A retrospective analysis of the MIMIC-III database. Ann Intensive Care 2018;8:107
  19. 19. Benchekroune S, Karpati PC, Berton C, Nathan C, Mateo J, Chaara M, et al. Diastolic arterial blood pressure: a reliable early predictor of survival in human septic shock. J Trauma 2008;64(5):1188-1195.
  20. 20. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med 45(3):486-552, 2017
  21. 21. Kato R, Pinsky MR. Personalizing blood pressure management in septic shock. Ann Intensive Care 2015;5(1):41
  22. 22. Ait-Oufella H, Lemoinne S, Boelle PY, Galbois A, Baudel JL, Lemant J, et al. Mottling score predicts survival in septic shock. Intensive Care Med 2011;37:801-807
  23. 23. Ait-Oufella H, Bourcier S, Alves M, Galbois A, Baudel JL, Margetis D, et al. Alteration of skin perfusion in mottling area during septic shock. Ann Intensive Care 2013;3:31
  24. 24. Jouffroy R, Saade A, Tourtier JP, Gueye P, Bloch-Laine E, Ecollan P, et al. Skin mottling score and capillary refill time to assess mortality of septic shock since pre-hospital setting. Am J Emerg Med 2019;37:664-671
  25. 25. Dumas G, Lavillegrand JR, Joffre J, Bigé N, de-Moura EB, Baudel JL, et al. Mottling score is a strong predictor of 14-day mortality in septic patients whatever vasopressor doses and other tissue perfusion parameters. Crit Care 2019;23:211
  26. 26. Ait-Oufella H, Bakker J. Understanding clinical signs of poor tissue perfusion during septic shock. Intensive Care Med 2016;42:2070-2072
  27. 27. Bourcier S, Pichereau C, Boelle PY, Nemlaghi S, Dubée V, Lejour G, et al. Toe-to-room temperature gradient correlates with tissue perfusion and predicts outcome in selected critically ill patients with severe infections. Ann Intensive Care 2016;6:63
  28. 28. Hiemstra B, Koster G, Wiersema R, et al. The diagnostic accuracy of clinical & examination for estimating cardiac index in critically ill patients: the Simple Intensive Care Studies-I. Intensive Care Med 2019; 45:190-200
  29. 29. . Lima A,van Bommel J,Sikorska K,etal.The relation of near-infrared spectroscopy with changes in peripheral circulation in critically ill patients. Crit Care. Med 2011; 39:1649-1654
  30. 30. Lima A, van Genderen ME, Klijn E, Bakker J, van Bommel J. Peripheral vasoconstriction influences thenar oxygen saturation as measured by near-infrared spectroscopy. Intensive Care Med. 2012 Apr;38(4):606-611. doi: 10.1007/s00134-012-2486-3. Epub 2012 Feb 14
  31. 31. Mongkolpun W, Orbegozo D, Cordeiro CPR, Franco CJCS, Vincent JL, Creteur J. Alterations in Skin Blood Flow at the Fingertip Are Related to Mortality in Patients With Circulatory Shock. Crit Care Med. 2020 Apr;48(4):443-450. doi: 10.1097/CCM.0000000000004177
  32. 32. Brunauer A, Koköfer A, Bataar O, Gradwohl-Matis I, Dankl D, Bakker J, et al. Changes in peripheral perfusion relate to visceral organ perfusion in early septic shock: A pilot study. J Crit Care. 2016 Oct;35:105-109. doi: 10.1016/j.jcrc.2016.05.007. Epub 2016 May
  33. 33. Hernández G, Ospina-Tascón GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019 Feb 19;321(7):654-664. doi: 10.1001/jama.2019.0071
  34. 34. Kattan E, Hernández G, Ospina-Tascón G, Valenzuela ED, Bakker J, Castro R; ANDROMEDA-SHOCK Study Investigators and the Latin America Intensive Care Network (LIVEN). A lactate-targeted resuscitation strategy may be associated with higher mortality in patients with septic shock and normal capillary refill time: a post hoc analysis of the ANDROMEDA-SHOCK study. Ann Intensive Care. 2020 Aug 26;10(1):114. doi: 10.1186/s13613-020-00732-1
  35. 35. Zampieri FG, Damiani LP, Bakker J, Ospina-Tascón GA, Castro R, Cavalcanti AB, et al. Effects of a Resuscitation Strategy Targeting Peripheral Perfusion Status versus Serum Lactate Levels among Patients with Septic Shock. A Bayesian Reanalysis of the ANDROMEDA-SHOCK Trial. Am J Respir Crit Care Med. 2020 Feb 15;201(4):423-429. doi: 10.1164/rccm.201905-0968OC
  36. 36. Kattan E, Ospina-Tascón GA, Teboul JL, Castro R, Cecconi M, Ferri G, et al. ANDROMEDA-SHOCK Investigators. Systematic assessment of fluid responsiveness during early septic shock resuscitation: secondary analysis of the ANDROMEDA-SHOCK trial. Crit Care. 2020 Jan 23;24(1):23. doi: 10.1186/s13054-020-2732-y
  37. 37. Lara B, Enberg L, Ortega M, Leon P, Kripper C, Aguilera P, Kattan E, et al. Capillary refill time during fluid resuscitation in patients with sepsis-related hyperlactatemia at the emergency department is related to mortality. PLoS One. 2017 Nov 27;12(11):e0188548. doi: 10.1371/journal.pone.0188548
  38. 38. Douglas IS, Alapat PM, Corl KA, Exline MC, Forni LG, Holder AL, et al. Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial. Chest. 2020 Oct;158(4):1431-1445. doi: 10.1016/j.chest.2020.04.025. Epub 2020 Apr 27
  39. 39. Monnet X, Teboul JL. Passive leg raising: five rules, not a drop of fluid! Crit Care. 2015 Jan 14;19(1):18. doi: 10.1186/s13054-014-0708-5
  40. 40. Monnet X, Marik P, Teboul JL. Passive leg raising for predicting fluid responsiveness: a systematic review and meta-analysis. Intensive Care Med 2016; 42(12):1935-1947. doi:10.1007/s00134-015-4134-1
  41. 41. Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-1309
  42. 42. Godin M, Murray P, Mehta RL. Clinical approach to the patient with AKI and sepsis. Semin Nephrol. 2015;35(1):12-22. doi:10.1016/j.semnephrol.2015.01.003
  43. 43. De Backer D, Vincent JL. Should we measure the central venous pressure to guide fluid management? Ten answers to 10 questions. Crit Care. 2018 Feb 23;22(1):43. doi: 10.1186/s13054-018-1959-3
  44. 44. Marik PE, Cavallazzi R. Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense. Crit Care Med. 2013 Jul;41(7):1774-1781. doi: 10.1097/CCM.0b013e31828a25fd
  45. 45. Cecconi M, Aya HD. Central venous pressure cannot predict fluid-responsiveness. Evid Based Med. 2014;19:63. doi: 10.1136/eb-2013-101496
  46. 46. Eskesen TG, Wetterslev M, Perner A. Systematic review including re-analyses of 1148 individual data sets of central venous pressure as a predictor of fluid responsiveness. Intensive Care Med. 2016;42:324-332. doi: 10.1007/s00134-015-4168-4
  47. 47. Rimachi R, Bruzzi de Carvahlo F, Orellano-Jimenez C, Cotton F, Vincent JL, et al. Lactate/pyruvate ratio as a marker of tissue hypoxia in circulatory and septic shock. Anaesth Intensive Care 2012;40:427-432
  48. 48. Casserly B, Phillips GS, Schorr C, Dellinger RP, Townsend SR, Osborn TM, et al. Lactate measurements in sepsis-induced tissue hypoperfusion: Results from the Surviving Sepsis Campaign database. Crit Care Med 2015;43:567-573
  49. 49. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA, et al. Lactate clearance vs. central venous oxygen saturation as goals of early sepsis therapy: A randomized clinical trial. JAMA 2010;303:739-746
  50. 50. Bakker J, De Backer D, Hernandez G. Lactate-guided resuscitation saves lives: We are not sure. Intensive Care Med 2016;42:472-474
  51. 51. Hernandez G, Luengo C, Bruhn A, Kattan E, Friedman G, Ospina-Tascon GA, et al. When to stop septic shock resuscitation: clues from a dynamic perfusion monitoring. Ann Intensive Care. 2014 Oct 11;4:30. doi: 10.1186/s13613-014-0030-z
  52. 52. Monnet X, Teboul JL. Prediction of fluid responsiveness in spontaneously breathing patients. Ann Transl Med. 2020 Jun;8(12):790. doi: 10.21037/atm-2020-hdm-18
  53. 53. Marik PE, Lemson J. Fluid responsiveness: an evolution of our understanding. Br J Anaesth. 2014 Apr;112(4):617-620. doi: 10.1093/bja/aet590. Epub 2014 Feb 16
  54. 54. Dugar S, Choudhary C, Duggal A. Sepsis and septic shock: Guideline-based management. Cleve Clin J Med. 2020 Jan;87(1):53-64. doi: 10.3949/ccjm.87a.18143. Epub 2020 Jan 2
  55. 55. Bissell BD, Mefford B. Pathophysiology of Volume Administration in Septic Shock and the Role of the Clinical Pharmacist. Ann Pharmacother. 2020 Apr;54(4):388-396. doi: 10.1177/1060028019887160. Epub 2019 Nov 6
  56. 56. Aya HD, Ster IC, Fletcher N, Grounds RM, Rhodes A, Cecconi M. Pharmacodynamic Analysis of a Fluid Challenge. Crit Care Med. 2016 May;44(5):880-891. doi: 10.1097/CCM.0000000000001517
  57. 57. Monge García MI, Guijo González P, Gracia Romero M, Gil Cano A, Oscier C, Rhodes A, et al. Effects of fluid administration on arterial load in septic shock patients. Intensive Care Med. 2015 Jul;41(7):1247-1255
  58. 58. Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med 43(5):625-632, 2017
  59. 59. Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med 2017;376(23):2235-2244
  60. 60. Monnet X, Teboul JL. My patient has received fluid. How to assess its efficacy and side effects? Ann Intensive Care. 2018 Apr 24;8(1):54. doi: 10.1186/s13613-018-0400-z
  61. 61. Kuttab HI, Lykins JD, Hughes MD, Wroblewski K, Keast EP, Kukoyi O, et al. Evaluation and Predictors of Fluid Resuscitation in Patients With Severe Sepsis and Septic Shock. Crit Care Med 2019;47(11):1582-1590
  62. 62. Levy MM, Gesten FC, Phillips GS, Terry KM, Seymour CW, Prescott HC, et al. The Results of the New York State Initiative. Am J Respir Crit Care Med 2018;198:1406-1412
  63. 63. Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, et al. SMART Investigators and the Pragmatic Critical Care Research Group. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):829-839. doi: 10.1056/NEJMoa1711584. Epub 2018 Feb 27
  64. 64. Brown RM, Wang L, Coston TD, Krishnan NI, Casey JD, Wanderer JP, et al. Balanced Crystalloids versus Saline in Sepsis. A Secondary Analysis of the SMART Clinical Trial. Am J Respir Crit Care Med. 2019 Dec 15;200(12):1487-1495. doi: 10.1164/rccm.201903-0557OC
  65. 65. Tigabu BM, Davari M, Kebriaeezadeh A, Mojtahedzadeh M. Fluid volume, fluid balance and patient outcome in severe sepsis and septic shock: A systematic review. J Crit Care 2018;48:153-159
  66. 66. Sakr Y, Rubatto Birri PN, Kotfis K, Nanchal R, Shah B, Kluge S, et al. Intensive Care Over Nations Investigators. Higher Fluid Balance Increases the Risk of Death From Sepsis: Results From a Large International Audit. Crit Care Med. 2017 Mar;45(3):386-394. doi: 10.1097/CCM.0000000000002189
  67. 67. Vallabhajosyula S, Ahmed AM, Sundaragiri PR. Role of echocardiography in sepsis and septic shock. Ann Transl Med 2020; 8(5):150-150
  68. 68. Suetrong B, Pisitsak C, Boyd JH, Russell JA, Walley KR. Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients. Crit Care. 2016 Oct 6;20(1):315. doi: 10.1186/s13054-016-1499-7
  69. 69. Yeh P, Pan Y, Sanchez-Pinto LN, Luo Y. Hyperchloremia in critically ill patients: association with outcomes and prediction using electronic health record data. BMC Med Inform Decis Mak. 2020 Dec 15;20(Suppl 14):302. doi: 10.1186/s12911-020-01326-4
  70. 70. Jozwiak M, Hamzaoui O, Monnet X, Teboul JL. Fluid resuscitation during early sepsis: a need for individualization. Minerva Anestesiol. 2018 Aug;84(8):987-992. doi: 10.23736/S0375-9393.18.12422-9. Epub 2018 Feb 14
  71. 71. Saugel B, Malbrain MLNG, Perel A. Hemodynamic monitoring in the era of evidence- based medicine. Crit Care 2016;20(1):401
  72. 72. Manolopoulos PP, Boutsikos I, Boutsikos P, Iacovidou N, Ekmektzoglou K. Current use and advances in vasopressors and inotropes support in shock. J Emerg Crit Care Med 2020; 4(0):20-20
  73. 73. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 Update. Crit Care Med. 2018 Jun;46(6):997-1000. doi: 10.1097/CCM.0000000000003119
  74. 74. Colon Hidalgo D, Patel J, Masic D, Park D, Rech MA. Delayed vasopressor initiation is associated with increased mortality in patients with septic shock. J Crit Care. 2020 Feb;55:145-148. doi: 10.1016/j.jcrc.2019.11.004. Epub 2019 Nov 9
  75. 75. 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 May 1;199(9):1097-1105. doi: 10.1164/rccm.201806-1034OC
  76. 76. Li Y, Li H, Zhang D. Timing of norepinephrine initiation in patients with septic shock: a systematic review and meta-analysis. Crit Care. 2020 Aug 6;24(1):488. doi: 10.1186/s13054-020-03204-x
  77. 77. Hammond DA, Cullen J, Painter JT, McCain K, Clem OA, Brotherton AL, et al. Efficacy and Safety of the Early Addition of Vasopressin to Norepinephrine in Septic Shock. J Intensive Care Med. 2019 Nov-Dec;34(11-12):910-916. doi: 10.1177/0885066617725255. Epub 2017 Aug 18
  78. 78. Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, et al. VANISH Investigators. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):509-518. doi: 10.1001/jama.2016.10485
  79. 79. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, et al. VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-887. doi: 10.1056/NEJMoa067373
  80. 80. McIntyre WF, Um KJ, Alhazzani W, Lengyel AP, Hajjar L, Gordon AC, Lamontagne F, 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 319(18):1889- 1900, 2018
  81. 81. De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, et al. SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 4;362(9):779-789. doi: 10.1056/NEJMoa0907118
  82. 82. Tian DH, Smyth C, Keijzers G, Macdonald SP, Peake S, Udy A, et al. Safety of peripheral administration of vasopressor medications: A systematic review. Emerg Med Australas. 2020 Apr;32(2):220-227. doi: 10.1111/1742-6723.13406. Epub 2019 Nov 7
  83. 83. 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):581-585.
  84. 84. Lewis T, Merchan C, Altshuler D, Papadopoulos J. Safety of the peripheral administration of vasopressor agents. J Intensive Care Med 2019;34(1):26-33. https://doi. org/10.1177/0885066616686035
  85. 85. Ospina-Tascón GA, Hernandez G, Alvarez I, Calderón-Tapia LE, Manzano-Nunez R, Sánchez-Ortiz AI, et al. Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis. Crit Care. 2020 Feb 14;24(1):52. doi: 10.1186/s13054-020-2756-3

Written By

Zohair Al Aseri

Submitted: 26 February 2021 Reviewed: 14 June 2021 Published: 30 July 2021