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A rational approach to fluid therapy in sepsis20160403


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ICU Management of Spesis and Septic Shock

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A rational approach to fluid therapy in sepsis20160403

  1. 1. A Rational Approach to Fluid Therapy in Sepsis Dr. A. Alisher MD PhD ICU, KCCC, MOH, Kuwait City, KUWAIT
  2. 2. A rational approach to fluid therapy in sepsis • Marik P, et al. • A rational approach to fluid therapy in sepsis. • Br. J. Anaesth. (2016) 116 (3): 339-349. • A HD guided fluid therapy in pts with sepsis prudent • Reduce the morbidity • Improve the outcome
  3. 3. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Mervyn Singer, MD, FRCP1; Clifford S. Deutschman, MD, MS2; Christopher Warren Seymour, MD, MSc3; Manu Shankar-Hari, MSc, MD, FFICM4; Djillali Annane, MD, PhD5; Michael Bauer, MD6; Rinaldo Bellomo, MD7; Gordon R. Bernard, MD8; Jean-Daniel Chiche, MD, PhD9; Craig M. Coopersmith, MD10; Richard S. Hotchkiss, MD11; Mitchell M. Levy, MD12; John C. Marshall, MD13; Greg S. Martin, MD, MSc14; Steven M. Opal, MD12; Gordon D. Rubenfeld, MD, MS15,16; Tom van der Poll, MD, PhD17; Jean-Louis Vincent, MD, PhD18; Derek C. Angus, MD, MPH19,20 JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287. • Importance • Definitions of sepsis and septic shock were last revised in 2001. • Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
  4. 4. Objective and Process • To evaluate and update definitions for sepsis and septic shock. • Sepsis pathobiology, clinical trials, and epidemiology • Definitions and clinical criteria, Delphi processes, analysis of databases, followed by peer review and endorsement by 31 societies worldwide.
  5. 5. Key Findings • Evidence included an excessive focus on inflammation • Sepsis a continuum through Severe Sepsis to Shock • Specificity and sensitivity of the SIRS criteria. • Multiple definitions and terminologies in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in incidence and mortality. • The term severe sepsis was redundant.
  6. 6. Recommendations • Sepsis: life-threatening organ dysfunction caused by a dysregulated host response to infection. • Organ dysfunction in (SOFA) score of 2 points or more • Mortality > 10%
  7. 7. Recommendations • SSH: a subset of SS profound circulatory, cellular, and metabolic abnormalities with a greater risk of mortality than with SS alone. • Pts with SSH clinically identified by a vasopressor requirement to maintain a MAP of 65 mm Hg or greater and SL level > 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. • Mortality > 40%.
  8. 8. Recommendations • Pts with suspected infection to have poor outcomes typical of SS if they have at least 2 of the following clinical criteria qSOFA: • RR of 22/min or greater • Altered Mentation or • SBP of 100 mm Hg or less
  9. 9. Conclusions and Relevance • Updated definitions & clinical criteria • Offer greater studies and clinical trials • Earlier recognition • A timely management of pts. with Sepsis or • At risk of developing Sepsis.
  10. 10. INTRODUCTION • Sepsis: a syndrome of physiologic, pathologic and biochemical abnormalities induced by infection • The incidence of sepsis is increasing • Aging pts. with more comorbidities • The true incidence is unknown • Sepsis: a leading cause of mortality and critical illness. • Pts who survive sepsis have long-term physical, psychological, cognitive disabilities with significant health care and social implications.
  11. 11. INTRODUCTION • 1991 consensus: sepsis resulted from a host’s SIRS to infection (Box 1). • Sepsis complicated by organ dysfunction was severe sepsis, which could progress to septic shock, defined as “sepsis-induced hypotension persisting despite adequate fluid resuscitation.” • 2001: expanded the list of diagnostic criteria but did not offer alternatives because of the lack of supporting evidence. • The definitions of sepsis, septic shock, and organ dysfunction have remained largely unchanged for more than 2 decades.
  12. 12. Box 1. SIRS (Systemic Inflammatory Response Syndrome) • Two or more of: • T >38°C or <36°C • HR >90/min • RR >20/min or PaCO2 <32 mm Hg (4.3 kPa) • WBC >12 000/mm3 or <4000/mm3 or • WBC >10% immature bands
  13. 13. THE PROCESS OF DEVELOPING NEW DEFINITIONS • Recognizing the need to reexamine the current definitions,11 the European Society of Intensive Care Medicine and the Society of Critical Care Medicine convened a task force of 19 critical care, infectious disease, surgical, and pulmonary specialists in January 2014. • Unrestricted funding support was provided by the societies, and the task force retained complete autonomy. • The societies each nominated cochairs (Drs Deutschman and Singer), who selected members according to their scientific expertise in sepsis epidemiology, clinical trials, and basic or translational research. • The group engaged in iterative discussions via 4 face-to-face meetings between January 2014 and January 2015, email correspondence, and voting. • Existing definitions were revisited in light of an enhanced appreciation of the pathobiology and the availability of large electronic health record databases and patient cohorts.
  14. 14. THE PROCESS OF DEVELOPING NEW DEFINITIONS • A current understanding of sepsis-induced changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation (pathobiology), updated definition(s) and the criteria to be tested in the clinical arena. • The definitions and clinical criteria. • The potential clinical criteria (construct validity) and the ability of the criteria to predict outcomes typical of sepsis, such as need for ICU admission or death (predictive validity) • Databases:the absence (missingness) of individual elements of different organ dysfunction scores and the question of generalizability (ecologic validity). • A literature review and Delphi consensus methods used for the definition and clinical criteria describing septic shock. • Recommendations with evidence, including original research..
  15. 15. ISSUES ADDRESSED BY THE TASK FORCE • The task force sought to differentiate sepsis from uncomplicated infection and to update definitions of sepsis and septic shock to be consistent with improved understanding of the pathobiology. • A definition is the description of an illness concept; thus, a definition of sepsis should describe what sepsis “is.” • This chosen approach allowed discussion of biological concepts that are currently incompletely understood, such as genetic influences and cellular abnormalities. • The sepsis illness concept is predicated on infection as its trigger, acknowledging the current challenges in the microbiological identification of infection. • It was not, however, within the task force brief to examine definitions of infection.
  16. 16. ISSUES ADDRESSED BY THE TASK FORCE • The task force recognized that sepsis is a syndrome without, at present, a validated criterion standard diagnostic test. • There is currently no process to operationalize the definitions of sepsis and septic shock, a key deficit that has led to major variations in reported incidence and mortality rates (see later discussion). • The task force determined that there was an important need for features that can be identified and measured in individual patients and sought to provide such criteria to offer uniformity. Ideally, these clinical criteria should identify all the elements of sepsis (infection, host response, and organ dysfunction), be simple to obtain, and be available promptly and at a reasonable cost or burden. • Furthermore, it should be possible to test the validity of these criteria with available large clinical data sets and, ultimately, prospectively. In addition, clinical criteria should be available to provide practitioners in out-of-hospital, emergency department, and hospital ward settings with the capacity to better identify patients with suspected infection likely to progress to a life-threatening state. • Such early recognition is particularly important because prompt management of septic patients may improve outcomes.4 • In addition, to provide a more consistent and reproducible picture of sepsis incidence and outcomes, the task force sought to integrate the biology and clinical identification of sepsis with its epidemiology and coding.
  17. 17. IDENTIFIED CHALLENGES AND OPPORTUNITIES • Assessing the Validity of Definitions When There Is No Gold Standard • Sepsis is not a specific illness but rather a syndrome encompassing a still-uncertain pathobiology. At present, it can be identified by a constellation of clinical signs and symptoms in a patient with suspected infection. Because no gold standard diagnostic test exists, the task force sought definitions and supporting clinical criteria that were clear and fulfilled multiple domains of usefulness and validity.
  18. 18. Improved Understanding of Sepsis Pathobiology • Sepsis is a multifaceted host response to an infecting pathogen that may be significantly amplified by endogenous factors.14,15 • The original conceptualization of sepsis as infection with at least 2 of the 4 SIRS criteria focused solely on inflammatory excess. • However, the validity of SIRS as a descriptor of sepsis pathobiology has been challenged. • Sepsis is now recognized to involve early activation of both pro- and anti-inflammatory responses,16 along with major modifications in nonimmunologic pathways such as cardiovascular, neuronal, autonomic, hormonal, bioenergetic, metabolic, and coagulation,14,17,18 all of which have prognostic significance. • Organ dysfunction, even when severe, is not associated with substantial cell death.19
  19. 19. • The broader perspective also emphasizes the significant biological and clinical heterogeneity in affected individuals,20 with age, underlying comorbidities, concurrent injuries (including surgery) and medications, and source of infection adding further complexity.21 • This diversity cannot be appropriately recapitulated in either animal models or computer simulations.14 • With further validation, multichannel molecular signatures (eg, transcriptomic, metabolomic, proteomic) will likely lead to better characterization of specific population subsets.22,23 • Such signatures may also help to differentiate sepsis from noninfectious insults such as trauma or pancreatitis, in which a similar biological and clinical host response may be triggered by endogenous factors.24 • Key concepts of sepsis describing its protean nature are highlighted in Box 2.
  20. 20. Box 2. Key Concepts of Sepsis • Cause of death from infection, if not recognized and treated promptly. • Urgent attention. • By pathogen factors and host factors with time. • An aberrant or dysregulated host response and organ dysfunction. • Organ dysfunction in any patient presenting with infection. • Unrecognized infection cause new-onset organ dysfunction. • Any organ dysfunction ~ underlying infection. • Acute illness, comorbidities, medication, and interventions. • Specific infections ~ in local organ dysfunction without dysregulated systemic host response.
  21. 21. Variable Definitions • A better understanding of the underlying pathobiology: • Sepsis • Severe sepsis • Sepsis syndrome • Septicemia • ICD-9 and • ICD-10 codes
  22. 22. Sepsis • The current use of 2 or more SIRS criteria (Box 1) to identify sepsis • Changes in WBC, T and HR reflect inflammation, the host response to “danger” in the form of infection or other insults. • The SIRS criteria do not necessarily indicate a dysregulated, life-threatening response. • SIRS criteria are present in many hospitalized patients, including those who never develop infection and never incur adverse outcomes (poor discriminant validity). • In addition, 1 in 8 patients admitted to critical care units in Australia and New Zealand with infection and new organ failure did not have the requisite minimum of 2 SIRS criteria to fulfill the definition of sepsis (poor concurrent validity) yet had protracted courses with significant morbidity and mortality. • Discriminant validity and convergent validity constitute the 2 domains of construct validity; the SIRS criteria thus perform poorly on both counts.
  23. 23. Organ Dysfunction or Failure • Severity of organ dysfunction assessed with various scoring systems that quantify abnormalities according to clinical findings, laboratory data, or therapeutic interventions. • The Sequential Organ Failure Assessment (SOFA) • A higher SOFA score with an increased probability of mortality. • The score grades abnormality by organ system and accounts for clinical interventions. • Laboratory variables: PaO2, platelet count, creatinine level, and bilirubin level, are needed for full computation. • Selection of variables and cutoff values by SOFA • Other organ failure scoring systems exist.
  24. 24. Septic Shock • Multiple definitions for septic shock are currently in use. Further details are provided in an accompanying article by Shankar-Hari et al.13 • A systematic review of the operationalization of current definitions highlights significant heterogeneity in reported mortality. • This heterogeneity resulted from differences in the clinical variables chosen (varying cutoffs for systolic or mean blood pressure ± diverse levels of hyperlactatemia ± vasopressor use ± concurrent new organ dysfunction ± defined fluid resuscitation volume/targets), the data source and coding methods, and enrollment dates.
  25. 25. A NEED FOR SEPSIS DEFINITIONS FOR THE PUBLIC AND FOR HEALTH CARE PRACTITIONERS • Despite its worldwide importance,6,7 public awareness of sepsis is poor.29 • Furthermore, the various manifestations of sepsis make diagnosis difficult, even for experienced clinicians. • Thus, the public needs an understandable definition of sepsis; • Whereas health care practitioners require improved clinical prompts and diagnostic approaches to facilitate earlier identification and an accurate quantification of the burden of sepsis.
  26. 26. RESULTS/RECOMMENDATIONS • Definition of Sepsis • Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (Box 3). • This new definition emphasizes the primacy of the nonhomeostatic host response to infection, the potential lethality that is considerably in excess of a straightforward infection, and the need for urgent recognition. • As described later, even a modest degree of organ dysfunction when infection is first suspected is associated with an in-hospital mortality in excess of 10%. • Recognition of this condition thus merits a prompt and appropriate response.
  27. 27. Box 3. New Terms and Definitions • Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. • Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points consequent to the infection. • The baseline SOFA score can be assumed to be zero in patients not known to have preexisting organ dysfunction. • A SOFA score ≥2 reflects an overall mortality risk of approximately 10% in a general hospital population with suspected infection. Even patients presenting with modest dysfunction can deteriorate further, emphasizing the seriousness of this condition and the need for prompt and appropriate intervention, if not already being instituted. • In lay terms, sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs. • Patients with suspected infection who are likely to have a prolonged ICU stay or to die in the hospital can be promptly identified at the bedside with qSOFA, ie, alteration in mental status, systolic blood pressure ≤100 mm Hg, or respiratory rate ≥22/min. • Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. • Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate level >2 mmol/L (18 mg/dL) despite adequate volume resuscitation. With these criteria, hospital mortality is in excess of 40%. • Abbreviations: MAP, mean arterial pressure; qSOFA, quick SOFA; SOFA: Sequential [Sepsis-related] Organ Failure Assessment.
  28. 28. Clinical Criteria to Identify Patients With Sepsis • SIRS: pyrexia or neutrophilia to aid in the diagnosis of infection. • Specific infections: rash, lung consolidation, dysuria, peritonitis that focus attention toward the anatomical source and infecting organism. • SIRS reflect an appropriate host response. • Sepsis involves organ dysfunction, indicating a pathobiology more complex than infection plus an inflammatory response alone. • The life-threatening organ dysfunction is consistent with cellular defects underlie physiologic and biochemical abnormalities within specific organ systems. • Sepsis warrant greater levels of monitoring and intervention, including possible admission to ICU or HDU.
  29. 29. Clinical Criteria to Identify Patients With Sepsis • The task force recognized that no current clinical measures reflect the concept of a dysregulated host response. • However, as noted by the 2001 task force, many bedside examination findings and routine laboratory test results are indicative of inflammation or organ dysfunction.10 • The task force therefore evaluated which clinical criteria best identified infected patients most likely to have sepsis. • This objective was achieved by interrogating large data sets of hospitalized patients with presumed infection, assessing agreement among existing scores of inflammation (SIRS)9 or organ dysfunction (eg, SOFA,27,28 Logistic Organ Dysfunction System30) (construct validity), and delineating their correlation with subsequent outcomes (predictive validity). • In addition, multivariable regression was used to explore the performance of 21 bedside and laboratory criteria proposed by the 2001 task force.10
  30. 30. Clinical Criteria to Identify Patients With Sepsis • Full details are found in the accompanying article by Seymour et al.12 In brief, electronic health record data of 1.3 million encounters at 12 community and academic hospitals within the University of Pittsburgh Medical Center health system in southwestern Pennsylvania were studied. • There were 148 907 patients with suspected infection, identified as those who had body fluids sampled for culture and received antibiotics. • Two outcomes—hospital mortality and mortality, ICU stay of 3 days or longer, or both—were used to assess predictive validity both overall and across deciles of baseline risk as determined by age, sex, and comorbidity. • For infected patients both inside and outside of the ICU, predictive validity was determined with 2 metrics for each criterion: the area under the receiver operating characteristic curve (AUROC) and the change in outcomes comparing patients with a score of either 2 points or more or fewer than 2 points in the different scoring systems9,27,30 across deciles of baseline risk.
  31. 31. Clinical Criteria to Identify Patients With Sepsis • These criteria were also analyzed in 4 external US and non-US data sets containing data from more than 700 000 patients (cared for in both community and tertiary care facilities) with both community- and hospital- acquired infection. • In ICU patients with suspected infection in the University of Pittsburgh Medical Center data set, discrimination for hospital mortality with SOFA (AUROC = 0.74; 95% CI, 0.73-0.76) and the Logistic Organ Dysfunction System (AUROC = 0.75; 95% CI, 0.72-0.76) was superior to that with SIRS (AUROC = 0.64; 95% CI, 0.62-0.66). • The predictive validity of a change in SOFA score of 2 or greater was similar (AUROC = 0.72; 95% CI, 0.70-0.73). • For patients outside the ICU and with suspected infection, discrimination of hospital mortality with SOFA (AUROC = 0.79; 95% CI, 0.78-0.80) or change in SOFA score (AUROC = 0.79; 95% CI, 0.78-0.79) was similar to that with SIRS (AUROC = 0.76; 95% CI, 0.75-0.77).
  32. 32. SOFA • Because SOFA is better known and simpler than the Logistic Organ Dysfunction System, the task force recommends using a change in baseline of the total SOFA score of 2 points or more to represent organ dysfunction (Box 3). • The baseline SOFA score should be assumed to be zero unless the patient is known to have preexisting (acute or chronic) organ dysfunction before the onset of infection. • Patients with a SOFA score of 2 or more had an overall mortality risk of approximately 10% in a general hospital population with presumed infection.12 • This is greater than the overall mortality rate of 8.1% for ST-segment elevation myocardial infarction,31 a condition widely held to be life threatening by the community and by clinicians. • Depending on a patient’s baseline level of risk, a SOFA score of 2 or greater identified a 2- to 25-fold increased risk of dying compared
  33. 33. the SOFA score • As discussed later, the SOFA score is not intended to be used as a tool for patient management but as a means to clinically characterize a septic patient. • Components of SOFA (such as creatinine or bilirubin level) require laboratory testing and thus may not promptly capture dysfunction in individual organ systems. • Other elements, such as the cardiovascular score, can be affected by iatrogenic interventions. • However, SOFA has widespread familiarity within the critical care community and a well- validated relationship to mortality risk. It can be scored retrospectively, either manually or by automated systems, from clinical and laboratory measures often performed routinely as part of acute patient management. • The task force noted that there are a number of novel biomarkers that can identify renal and hepatic dysfunction or coagulopathy earlier than the elements used in SOFA, but these require broader validation before they can be incorporated into the clinical criteria describing sepsis. • Future iterations of the sepsis definitions should include an updated SOFA score with more optimal variable selection, cutoff values, and weighting, or a superior scoring system.
  34. 34. Screening for Patients Likely to Have Sepsis • A parsimonious clinical model developed with multivariable logistic regression identified that any 2 of 3 clinical variables—Glasgow Coma Scale score of 13 or less, systolic blood pressure of 100 mm Hg or less, and respiratory rate 22/min or greater—offered predictive validity (AUROC = 0.81; 95% CI, 0.80-0.82) similar to that of the full SOFA score outside the ICU.12 • This model was robust to multiple sensitivity analyses including a more simple assessment of altered mentation (Glasgow Coma Scale score <15) and in the out-of-hospital, emergency department, and ward settings within the external US and non-US data sets. • For patients with suspected infection within the ICU, the SOFA score had predictive validity (AUROC = 0.74; 95% CI, 0.73-0.76) superior to that of this model (AUROC = 0.66; 95% CI, 0.64-0.68), likely reflecting the modifying effects of interventions (eg, vasopressors, sedative agents, mechanical ventilation). Addition of lactate measurement did not meaningfully improve predictive validity but may help identify patients at intermediate risk.
  35. 35. This new measure, termed qSOFA (for quick SOFA) • This new measure, termed qSOFA (for quick SOFA) and incorporating altered mentation, systolic blood pressure of 100 mm Hg or less, and respiratory rate of 22/min or greater, provides simple bedside criteria to identify adult patients with suspected infection who are likely to have poor outcomes (Box 4). • Because predictive validity was unchanged (P = .55), the task force chose to emphasize altered mentation because it represents any Glasgow Coma Scale score less than 15 and will reduce the measurement burden. • Although qSOFA is less robust than a SOFA score of 2 or greater in the ICU, it does not require laboratory tests and can be assessed quickly and repeatedly. • The task force suggests that qSOFA criteria be used to prompt clinicians to further investigate for organ dysfunction, to initiate or escalate therapy as appropriate, and to consider referral to critical care or increase the frequency of monitoring, if such actions have not already been undertaken. • The task force considered that positive qSOFA criteria should also prompt consideration of possible infection in patients not previously recognized as infected.
  36. 36. Box 4. qSOFA (Quick SOFA) Criteria • RR ≥22/min • Altered Mentation • SABP ≤100 mm Hg
  37. 37. Definition of Septic Shock • Septic shock is defined as a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality (Box 3). • Septic shock: “a state of acute circulatory failure.” • A view to differentiate septic shock from cardiovascular dysfunction alone and to recognize the importance of cellular abnormalities (Box 3). • Septic shock reflect a more severe illness with a much higher of death than sepsis alone.
  38. 38. Definition of Septic Shock • Clinical Criteria to Identify Septic Shock • Further details are provided in the accompanying article by Shankar-Hari et al.13 First, a systematic review assessed how current definitions were operationalized. • This informed a Delphi process conducted among the task force members to determine the updated septic shock definition and clinical criteria. • This process was iterative and informed by interrogation of databases, as summarized below.
  39. 39. Definition of Septic Shock • The Delphi process assessed agreements on descriptions of terms such as “hypotension,” “need for vasopressor therapy,” “raised lactate,” and “adequate fluid resuscitation” for inclusion within the new clinical criteria. • The majority (n = 14/17; 82.4%) of task force members voting on this agreed that hypotension should be denoted as a mean arterial pressure less than 65 mm Hg according to the pragmatic decision that this was most often recorded in data sets derived from patients with sepsis. • Systolic blood pressure was used as a qSOFA criterion because it was most widely recorded in the electronic health record data sets.
  40. 40. Definition of Septic Shock • An elevated lactate level is reflective of cellular dysfunction in sepsis, albeit multiple factors, such as insufficient tissue oxygen delivery, impaired aerobic respiration, accelerated aerobic glycolysis, and reduced hepatic clearance, also contribute. • Hyperlactatemia a marker of illness severity, with higher levels predictive of higher mortality. • Criteria for “adequate fluid resuscitation” or “need for vasopressor therapy” relying on variable monitoring modalities and hemodynamic targets for treatment. • Sedation and volume status assessment also potential confounders in the hypotension-vasopressor relationship.
  41. 41. By Delphi Consensus Process • By Delphi consensus process, 3 variables were identified (hypotension, elevated lactate level, and a sustained need for vasopressor therapy) to test in cohort studies, exploring alternative combinations and different lactate thresholds. • The first database interrogated was the Surviving Sepsis Campaign’s international multicenter registry of 28 150 infected patients with at least 2 SIRS criteria and at least 1 organ dysfunction criterion. • Hypotension was defined as a mean arterial pressure less than 65 mm Hg, the only available cutoff. • A total of 18 840 patients with vasopressor therapy, hypotension, or hyperlactatemia (>2 mmol/L [18 mg/dL]) after volume resuscitation were identified. • Patients with fluid-resistant hypotension requiring vasopressors and with hyperlactatemia were used as the referent group for comparing between-group differences in the risk-adjusted odds ratio for mortality. • Risk adjustment was performed with a generalized estimating equation population- averaged logistic regression model with exchangeable correlation structure.
  42. 42. Delphi Consensus • Risk-adjusted hospital mortality was significantly higher (P < .001 compared with the referent group) in patients with fluid-resistant hypotension requiring vasopressors and hyperlactatemia (42.3% and 49.7% at thresholds for serum lactate level of >2 mmol/L [18 mg/dL] or >4 mmol/L [36 mg/dL], respectively) compared with either hyperlactatemia alone (25.7% and 29.9% mortality for those with serum lactate level of >2 mmol/L [18 mg/dL] and >4 mmol/L [36 mg/dL], respectively) or with fluid- resistant hypotension requiring vasopressors but with lactate level of 2 mmol/L (18 mg/dL) or less (30.1%).
  43. 43. Delphi Consensus • With the same 3 variables and similar categorization, the unadjusted mortality in infected patients within 2 unrelated large electronic health record data sets (University of Pittsburgh Medical Center [12 hospitals; 2010-2012; n = 5984] and Kaiser Permanente Northern California [20 hospitals; 2009- 2013; n = 54 135]) showed reproducible results. • The combination of hypotension, vasopressor use, and lactate level greater than 2 mmol/L (18 mg/dL) identified patients with mortality rates of 54% at University of Pittsburgh Medical Center (n = 315) and 35% at Kaiser Permanente Northern California (n = 8051). • These rates were higher than the mortality rates of 25.2% (n = 147) and 18.8% (n = 3094) in patients with hypotension alone, 17.9% (n = 1978) and 6.8% (n = 30 209) in patients with lactate level greater than 2 mmol/L (18 mg/dL) alone, and 20% (n = 5984) and 8% (n = 54 135) in patients with sepsis at University of Pittsburgh Medical Center and Kaiser Permanente Northern California, respectively.
  44. 44. Delphi Consensus • The task force recognized that serum lactate measurements are commonly, but not universally, available, especially in developing countries. • Nonetheless, clinical criteria for septic shock were developed with hypotension and hyperlactatemia rather than either alone because the combination encompasses both cellular dysfunction and cardiovascular compromise and is associated with a significantly higher risk-adjusted mortality. • This proposal was approved by a majority (13/18; 72.2%) of voting members13 but warrants revisiting. • The Controversies and Limitations section below provides further discussion about the inclusion of both parameters and options for when lactate level cannot be measured.
  45. 45. RECOMMENDATIONS FOR ICD CODING AND FOR LAY DEFINITIONS • In accordance with the importance of accurately applying diagnostic codes, Table 2 details how the new sepsis and septic shock clinical criteria correlate with ICD-9-CM and ICD-10 codes. • The task force also endorsed the recently published lay definition that “sepsis is a life-threatening condition that arises when the body’s response to infection injures its own tissues,” which is consistent with the newly proposed definitions described above.35 • To transmit the importance of sepsis to the public at large, the task force emphasizes that sepsis may portend death, especially if not recognized early and treated promptly. • Indeed, despite advances that include vaccines, antibiotics, and acute care, sepsis remains the primary cause of death from infection. • Widespread educational campaigns are recommended to better inform the public about this lethal condition.
  46. 46. CONTROVERSIES AND LIMITATIONS There are inherent challenges in defining sepsis and septic shock. First and foremost, sepsis is a broad term applied to an incompletely understood process. There are, as yet, no simple and unambiguous clinical criteria or biological, imaging, or laboratory features that uniquely identify a septic patient. The task force recognized the impossibility of trying to achieve total consensus on all points. Pragmatic compromises were necessary, so emphasis was placed on generalizability and the use of readily measurable identifiers that could best capture the current conceptualization of underlying mechanisms. The detailed, data-guided deliberations of the task force during an 18-month period and the peer review provided by bodies approached for endorsement highlighted multiple areas for discussion. It is useful to identify these issues and provide justifications for the final positions adopted.
  47. 47. CONTROVERSIES AND LIMITATIONS • The new definition of sepsis reflects an up-to-date view of pathobiology, particularly in regard to what distinguishes sepsis from uncomplicated infection. • The task force also offers easily measurable clinical criteria that capture the essence of sepsis yet can be translated and recorded objectively (Figure). • Although these criteria cannot be all-encompassing, they are simple to use and offer consistency of terminology to clinical practitioners, researchers, administrators, and funders. • The physiologic and biochemical tests required to score SOFA are often included in routine patient care, and scoring can be performed retrospectively.
  48. 48. Figure. • Operationalization of Clinical Criteria Identifying Patients With Sepsis and Septic Shock • The baseline Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score should be assumed to be zero unless the patient is known to have preexisting (acute or chronic) organ dysfunction before the onset of infection. • qSOFA indicates quick SOFA; • MAP, mean arterial pressure.
  49. 49. The initial, retrospective analysis indicated that qSOFA could be a useful clinical tool… • The initial, retrospective analysis indicated that qSOFA could be a useful clinical tool, especially to physicians and other practitioners working outside the ICU (and perhaps even outside the hospital, given that qSOFA relies only on clinical examination findings), to promptly identify infected patients likely to fare poorly. • However, because most of the data were extracted from extracted US databases, the task force strongly encourages prospective validation in multiple US and non-US health care settings to confirm its robustness and potential for incorporation into future iterations of the definitions. • This simple bedside score may be particularly relevant in resource- poor settings in which laboratory data are not readily available, and when the literature about sepsis epidemiology is sparse.
  50. 50. qSOFA • Neither qSOFA nor SOFA is intended to be a stand-alone definition of sepsis. • It is crucial, however, that failure to meet 2 or more qSOFA or SOFA criteria should not lead to a deferral of investigation or treatment of infection or to a delay in any other aspect of care deemed necessary by the practitioners. • qSOFA can be rapidly scored at the bedside without the need for blood tests, and it is hoped that it will facilitate prompt identification of an infection that poses a greater threat to life. If appropriate laboratory tests have not already been undertaken, this may prompt testing to identify biochemical organ dysfunction. • These data will primarily aid patient management but will also enable subsequent SOFA scoring. • The task force wishes to stress that SIRS criteria may still remain useful for the identification of infection. • Some have argued that lactate measurement should be mandated as an important biochemical identifier of sepsis in an infected patient. • Because lactate measurement offered no meaningful change in the predictive validity beyond 2 or more qSOFA criteria in the identification of patients likely to be septic, the task force could not justify the added complexity and cost of lactate measurement alongside these simple bedside criteria. • The task force recommendations should not, however, constrain the monitoring of lactate as a guide to therapeutic response or as an indicator of illness severity.
  51. 51. qSOFA • Our approach to hyperlactatemia within the clinical criteria for septic shock also generated conflicting views. • Some task force members suggested that elevated lactate levels represent an important marker of “cryptic shock” in the absence of hypotension. • Others voiced concern about its specificity and that the nonavailability of lactate measurement in resource-poor settings would preclude a diagnosis of septic shock. • No solution can satisfy all concerns. • Lactate level is a sensitive, albeit nonspecific, stand-alone indicator of cellular or metabolic stress rather than “shock.”32 • However, the combination of hyperlactatemia with fluid-resistant hypotension identifies a group with particularly high mortality and thus offers a more robust identifier of the physiologic and epidemiologic concept of septic shock than either criterion alone. • Identification of septic shock as a distinct entity is of epidemiologic rather than clinical importance.
  52. 52. qSOFA • Although hyperlactatemia and hypotension are clinically concerning as separate entities, and although the proposed criteria differ from those of other recent consensus statements,34 clinical management should not be affected. • The greater precision offered by data-driven analysis will improve reporting of both the incidence of septic shock and the associated mortality, in which current figures vary 4-fold.3 • The criteria may also enhance insight into the pathobiology of sepsis and septic shock. In settings in which lactate measurement is not available, the use of a working diagnosis of septic shock using hypotension and other criteria consistent with tissue hypoperfusion (eg, delayed capillary refill36) may be necessary. • The task force focused on adult patients yet recognizes the need to develop similar updated definitions for pediatric populations and the use of clinical criteria that take into account their age-dependent variation in normal physiologic ranges and in pathophysiologic responses.
  53. 53. IMPLICATIONS • The task force has generated new definitions that incorporate an up-to-date understanding of sepsis biology, including organ dysfunction (Box 3). • However, the lack of a criterion standard, similar to its absence in many other syndromic conditions, precludes unambiguous validation and instead requires approximate estimations of performance across a variety of validity domains, as outlined above. • To assist the bedside clinician, and perhaps prompt an escalation of care if not already instituted, simple clinical criteria (qSOFA) that identify patients with suspected infection who are likely to have poor outcomes, that is, a prolonged ICU course and death, have been developed and validated. • This approach has important epidemiologic and investigative implications. • The proposed criteria should aid diagnostic categorization once initial assessment and immediate management are completed. qSOFA or SOFA may at some point be used as entry criteria for clinical trials.
  54. 54. IMPLICATIONS • There is potential conflict with current organ dysfunction scoring systems, early warning scores, ongoing research studies, and pathway developments. • Many of these scores and pathways have been developed by consensus, whereas an important aspect of the current work is the interrogation of data, albeit retrospectively, from large patient populations. • The task force maintains that standardization of definitions and clinical criteria is crucial in ensuring clear communication and a more accurate appreciation of the scale of the problem of sepsis. • An added challenge is that infection is seldom confirmed microbiologically when treatment is started; even when microbiological tests are completed, culture- positive “sepsis” is observed in only 30% to 40% of cases. • Thus, when sepsis epidemiology is assessed and reported, operationalization will necessarily involve proxies such as antibiotic commencement or a clinically determined probability of infection. • Future epidemiology studies should consider reporting the proportion of microbiology-positive sepsis.
  55. 55. IMPLICATIONS • Greater clarity and consistency will also facilitate research and more accurate coding. • Changes to ICD coding may take several years to enact, so the recommendations provided in Table 2 demonstrate how the new definitions can be applied in the interim within the current ICD system. • The debate and discussion that this work will inevitably generate are encouraged. • Aspects of the new definitions do indeed rely on expert opinion; further understanding of the biology of sepsis, the availability of new diagnostic approaches, and enhanced collection of data will fuel their continued reevaluation and revision.
  56. 56. CONCLUSIONS • These updated definitions and clinical criteria should clarify long-used descriptors and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing it. • This process, however, remains a work in progress.
  57. 57. CONCLUSIONS • As is done with software and other coding updates, • the task force recommends that the new definition be designated Sepsis-3, • with the 1991 and 2001 iterations being recognized as Sepsis-1 and Sepsis-2, respectively, • to emphasize the need for future iterations.
  58. 58. ARTICLE INFORMATION • Corresponding Author: Clifford S. Deutschman, MD, MS, Departments of Pediatrics and Molecular Medicine, Hofstra–Northwell School of Medicine, Feinstein Institute for Medical Research, 269-01 76th Ave, New Hyde Park, NY 11040 ( • Author Contributions: Drs Singer and Deutschman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. • Administrative, technical, or material support: Singer, Deutschman, Chiche, Coopersmith, Levy, Angus. • Study supervision: Singer, Deutschman. • Drs Singer and Deutschman are joint first authors. • Disclaimer: Dr Angus, JAMA Associate Editor, had no role in the evaluation of or decision to publish this article. • Endorsing Societies: Academy of Medical Royal Colleges (UK); American Association of Critical Care Nurses; American ThoracicSociety (endorsed August 25, 2015); Australian–New Zealand Intensive Care Society (ANZICS); Asia Pacific Association of Critical Care Medicine; Brasilian Society of Critical Care; Central American and Caribbean Intensive Therapy Consortium; Chinese Society of Critical Care Medicine; Chinese Society of Critical Care Medicine–China Medical Association; Critical Care Society of South Africa; Emirates Intensive Care Society; European Respiratory Society; European Resuscitation Council; European Society of Clinical Microbiology and Infectious Diseases and its Study Group of Bloodstream Infections and Sepsis; European Society of Emergency Medicine; European Society of Intensive Care Medicine; European Society of Paediatric and Neonatal Intensive Care; German Sepsis Society; Indian Society of Critical Care Medicine; International Pan Arabian Critical Care Medicine Society; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Pan American/Pan Iberian Congress of Intensive Care; Red Intensiva (Sociedad Chilena de Medicina Crítica y Urgencias); Sociedad Peruana de Medicina Critica; Shock Society; Sociedad Argentina de Terapia Intensiva; Society of Critical Care Medicine; Surgical Infection Society; World Federation of Pediatric Intensive and Critical Care Societies; World Federation of Critical Care Nurses; World Federation of Societies of Intensive and Critical Care Medicine. • Additional Contributions: The task force would like to thank Frank Brunkhorst, MD, University Hospital Jena, Germany; Theodore J. Iwashyna, MD, PhD, University of Michigan; Vincent Liu, MD, MSc, Kaiser Permanente Northern California; Thomas Rea, MD, MPH, University of Washington; and Gary Phillips, MAS, Ohio State University; for their invaluable assistance, and the administrations and leadership of SCCM and ESICM for facilitating its work. Payment was provided to the Center for Biostatistics, Ohio State University, to support the work of Mr Phillips.
  59. 59. REFERENCES • 1. Torio CM, Andrews RM. National inpatient hospital costs: the most expensive conditions by payer, 2011. Statistical Brief #160. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. August 2013. Accessed October 31, 2015. • 2. Iwashyna TJ, Cooke CR, Wunsch H, Kahn JM. Population burden of long-term survivorship after severe sepsis in older Americans. J Am Geriatr Soc. 2012;60(6):1070-1077. • 3. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41(5):1167-1174. • PubMed | Link to Article • 4. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee Including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637. • 5. Rhee C, Gohil S, Klompas M. Regulatory mandates for sepsis care—reasons for caution. N Engl J Med. 2014;370(18):1673-1676. • PubMed | Link to Article • 6, Vincent J-L, Marshall JC, Namendys-Silva SA, et al; ICON Investigators. Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit. Lancet Respir Med. 2014;2(5):380-386. • PubMed | Link to Article • 7. Fleischmann C, Scherag A, Adhikari NK, et al; International Forum of Acute Care Trialists. Assessment of global incidence and mortality of hospital-treated sepsis: current estimates and limitations. Am J Respir Crit Care Med. 2015. • PubMed • 8. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787-1794. • PubMed | Link to Article • 9. Bone RC, Balk RA, Cerra FB, et al. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20(6):864-874. • PubMed | Link to Article • 10. Levy MM, Fink MP, Marshall JC, et al; International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003;29(4):530-538. • PubMed | Link to Article • 11. Vincent J-L, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change. Lancet. 2013;381(9868):774-775. • PubMed | Link to Article • 12. Seymour CW, Liu V, Iwashyna TJ, et al Assessment of clinical criteria for sepsis. JAMA. doi:10.1001/jama.2016.0288. • 13. Shankar-Hari M, Phillips G, Levy ML, et al Assessment of definition and clinical criteria for septic shock. JAMA.doi:10.1001/jama.2016.0289 • 14. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840-851. • PubMed | Link to Article • 15. Wiersinga WJ, Leopold SJ, Cranendonk DR, van der Poll T. Host innate immune responses to sepsis. Virulence. 2014;5(1):36-44. • PubMed | Link to Article • 16. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862-874. • PubMed | Link to Article • 17. Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity. 2014;40(4):463-475. • PubMed | Link to Article • 18. Singer M, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet. 2004;364(9433):545-548. • PubMed | Link to Article • 19. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27(7):1230-1251. • PubMed | Link to Article • 20. Kwan A, Hubank M, Rashid A, Klein N, Peters MJ. Transcriptional instability during evolving sepsis may limit biomarker based risk stratification. PLoS One. 2013;8(3):e60501. • PubMed | Link to Article
  60. 60. REFERENCES • 21. Iskander KN, Osuchowski MF, Stearns-Kurosawa DJ, et al. Sepsis: multiple abnormalities, heterogeneous responses, and evolving understanding. Physiol Rev. 2013;93(3):1247-1288. • PubMed | Link to Article • 22. Wong HR, Cvijanovich NZ, Anas N, et al. Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med. 2015;191(3):309-315. • PubMed | Link to Article • 23. Langley RJ, Tsalik EL, van Velkinburgh JC, et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med. 2013;5(195):195ra95. • PubMed | Link to Article • 24. Chan JK, Roth J, Oppenheim JJ, et al. Alarmins: awaiting a clinical response. J Clin Invest. 2012;122(8):2711-2719. • PubMed | Link to Article • 25. Churpek MM, Zadravecz FJ, Winslow C, Howell MD, Edelson DP. Incidence and prognostic value of the systemic inflammatory response syndrome and organ dysfunctions in ward patients. Am J Respir Crit Care Med. 2015;192(8):958-964. • PubMed | Link to Article • 26. Kaukonen K-M, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372(17):1629-1638. • PubMed | Link to Article • 27. Vincent JL, Moreno R, Takala J, et al; Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med. 1996;22(7):707-710. • PubMed | Link to Article • 28. Vincent JL, de Mendonça A, Cantraine F, et al; Working Group on “Sepsis-Related Problems” of the European Society of Intensive Care Medicine. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Crit Care Med. 1998;26(11):1793-1800. • PubMed | Link to Article • 29. Rubulotta FM, Ramsay G, Parker MM, Dellinger RP, Levy MM, Poeze M; Surviving Sepsis Campaign Steering Committee; European Society of Intensive Care Medicine; Society of Critical Care Medicine. An international survey: public awareness and perception of sepsis. Crit Care Med. 2009;37(1):167-170. • PubMed | Link to Article • 30. Le Gall J-R, Klar J, Lemeshow S, et al; ICU Scoring Group. The Logistic Organ Dysfunction system: a new way to assess organ dysfunction in the intensive care unit. JAMA. 1996;276(10):802-810. • PubMed | Link to Article • 31. Shah RU, Henry TD, Rutten-Ramos S, Garberich RF, Tighiouart M, Bairey Merz CN. Increasing percutaneous coronary interventions for ST-segment elevation myocardial infarction in the United States: progress and opportunity. JACC Cardiovasc Interv. 2015;8(1 pt B):139-146. • PubMed | Link to Article • 32. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371(24):2309-2319. • PubMed | Link to Article • 33. Casserly B, Phillips GS, Schorr C, et al. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med. 2015;43(3):567-573. • PubMed | Link to Article • 34. Cecconi M, De Backer D, Antonelli M, et al. Consensus on circulatory shock and hemodynamic monitoring. Task Force of the European Society of Intensive Care Medicine. Intensive Care Med. 2014;40(12):1795-1815. • PubMed | Link to Article • 35. Czura CJ. “Merinoff symposium 2010: sepsis”—speaking with one voice. Mol Med. 2011;17(1-2):2-3. • PubMed | Link to Article • 36. Ait-Oufella H, Bige N, Boelle PY, et al. Capillary refill time exploration during septic shock. Intensive Care Med. 2014;40(7):958-964. • PubMed | Link to Article
  61. 61. A fluid therapy in sepsis • P. Marik,* and R. Bellomo • * Corresponding author: • E-mail: • Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, 825 Fairfax Av, Suite 410, Norfolk, VA 23507, USA • 2 ICU, Austin Health, Heidelberg, Victoria, Australia
  62. 62. A fluid therapy in sepsis • Aggressive fluid resuscitation to achieve a CVP > 8 mm Hg - the standard of care, in the management of pts with severe sepsis and septic shock. • Improve the outcome of pts with severe sepsis and septic shock.
  63. 63. A fluid therapy in sepsis • Pathophysiologically, sepsis is characterized by: • vasoplegia with loss of arterial tone, • venodilation with sequestration of blood in the unstressed blood compartment and • changes in ventricular function with • reduced compliance and • reduced preload responsiveness.
  64. 64. A fluid therapy in sepsis • Sepsis not a volume-depleted state • Most septic pts are poorly responsive to fluids • All of the IV fluids is sequestered in the tissues • resulting in severe oedema in vital organs • increasing the risk of organ dysfunction. • A haemodynamically guided approach to fluid therapy in pts with sepsis prudent • reduce the morbidity • improve the outcome of this disease
  65. 65. Editor's key points • The physiology of hypo-and hypervolaemia • The effects of venodilation and arteriodilation • Aggressive IV fluid in septic shock carries risk • Haemodynamically-guided approach to produce better outcome. • Early Norepinephrine therapy to improve outcome.
  66. 66. Sepsis • In the 19th century, pts with cholera dying from hypovolaemic shock were treated by venesection or blood-letting. • The standard of care for this disorder. • In the 21st century pts with septic shock were treated with crystalloids >17 L in the first 72 hrs.
  67. 67. Sepsis • This approach was considered the standard of care. • These treatment approaches failed to appreciate the pathophysiological changes of both disorders • The prescribed treatments were harmful. • Cholera: associated with volume depletion through diarrhoea and requires replacement with i.v. fluids. • Severe sepsis & Septic shock are not associated with volume loss.
  68. 68. Sepsis • Arterio- and venodilation together with • Microcirculatory and myocardial dysfunction, with • Septic pts poorly responsive to fluid administration.
  69. 69. Sepsis • Aggressive fluid resuscitation to achieve a CVP greater than 8 mm Hg; • (‘Early Goal Directed Therapy’ - EGDT); • The standard of care in the management of pts with severe sepsis and septic shock.
  70. 70. Sepsis • ProCESS, ARISE, PROMISE and a meta-analysis of EGDT does not improve the outcome of pts. with SS and SSH. • A reviews the haemodynamic changes associated with sepsis and a rational approach to fluid management in this complex disorder.
  71. 71. Pertinent normal cardiovascular physiology • The amount of blood pumped out of the heart (cardiac output) is equivalent to venous return (volume entering the right atrium). • According to Guyton, venous return is determined by the pressure gradient between the peripheral veins and the right atrium (CVP). • The venous system can be divided into two theoretical compartments, the unstressed and stressed volume.
  72. 72. Pertinent normal cardiovascular physiology • The intravascular volume that fills the venous system to the point where intravascular pressure starts to increase is called unstressed volume, whereas the volume that stretches the veins and causes intravascular pressure to increase is called the stressed volume.
  73. 73. Pertinent normal cardiovascular physiology • The mean circulatory filling pressure (MCFP) is conceptualized as the pressure distending the vasculature, when the heart is stopped (zero flow) and the pressures in all segments of the circulatory system have equalized. • The stressed venous system is the major contributor to the MCFP. • The MCFP in humans is normally in the range of 8–l0 mm Hg. • The MCFP is the major determinant of venous return.
  74. 74. Pertinent normal cardiovascular physiology • The venous system has a large vascular capacitance and a constant compliance in which an increased blood volume is associated with a relatively small change in the MCFP.14 • However, because of the restraining effects of the pericardium and cardiac cytoskeleton, the diastolic compliance of the normal heart (both left and right ventricles) reduces as distending volume increases; consequently, with large volume fluid resuscitation, the cardiac filling pressures (particularly on the right side, i.e. CVP) increase faster than the MCFP, decreasing the gradient for venous return.16–18
  75. 75. Pertinent normal cardiovascular physiology • Organ blood flow is determined by the difference in the pressure between the arterial and venous sides of the circulation. • The mean arterial pressure (MAP) minus the CVP is therefore the overall driving force for organ blood flow. • A high CVP therefore decreases the gradient for venous return, while at the same time decreasing organ driving pressure and therefore blood flow. • Venous pressure has a much greater effect on microcirculatory flow than the MAP; provided that the MAP is within an organ's autoregulatory range, the CVP becomes the major determinant of capillary blood flow.19,20
  76. 76. Pertinent normal cardiovascular physiology • According to the Frank-Starling principle, as left-ventricular (LV) end-diastolic volume (i.e. preload) increases, LV stroke volume (SV) increases until the optimal preload is achieved, at which point the SV remains relatively constant.21 • This optimal preload is related to the maximal overlap of the actin-myosin myofibrils. • Fluid administration will only increase SV if two conditions are met, namely: i) that the fluid bolus increases the MCFP more than it increases the CVP, thereby increasing the gradient for venous return, and ii) that both ventricles are functioning on the ‘ascending limb’ of the Frank-Starling curve.22,23
  77. 77. Pertinent normal cardiovascular physiology • The vascular endothelium is coated on the luminal side by a web of membrane-bound glycoproteins and proteoglycans known as the endothelial glycocalyx.24– 26 • The glycocalyx plays a major role as a vascular barrier, preventing large macromolecules moving across the endothelium, preventing leucocyte and platelet aggregation and limiting tissue oedema. • An intact endothelial glycocalyx is a prerequisite of a functioning vascular barrier.27
  78. 78. Pertinent normal cardiovascular physiology • Increased cardiac filling pressures after aggressive fluid resuscitation increase the release of natriuretic peptides.28,29 • Natriuretic peptides cleave membrane-bound proteoglycans and glycoproteins (most notably syndecan-1 and hyaluronic acid) off the endothelial glycocalyx.30–32 • Damage to the glycocalyx profoundly increases endothelial permeability. • In addition, increased natriuretic peptides inhibit the lymphatic propulsive motor activity reducing lymphatic drainage.33–35
  79. 79. Vascular dysfunction with sepsis • Septic shock is primarily a vasoplegic state with arterial and venous dilatation, as a result of failure of the vascular smooth muscle to constrict.36 • Vasoplegic shock is believed to be because of increased expression of inducible nitric oxide synthetase with increased production of nitric oxide (NO), activation of KATP channels resulting in hyperpolarisation of the muscle cell membrane, increased production of natriuretic peptides (which act synergistically with NO) and a relative vasopressin deficiency.36
  80. 80. Vascular dysfunction with sepsis • Arterial dilatation results in systemic hypotension. • However, more importantly, profound venodilation occurs in the splanchnic and cutaneous vascular beds increasing the unstressed blood volume, decreasing venous return and cardiac output.14,15 • As approximately 70% of the blood volume is within the venous system, changes in venous blood volume play a major role in determining venous return.15
  81. 81. Vascular dysfunction with sepsis • Sepsis is characterized by increased expression and activation of endothelial adhesion molecules with adhesion and activation of platelets, leucocytes and mononuclear cells and activation of the coagulation cascade.37 • This results in a diffuse endothelial injury, microvascular thrombosis, gaps between the endothelial cells (paracellular leak) and shedding of the endothelial-glycocalyx.38,39 • The combination of these mechanisms contributes to a reduction in functional capillary density, heterogeneous abnormalities in microcirculatory blood flow and increased capillary permeability.40,41
  82. 82. Cardiac changes with sepsis • Myocardial depression in patients with septic shock was first described in 1984 by Parker and colleagues42 using radionuclide cineangiography. • In a series of 20 patients, these investigators reported a 50% incidence of LV systolic dysfunction. • Notably, in this study the initial ejection fraction and ventricular volumes were normal in non-survivors and these indices did not change during serial studies; it is likely that these patients had significant diastolic dysfunction. • The initial studies evaluating cardiac function in sepsis focused on LV systolic function. • However, LV diastolic dysfunction has emerged as a common finding in patients with severe sepsis and septic shock.43
  83. 83. Cardiac changes with sepsis • Adequate filling during diastole is a crucial component of effective ventricular pump function. • Diastolic dysfunction refers to the presence of an abnormal LV diastolic distensibility, filling, or relaxation, regardless of LV ejection fraction. • Predominant diastolic dysfunction appears to be at least twice as common as systolic dysfunction in patients with sepsis.43 • In the largest study to date (n=262), Landesberg and colleagues44 reported diastolic dysfunction in 54% of patients with sepsis while 23% of patients had systolic dysfunction. • Brown and colleagues45 performed serial echocardiograms in 78 patients with severe sepsis or septic shock. In this study 62% of patients had diastolic dysfunction on at least one echocardiogram.
  84. 84. Cardiac changes with sepsis • Unlike systolic LV dysfunction, diastolic dysfunction is an important prognostic marker in patients with sepsis.43–45 • Diastolic dysfunction is becoming increasing recognized in the community, particularly in patients with hypertension, diabetes, obesity and with advancing age.46–48 • These conditions are associated with an increased risk of sepsis and may therefore further increase the prevalence and severity of diastolic dysfunction in patients with sepsis. • Patients' with diastolic dysfunction respond very poorly to fluid loading.44
  85. 85. Cardiac changes with sepsis • This was demonstrated in a landmark study published by Ognibene and colleagues49 in 1988, who reported an insignificant increase LV stroke work index and LV end-diastolic volume index in patients with septic shock who received a fluid challenge. • In these patients, fluid loading will increase cardiac filling pressures, increase venous and pulmonary hydrostatic pressures with the increased release of natriuretic peptides with minimal (if any) increase in SV. • Furthermore, as reviewed above, aggressive fluid resuscitation in itself causes diastolic dysfunction which will compound the pre- existing and/or sepsis-induced diastolic dysfunction.
  86. 86. Fluid responsiveness • A rationale behind fluid resuscitation in SS is to improve CO and organ perfusion, thereby limiting organ dysfunction. • The only reason to resuscitate a pt. with fluid (give a fluid bolus) would be to cause a clinically significant increase in SV. • A patient whose SV increases by 10–15% after a fluid challenge (250–500 ml) is considered to be a fluid responder.
  87. 87. Fluid responsiveness • According to the Frank-Starling principle, as the preload increases, • SV increases until the optimal preload is achieved, • At which point the SV remains relatively constant. • If the fluid challenge does not increase SV, • volume loading serves the pt no useful benefit and • It is likely harmful.
  88. 88. Fluid responsiveness • The adverse effects of fluid loading when a patient is on the flat portion of the Frank-Starling curve, is related to the curvilinear shape of the left ventricular pressure-volume curve, resulting from altered diastolic compliance at higher filing pressures.16–18 • As the patient reaches the plateau of his/her Frank-Starling curve, atrial pressures increase, increasing venous and pulmonary hydrostatic pressures which combined with the increased release of natriuretic peptides, causes a shift of fluid into the interstitial space, with an increase in pulmonary and tissue oedema (see Fig. 1).
  89. 89. Fluid responsiveness • Tissue oedema impairs oxygen and metabolite diffusion, distorts tissue architecture, impedes capillary blood flow and lymphatic drainage and disturbs cell-cell interactions. • Increased right atrial pressure (CVP) is transmitted backwards increasing venous pressure in vital organs, with
  90. 90. Fluid responsiveness • A profound effect on microcirculatory flow and organ function. • The kidney is particularly affected by increased venous pressure, which • Leads to increased renal subcapsular pressure and • Reduced renal blood flow and • Glomerular filtration rate.
  91. 91. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • Only about 50% of haemodynamically unstable patients are fluid responders.
  92. 92. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • A fundamental concept: the fluid administration is the ‘cornerstone of resuscitation’. • The effects of sepsis on the venous capacitance vessels and myocardial function; • Less than 40% of hypotensive pts with SS or SSH are ‘fluid responders’.
  93. 93. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • The goal of fluid resuscitation is to increase the stressed blood volume and MCFP more than the CVP, and • Thereby increase the pressure gradient for venous return. • The ability of crystalloids (fluids used for the resuscitation of pts with SS) to expand the intravascular volume is poor. • In pts, only 15% of a crystalloid bolus remained in the intravascular space at 3 h, with • 50% of the infused volume being in the extravascular extracellular compartment. • In pts with SS & SSH less than 5% of a crystalloid bolus remains intravascular an 1 hour after the end of the infusion. • The haemodynamic effects of a fluid bolus (in the fluid responders) are short- lived, with the net effect being the shift of fluid into the interstitial compartment with tissue oedema.
  94. 94. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • In fluid responders, the SV returned to baseline 60 min after a crystalloid bolus. • The haemodynamic response of fluid boluses in pts with SS. • MAP increased by 7.8 (3.8) mm Hg immediately after the fluid bolus; • MAP had returned close to baseline at 1 h with no increase in U/O. • ARDSnet Fluid and Catheter Treatment Trial (FACTT) • The physiological effect of 569 fluid boluses (15 ml/kg; 1025±243 ml) in 127 pts SS & SSH with the pulmonary artery catheter arm of the study.
  95. 95. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • FACTT: reassessment of the haemodynamic profile 1 h after the fluid bolus; • if the indication for fluids was SSH, ineffective circulation, or low U/O and 4 hrs. if the indication was a low pulmonary artery occlusion pressure (PAOP). • 58 % of fluid boluses were given for SSH or poor U/O & ineffective circulation, with • 42% of boluses given for a low PAOP. • 23% of pts: fluid responders (increase in CI > 15%). • Increase in the MAP (78.3 16.4 to 80.4 16.5 mm Hg) while • U/O did not change in the 1–4 h after the fluid bolus.
  96. 96. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • Measurement the effects of a fluid bolus on arterial load in pts with SSH shows: • 67% of pts were fluid responders; • MAP increase only 44% of pts (pressure responder). • A reduction in effective arterial elastance (Ea) and systemic vascular resistance (SVR), • This effect most marked in the pre-load responders who were pressure non-responders.
  97. 97. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • A decrease in SVR after fluid resuscitation in pts with SS & SSH. • This suggests that fluid boluses considered vasodilator therapy, in pts with SS and that • An aggressive fluid resuscitation potentiate the hyperdynamic state.
  98. 98. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • The majority of pts with SS&SSH not fluid responders. • The haemodynamic changes in the fluid responders are small, short-lived and clinically insignificant. • Aggressive fluid resuscitation have adverse haemodynamic consequences including: • An increase in cardiac filling pressures, • Damage to the endothelial glycocalyx, • Arterial vasodilation and • Tissue oedema.
  99. 99. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • The concept that aggressive fluid resuscitation is the ‘cornerstone of resuscitation’ of pts with SS and SSH needs to be reconsidered. • An aggressive fluid resuscitation increases the morbidly and mortality of pts with SS.
  100. 100. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • IV ‘30 ml/kg crystalloids for hypotension or lactate ≥4 mmol/L’ within 3 h of presentation to hospital. • The majority of hypotensive pts with SS will not respond to fluids; • ” Salt water drowning’ with an increase in the morbidity and mortality of these pts ”.
  101. 101. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • An increased blood lactate unlikely associated with anaerobic metabolism; • 0r inadequate 02 delivery, attempts at increasing 02 delivery do not increase 02 consumption or lower lactate concentrations. • Indeed such an approach to increase the risk of death of critically ill ICU pts.
  102. 102. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • Only pts who are fluid responsive should treated with fluid boluses. • Pts' fluid responsiveness and the risk/benefit ratio of fluid administration needs to be determined before each fluid bolus. • The haemodynamic response to a fluid challenge is very short; • 20–30 ml/kg associated with severe volume overload • The mini-fluid bolus approach (200–500 ml) to fluid therapy • The passive leg raising manoeuvre (PLR), the fluid bolus test coupled with real-time SV monitoring; • Currently techniques with acceptable degree of clinical accuracy • Used for determining fluid responsiveness.
  103. 103. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • Ease of use, simplicity,accuracy, safety, short procedure time ( < 5 min to perform) • PLR: method to assess fluid responsiveness in ICU. • PLR: performed by lifting the legs passively from the horizontal position associated with the gravitational transfer of blood (~300 ml) from the lower limbs and abdomen toward the intrathoracic compartment. • PLR has the advantage of reversing its effects once the legs are returned to the horizontal position.
  104. 104. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • PLR: a reversible or ‘virtual’ fluid challenge. • PLR: a test of preload responsiveness in critically ill ICU pts. • PLR to predict fluid responsiveness in critically ill pts with ROC curve of 0.95 (95% CI, 0.92–0.95). • In an updated ROC AUC of 0.93–0.95
  105. 105. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • Max. haemodynamic effects of PLR occur within the first min of leg elevation • Assess effects with changes in CO or SV on a real-time basis. • The change in ABP after a PLR or fluid challenge is a poor guide to fluid responsiveness; • SV increase without a change in ABP • Furthermore, unlike techniques to determine fluid responsiveness based on heart-lung interactions, • PLR performed in spontaneously breathing pts, pts with cardiac arrhythmias pts receiving low Tv Ventilation.
  106. 106. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • The Chest Radiograph • CVP • Central Venous Oxygen Saturation (ScvO2) • Ultrasonography • The vena-caval collapsibility index • They have limited value in guiding fluid management and not be used for this purpose.
  107. 107. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • Physical examination cannot be used to predict fluid responsiveness; • Physical examination is unreliable for estimating intravascular volume status.
  108. 108. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • SSCG: • CVP or • ScvO2, or • ECHO, • CV US, • To assess the volume status of the pts SS & SSH • The curve of the CVP, for predicting fluid responsive ~ 0.5 = a ‘completely useless test’.
  109. 109. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • A normal CVP: 0–2 mm Hg; • This is necessary to ensure adequate venous return and CO. • The change in CVP in response to a fluid challenge is a method to guide fluid therapy; • This technique has no physiologic basis • It is unable to predict fluid responsiveness with any degree of accuracy.
  110. 110. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • A measuring dynamic changes in the carotid Doppler peak velocity; • Bedside USS including the IVC distensibility index predict fluid responsiveness. • ScvO2 still to guide the resuscitation of critically ill SS pts and • Used as an indicator of the quality of care delivered.
  111. 111. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • Monitoring the ScvO2 in pts with sepsis • Pts with SS have a normal or increased ScvO2 • A high (ScvO2 > 90%) than low ScvO2 - an independent predictor of death. • ProCESS, ARISE, PROMISE: titrating therapy to a ScvO2 > 70% does not improve outcome, but rather increases the risk of organ dysfunction, length of ICU stay and increased use of resources and costs. • EGDT valid and should be used to guide the management of pts with SS and SSH.
  112. 112. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • To targeting a CVP greater than 8 mm Hg; • “Targeting resuscitation to normalize lactate in pts with elevated lactate levels as a marker of tissue hypoperfusion” • An elevated Lactate is a consequence of tissue hypoxia and inadequate 02 delivery.
  113. 113. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • However, these assertions are likely wrong. • The cellular hypoxia and bioenergetic failure does not occur in sepsis. • Epinephrine released as part of the stress response in pts with SS, stimulates Na+ K+-ATPase activity.
  114. 114. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • Increased activity of Na+ K+ ATPase leads to increased Lactate production under well-oxygenated conditions in various cells, including erythrocytes, vascular smooth muscle, neurons, glia, and skeletal muscle. • Sepsis: a ‘hypermetabolic’ condition 02 consumption and energy expenditure are broadly comparable with that of ICU Pts; • With energy expenditure decreasing with increasing Sepsis severity.
  115. 115. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • No requirement that O2 delivery increase with SS. • Increasing 02 delivery in pts with SS does not increase 02 consumption nor decrease Lactate.
  116. 116. Fluid responsiveness and the haemodynamic effects of fluids in patients with sepsis • The critical O2 delivery for Pts (SS&NoSS) ~ • 3.8 (1.5) ml/min/kg • (270 ml/min in a 70 kg patient) • Values CO of ~ 2 L/min; • Pre-terminal pts with SSH have a low CO.
  117. 117. Evidence supporting the deleterious effects of aggressive fluid resuscitation • The harmful effects of aggressive fluid resuscitation on the outcome of sepsis; • An increasingly positive fluid balance and increased mortality in patient with sepsis; • Fluid loading in sepsis is harmful: (the ‘FEAST’ in 3141 children with SS).
  118. 118. Evidence supporting the deleterious effects of aggressive fluid resuscitation • An aggressive fluid loading associated with an increased risk of death. • EGDT or the concept of early aggressive fluid resuscitation
  119. 119. Evidence supporting the deleterious effects of aggressive fluid resuscitation • A marked reduction in mortality over this time period (see Fig. 2). • The early use of antibiotics; • The decline in the amount of fluids IV in the first 72 h is striking.
  120. 120. Evidence supporting the deleterious effects of aggressive fluid resuscitation • in Fig. 3 there is a very strong correlation between the amount of fluid administered (in first 6 h) and the target CVP. • CVP in both the ARISE & ProMISe trials was greater than 10 mm Hg; • identical to the EGDT with almost an identical amount of fluid being administered in the active EGDT • Clinicians seem compelled to give fluid when the CVP is less than 8 mm Hg; • The only solution to this pervasive problem is to stop measuring the CVP.
  121. 121. A haemodynamically-guided conservative fluid resuscitation strategy • A haemodynamically-guided fluid resuscitation strategy in pts with SS and SSH. • SS Pts to deal with hypovolemia; not hypervolemia. • Large fluid boluses counter the life preserving homeostatic mechanisms in unstable SS pts, increasing the risk of death. • Hypotension and tachycardia do resolve with limited fluid resuscitation.
  122. 122. A haemodynamically-guided conservative fluid resuscitation strategy • SS pts ~ dehydration: poor oral intake & delay in medical attention. • Fluids alone not reverse the haemodynamic instability of pts with SS & SSH; • Fluids alone to exacerbate the vasodilatory shock and increase the capillary leak and tissue oedema. • The initial resuscitation: 500 ml boluses Ringer's Lactate • Max.:20 ml/kg.124 • Fluid resuscitation guide by the fluid responsiveness.
  123. 123. A haemodynamically-guided conservative fluid resuscitation strategy • NS: an ‘unphysiologic’IV should be avoided, except in pts with acute neurological injuries. • NS causes a hyperchloraemic metabolic acidosis; • NS decreases renal blood flow • NS: increasing the risk of renal failure. • In pts with SS, the use of NS as compared with physiologic salt solutions associated with an increased risk of death. • Starch solutions increase the risk of renal failure and death in pts with SS and should be avoided.
  124. 124. A haemodynamically-guided conservative fluid resuscitation strategy • SS pts. with an intra-abdominal catastrophe, who requires urgent surgery, require more aggressive fluid resuscitation. • Aggressive fluid resuscitation results in intra-abdominal hypertension, with a high risk of complications and death. • Continuous SV monitoring essential; ongoing fluid requirements guide by SV and the haemodynamic response to a mini-fluid bolus. • Perioperative, intra-abdominal pressure monitoring.
  125. 125. Norepinephrine • NE initiated in SS pts with hypotension (MAP < 65 mm Hg) despite initial, limited fluid strategy. • NE increases arterial vascular tone increasing ABP and organ blood flow. • Venous capacitance vessels are much more sensitive to sympathetic stimulation than are arterial resistance vessels; • Consequently low dose α-1 agonists cause greater veno- than arterio-constriction.
  126. 126. Norepinephrine • In SS pts, α-1 agonists mobilize blood from the unstressed reservoirs in the splanchnic circulation and skin, thereby increasing venous return and CO. • In pts with endotoxic shock: NE increased the MCFP, leading to an increase in venous return.
  127. 127. Norepinephrine • In pts with SSH deceasing the dose of NE, decreased the MCFP with a decrease in venous return and CO. • In pts with SSH NE increased CI, SVR and CBVs (ITHBV, global EDV), as measured by transpulmonary thermodilution. • An extra-vascular lung water (EVLW) remained unchanged.
  128. 128. Norepinephrine • The early IV of NE increased preload, CO and MAP largely reversing the haemodynamic abnormalities of severe vasodilatory shock. • The early use of NE in pts with SSH ~ a strong predictor of survival.
  129. 129. Norepinephrine • In pts with SSH, the early use of NE restores the stressed blood volume, increasing the MCFP, venous return and cardiac output. • The increase in the stressed blood volume is as a result of the mobilization of blood, rather than the short-lived effect of a volume expander.
  130. 130. Norepinephrine • The effect of α-1 agonists on venous return is enduring and not associated with tissue oedema. • α-1 agonists not used in pts with hypovolaemic shock (e.g. cholera) who are already venoconstricted; • α-1 agonists cause severe vasoconstriction, impairing organ blood flow. • In septic veno- and arterio-dilated pts: • α-1 agonists increases: venous return, SV, arterial tone and organ blood flow.
  131. 131. Norepinephrine • Digital & limb ischaemia & ischaemic skin lesions ~: • Rare with the use of NE; • Occurring usually with high dosages • When used together with vasopressin. • Uncontrolled DIC plays a contributing role in SS pts.
  132. 132. Norepinephrine • No cases pts with digital or limb ischaemia with the early use of NE. • The early use of NE to reduce the peak and total dose of IV vasopressors.
  133. 133. Norepinephrine • NE safe via a peripheral IV; • The requirement for emergent CVC; • The early use of NE.
  134. 134. Norepinephrine • NE appears preferable to epinephrine and phenylephrine as a first-line therapy in restoring haemodynamic stability. • Dopamine as opposed to NE is associated with an increased risk of arrhythmias and death in patients with sepsis and should be avoided.
  135. 135. Conclusions • The concept of a haemodynamically-guided, restricted fluid resuscitation strategy in pts with SS and SSH.
  136. 136. Conclusions • Initial fluid resuscitation limited and • Guided by an assessment of fluid responsiveness.
  137. 137. Conclusions • NE increases preload, SVR and CO • NE use in pts with hypotension in septic shock.
  138. 138. Conclusions • Early ECHO assessment of cardiac function is a guide haemodynamic management
  139. 139. Conclusions • An early use of Norepinephrine • Haemodynamically-guided fluid resuscitation
  140. 140. References ↵ Cosnett JE . The origins of intravenous fluid therapy. Lancet 1989; 1: 768–71 • MedlineWeb of Science • ↵ MacGillivray N . Dr Latta of Leith: pioneer in the treatment of cholera by intravenous saline infusion. J R Coll Physicians Edinb 2006; 36: 80–5 • Medline • ↵ Rivers E, Nguyen B, Havstad S et al . Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345: 1368–77 • CrossRefMedlineWeb of Science • ↵ Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA . Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010; 303: 739–46 • CrossRefMedlineWeb of Science • ↵ Dellinger RP, Carlet JM, Masur H et al . Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32: 858–73 • CrossRefMedlineWeb of Science • Dellinger RP, Levy MM, Carlet JM et al . Surviving sepsis Campaign: International guidelines for management of severe sepsis and septic shock. 2008. Crit Care Med 2008; 36: 296–327 • CrossRefMedlineWeb of Science • ↵ Dellinger RP, Levy MM, Rhodes A et al . Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock. 2012. Crit Care Med 2013; 41: 580–637 • CrossRefMedlineWeb of Science • ↵ Yealy DM, Kellum JA, Huang DT et al . A Randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; 370: 1683–93 • CrossRefMedlineWeb of Science • ↵ Peake SL, Delasney A, Bailey M et al . Goal-directed resuscitation for patients with Early Septic Shock. N Engl J Med 2014; 371: 1496–506 • CrossRefMedlineWeb of Science • ↵ Mouncey PR, Osborn TM, Power S et al . Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015; 372: 1301–11 • CrossRefMedline • ↵ Angus DC, Barnato AE, Bell D et al . A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe investigators. Intensive Care Med 2015; 41: 1549–60 • CrossRefMedline • ↵ Funk DJ, Jacobsohn E, Kumar A . The role of venous return in critical illness and shock-part I: physiology. Crit Care Med 2013; 41: 250–7 • CrossRef • ↵ Guyton AC . Determination of cardiac output by equating venous return curves with cardiac response curves. Physiol Rev 1955; 35: 123–9 • FREE Full Text • ↵ Gelman S . Venous function and central venous pressure: a physiologic story. Anesthesiol 2008; 108: 735–48 • CrossRefMedlineWeb of Science • ↵ Peters J, Mack GW, Lister G . The importance of the peripheral circulation in critical illnesses. Intensive Care Med 2001; 27: 1446–58 • CrossRefMedlineWeb of Science • ↵ Applegate RA, Johnston WE, Vinten-Johansen J, Klopfenstein HS, Little WC . Restraining effect of intact pericardium during acute volume loading. Am J Physiol 1992; 262: H1725–33 • Tyson GS, Maier GW, Olsen CO, Davis JW, Rankin JS . Pericardial influences on ventricular filling in the conscious dog. An analysis based on pericardial pressure. Circ Res 1984; 54: 173–84 • Abstract/FREE Full Text • ↵ Fragata J, Areias JC . Effects of gradual volume loading on left ventricular diastolic function in dogs: implications for the optimisation of cardiac output. Heart 1996; 75: 352–7 • Abstract/FREE Full Text • ↵ Vellinga NA, Ince C, Boerma EC . Elevated central venous pressure is associated with impairment of microcirculatory blood flow in sepsis. BMC Anesthesiol 2013; 13: 17 • CrossRefMedline • ↵ Prowle JR, Echeverri JE, Ligabo EV, Ronco C, Bellomo R . Fluid balance and acute kidney injury. Nat Rev Nephrol 2010; 6: 107–15 • CrossRefMedlineWeb of Science • ↵ Starling EH . The Linacre Lecture on the Law of the Heart, Given at Cambridge, 1915. London: Longmans, 1918; 27 • ↵ Marik PE . The physiology of volume resuscitation. Curr Anesthesiol Rep 2014; 4: 353–9