Assessment of Adequate Fluid Resuscitation

Assessment of Adequate Fluid Resuscitation
Overview and Recommendations
Background
● Fluid resuscitation (also called volume expansion) is IV infusion of uids used for rst-line treatment of
acute circulatory failure, but it should be used with caution.
⚬ Treat uids as any other medication with bene ts and potential adverse e ects.
⚬ The purpose of uid resuscitation is to increase cardiac output and ensure adequate perfusion and
oxygen delivery to tissues.
⚬ In patients receiving uid resuscitation, the amount of uid needed for adequate resuscitation is
variable and patients should be reassessed before each additional uid bolus.
● Avoid uid overload, which is associated with an increased risk of lung and tissue edema, duration of
mechanical ventilation, and mortality.
Evaluation
● Dynamic variables may be superior to static variables to assess uid responsiveness.
⚬ Dynamic maneuvers provide a preload challenge by inducing changes in heart loading conditions.
⚬ The appropriate method of assessing uid responsiveness depends on patient characteristics
(such as presence of cardiac arrhythmia) and concurrent treatments (such as use of mechanical
ventilation), with possible methods including:
– uid challenge (gold standard) or mini uid challenge
– stroke volume variation and pulse pressure variation
– passive leg raising
– end-expiratory occlusion test
– inferior vena cava or superior vena cava dimension variations
– other methods of uid assessment
● Static variables (such central venous pressure) do not adequately predict uid responsiveness and
should not be used in isolation, though they may be helpful to measure for other clinical indications.
Extreme values – very high or very low - may be used with clinical features to guide therapy.
Management
● There is no consensus on the best method for determining uid responsiveness in the critically ill or
adequacy of uid resuscitation.
● Fluid responsiveness does not always mean the patient should receive uids; signs of hypoperfusion
should be assessed rst.
⚬ After hypoperfusion is identi ed, determine if uids are needed to increase blood ow or if other
therapies are more appropriate, as clinical signs of hypoperfusion cannot determine uid
responsiveness or volume status.
⚬ Only patients with preload responsiveness who are likely to bene t from uid therapy should
receive a uid bolus.
⚬ Caution in uid administration is warranted in patients with severe hypoxemia, as additional
volume loading may worsen shunt in patients with pneumonia or pulmonary edema; oxygen
should be monitored throughout uid resuscitation.
● Assess volume status and volume responsiveness frequently, as optimal uid management is the key
to avoiding hypovolemia and hypervolemia (Strong recommendation).
● In patients with sepsis:
⚬ Immediate resuscitation and treatment is recommended (Strong recommendation).

⚬ For initial resuscitation of sepsis-induced hypoperfusion, give IV crystalloids ≥ 30 mL/kg within the
rst 3 hours (Strong recommendation).
⚬ Blood products may be part of initial supportive care.
● If giving IV uids:
⚬ perform a uid challenge unless the patient has an obvious cause of hypovolemia (such as overt
bleeding in ruptured aneurysm) (Strong recommendation)
⚬ titrate uids carefully even in context of uid responsiveness, especially in patients with elevated
intravascular lling pressures or extravascular lung water or in those at high risk for developing
these (such as those with heart failure history, ischemic cardiomyopathy, dialysis dependent renal
failure) (Strong recommendation)
⚬ adding inotropic agents to uids is suggested if impaired cardiac function is accompanied by low or
inadequate cardiac output and signs of tissue hypoperfusion persist after preload optimization
(Weak recommendation)
● Fluid resuscitation strategies have been suggested to improve clinical outcomes, though results are
often limited or inconsistent.
⚬ There is inconsistent evidence for use of protocolized uid therapy (goal-directed therapy or
lactate-guided therapy), with studies performed mainly in patients with sepsis.
⚬ In trauma patients, delayed resuscitation may not a ect overall mortality rates, but might increase
survival in patients with penetrating torso injury.
⚬ After rescue therapy with boluses, titrate the intravenous uid infusion rate based on clinical
context to achieve optimization of tissue perfusion; de-escalate uid infusion as clinical condition
improves to avoid uid overload
Related Summaries
● Fluid selection for IV uid resuscitation
● Vasopressor and inotrope use in the intensive care unit
● Sepsis treatment in adults
● Hemorrhagic shock
● Hemodynamic monitoring
General Considerations for Fluid Resuscitation
● uid resuscitation (infusion of intravenous uid) is considered rst-line treatment for patients with
acute circulatory failure, but it should be treated as any other medication with both bene ts and
adverse e ects 1 , 2 , 3
● consider uid resuscitation if patients have acute circulatory failure with low blood pressure or cardiac
output and signs of tissue hypoperfusion 1

⚬ give uids without assessing preload responsiveness in patients with obvious uid loss or in initial
phase of septic shock
⚬ assess uid responsiveness in all other patients
● purpose of uid resuscitation (as well as treatment with vasopressors and inotropes) is to increased
cardiac output and ensure adequate oxygen delivery to prevent or treat organ dysfunction 1 , 3
⚬ oxygen delivery = arterial blood oxygen content × cardiac output
⚬ cardiac output = stroke volume × heart rate, with stroke volume de ned as amount of blood
ejected from heart with each beat
● amount of uid required to achieve adequate resuscitation is unpredictable and dependent upon
cardiovascular physiology 1 , 3 , 4
⚬ stroke volume is dependent on preload (end-diastolic wall tension), contractility, and afterload
(end-systolic wall tension)
⚬ preload is determined by pressure gradient between capacitance veins and right atrium
⚬ Frank-Starling curve depicts relationship between stroke volume and cardiac preload (end-diastolic
wall tension)
– stroke volume increases as preload increases, due to more forceful contractions when
myocytes are stretched (ascending portion of curve)
– as left-ventricular end-diastolic volume increases, force of myocyte contraction plateaus and
stroke volume no longer increases ( at portion of curve)
⚬ uid resuscitation only increases stroke volume if both ventricles are preload dependent (on
ascending portion of curve)
⚬ shape of Frank-Starling curve varies among patients and with time in individual patients due to its
dependence on ventricular systolic function
⚬ Frank-Starling curve may also be a ected by pericardial limitations in patients with cardiac
tamponade and open chest conditions (Crit Care 2015 Feb 16;19:55 full-text )
● only about 50% of critically ill patients are uid responsive 1 , 2 , 3 , 4
● uid responsiveness does not always mean patient should receive uids 2 , 3 , 4
⚬ look for signs and symptoms of hypoperfusion, including (but not limited to)
– hypotension
– tachycardia
– narrow pulse pressure
– oliguria
– elevated lactate levels
– mottled skin
– dry mucus membranes
– slow capillary re ll
– altered mental status
– echocardiographic signs of overt hypovolemia
⚬ after hypoperfusion is identi ed, determine if uids are needed to increase blood ow or if other
therapies are more appropriate as clinical signs of hypoperfusion cannot determine uid
responsiveness or volume status
– use dynamic methods to assess preload responsiveness before giving uids
– static measures (such as central venous pressure, pulmonary capillary wedge pressure, and
ventricular volumes) do not predict uid responsiveness but may provide important
information for patient care
● only patients with preload responsiveness who are likely to bene t from uid therapy should receive
uid bolus 4
⚬ most healthy persons are normally uid responsive (on ascending portion of Frank-Starling curve),
but have preload reserves and do not require uids for optimal function
⚬ critically ill patients should not be administered uids for sole purpose of reaching at portion of
Frank-Starling curve
– evaluate potential bene ts and risks before each uid bolus
– only continue administering uids if bene ts outweigh risk of positive uid balance
– do not repeat uids until patient no longer responsive if not clinically indicated
– avoid large uid boluses
● uid boluses have small and short-lived hemodynamic e ects 4

⚬ in patients with sepsis, consider norepinephrine to increase venous return, stroke volume, and
mean arterial pressure while reducing risk of tissue edema (in addition to correcting intravascular
volume depletion if present)
STUDY
⚬ SUMMARY
hemodynamic effects of fluid challenge may not be sustained at 60 minutes after infusion in
fluid responsive patients with acute circulatory shock
COHORT STUDY: Ann Intensive Care 2014;4:25 | Full Text
Details
– based on prospective cohort study
– 20 patients (mean age 64 years, 80% male) with circulatory shock receiving uid challenge with
500 mL crystalloid solution (0.9% saline or Ringer lactate) infused over 30 minutes were
monitored during infusion and for 60 minutes after
● all patients were treated with vasopressors for ≥ 6 hours, received mechanical ventilation and
continuous sedation (Ramsay score 5-6), and were monitored with arterial catheter and
pulmonary artery catheter
● patients were excluded if primary cause of hypotension was suspected or con rmed active
bleeding, burn injury, or cardiogenic shock
● circulatory shock was due to sepsis in 14 patients, major surgery in 5, and multiple trauma in
1
– 13 patients (65%) responded to uids, de ned as cardiac index increase ≥ 15%
– mean cardiac index in uid responders over 90-minute observation time
● 2.84 L/minute/m2 at baseline

● 3.57 L/minute/m2 at 30 minutes (p < 0.05 vs. baseline, 60 minutes, and 90 minutes)
● 3.19 L/minute/m2 at 60 minutes (p < 0.05 vs. baseline)
● 3.06 L/minute/m2 at 90 minutes (not signi cant vs. baseline)
– no signi cant di erences from baseline at any time point for nonresponders
– similar results for measurements of mean arterial pressure and pulmonary artery occlusion
pressure
– Reference - Ann Intensive Care 2014;4:25 full-text
● avoid uid overload
⚬ volume expansion in unresponsive patients causes hemodilution, increased cardiac lling
pressure, and uid overload 1

⚬ uid overload may cause lung and tissue edema and increase duration of mechanical ventilation
and mortality 1
⚬ oxygen should be monitored throughout uid resuscitation (N Engl J Med 2004 Jul 8;351(2):159 )
⚬ caution in uid administration warranted in patients with severe hypoxemia, as additional volume
loading may worsen shunt in patients with pneumonia or pulmonary edema
● high positive uid balance associated with increased mortality
STUDY
⚬ SUMMARY
higher positive fluid balance associated with increased 28-day mortality in patients with
severe sepsis or septic shock
COHORT STUDY: Am J Emerg Med 2015 Feb;33(2):186
Details
– based on prospective cohort study
– 42 patients (mean age 62 years, 64% male) with severe sepsis or septic shock were assessed
● 31% had severe sepsis de ned as acute infection and organ dysfunction
● 69% had septic shock de ned as acute infection with acute organ dysfunction and need for
vasopressor treatment for > 6 hours
– balanced electrolyte solution (Plasma-Lyte 148) was used for uid resuscitation in all patients
– 28-day mortality 35.7% (all patients with septic shock)
– increased mortality associated with
● higher admission Simpli ed Acute Physiology Score (SAPS) II score (p = 0.016)

● higher volume uid balance at 48 hours (p = 0.02), 72 hours (p = 0.002), or 96 hours (p =
0.001)
● uid balance > 2 L at 24 hours (p = 0.024)
● uid balance > 2.5 L at 72 hours (p = 0.014) or 96 hours (p = 0.008)
– no signi cant association with age, sex, Sepsis-related Organ Failure Assessment (SOFA) score,
creatinine, lactate, venous oxygen saturation, and troponin
– Reference - Am J Emerg Med 2015 Feb;33(2):186 , commentary can be found in Am J Emerg
Med 2015 Mar;33(3):471 and Am J Emerg Med 2015 Sep;33(9):1311
STUDY
⚬ SUMMARY
higher fluid balance at intensive care unit discharge associated with increased 90-day
mortality in critically ill patients
COHORT STUDY: J Intern Med 2015 Apr;277(4):468 | Full Text
Details
– based on retrospective cohort study
– 15,395 critically ill patients (mean age 63 years, 57% male) admitted to intensive care unit (ICU)
between 2001 and 2008 were assessed
● patients were excluded for unavailable uid balance documentation, dialysis, missing data on
renal function, or missing demographic data
● mean total uid balance was 2.6 L
– mortality within 90 days of hospital discharge 11.9%

– patients were divided into quartiles based on uid balance at discharge, with median uid
balance -1.5 L in lowest quartile and 7.6 L in highest quartile
– compared to lowest discharge uid balance quartile, highest quartile associated with increased
90-day postdischarge mortality
● overall (adjusted hazard ratio [HR] 1.35, 95% CI 1.13-1.61)
● in prede ned subgroup analyses of patients with conditions at discharge associated with
higher risk of acute uid retention including
⚬ congestive heart failure (adjusted HR 1.83, 95% CI 1.33-2.51)
⚬ acute kidney injury (adjusted HR 1.99, 95% CI 1.24-3.27)
⚬ estimated glomerular ltration rate (eGFR) < 60 mL/minute (adjusted HR 1.4, 95% CI 1.02-
1.92)
– no signi cant di erences in 90-day postdischarge mortality in patients without high risk
conditions (heart failure, acute kidney injury, or eGFR < 60 mL/minute)
– in adjusted dose-response analysis, each 1-L positive uid balance associated with increased
risk of death
● within 90 days of discharge (adjusted HR 1.04, 95% CI 1.03-1.05)
● during ICU stay (adjusted HR 1.07, 95% CI 1.06-1.08)
– no signi cant association with death after 90 days

– Reference - J Intern Med 2015 Apr;277(4):468 full-text
STUDY
⚬ SUMMARY
fluid overload after early goal-directed therapy associated with increased in-hospital
mortality and use of thoracentesis in patients with severe sepsis or septic shock
COHORT STUDY: Shock 2015 Jan;43(1):68 | Full Text
Details
– based on retrospective cohort study
– 405 adults admitted to ICU with severe sepsis or septic shock receiving adequate early goal
directed therapy were assessed for uid overload
● severe sepsis and septic shock were based on 2012 Surviving Sepsis Campaign guidelines
● adequate early goal directed therapy was de ned as central venous oxygen saturation ≥ 70%,
central venous pressure ≥ 8 mm Hg, mean arterial pressure ≥ 65 mm Hg, urine output ≥ 0.5
mL/kg/hour, and/or improvement in lactate within 6 hours
● crystalloids were used for uid resuscitation
– 67% had uid overload on day 1 and 48% had uid overload on both day 1 and day 3 (persistent
uid overload)
– in-hospital mortality 24%
– in multivariable analysis
● uid overload on day 1 associated with increased

⚬ use of thoracentesis (odds ratio [OR] 3.4, 95% CI 1.37-10.3)
⚬ in-hospital mortality (OR 2.27, 95% CI 1.31-4.09)
● persistent uid overload associated with increased
⚬ use of thoracentesis (OR 3.81, 95% CI 1.74-9.15)

⚬ use of diuretics (OR 1.65, 95% CI 1-2.72)
⚬ in-hospital mortality (OR 1.92, 95% CI 1.16-3.22)
● persistent uid overload associated with nonsigni cant increase in
⚬ use of ultra ltration (OR 1.9, 95% CI 0.9-4.19)

⚬ 30-day ICU readmission (OR 1.61, 95% CI 0.94-2.79)
– Reference - Shock 2015 Jan;43(1):68 full-text
Recommendations from Professional Organizations
● European Society of Intensive Care Medicine (ESICM) consensus on circulatory shock and
hemodynamic monitoring recommendations on uid management
⚬ assess volume status and volume responsiveness frequently (ESICM Best practice point), as
optimal uid management is key to avoid hypovolemia and hypervolemia
⚬ immediate uid resuscitation recommended in shock states associated with very low values of
commonly used preload parameters (ESICM Best practice point)
⚬ variables for guiding uid resuscitation
– do not exclusively use common preload measures (such as central venous pressure [CVP],
pulmonary artery occlusion pressure [PAOP], end-diastolic area, or global end-diastolic volume)
as only variable for guiding uid resuscitation (ESICM Level 1, Moderate-quality evidence)
– guide uid resuscitation using ≥ 1 single hemodynamic variable (ESICM Best practice point)
– for ventricular lling pressure and volume, no single or absolute target recommended (ESICM
Level 1, Moderate-quality evidence)
– dynamic variables recommended over static variables to predict uid responsiveness when
applicable (ESICM Level 1, Moderate-quality evidence)
– additional preload measures include
● volumetric parameters (evaluated using transpulmonary thermodilution methods)

● end-diastolic ventricular volumes (evaluated using echocardiography)
● vena cava collapsibility on echocardiography
● central venous pressure (CVP) respiratory variability
● pulse pressure gradient and variability
● blood pressure and CVP response to leg-raise maneuver
⚬ if giving IV uids
– perform a uid challenge unless patient has obvious cause of hypovolemia (such as overt
bleeding in ruptured aneurysm) (ESICM Level 1, Low-quality evidence)
– titrate uids carefully even in context of uid responsiveness, especially in presence of elevated
intravascular lling pressures or extravascular lung water (ESICM Best practice point)
– adding inotropic agents to uids suggested if impaired cardiac function is accompanied by low
or inadequate cardiac output and signs of tissue hypoperfusion persist after preload
optimization (ESICM Level 2, Low-quality evidence)
– inotropic agents are not recommended for patients with isolated impaired cardiac function
(ESICM Level 1, Moderate-quality evidence)
⚬ additional considerations for monitoring uid therapy
– targeting absolute values of oxygen delivery are not recommended in patients with shock
(ESICM Level 1, High-quality evidence), but instead aim for improving tissue perfusion (which
can be measured clinically with urine output, mentation, capillary re ll, and skin exam)
– for patients with shock responding to initial therapy, routine cardiac output measurements are
not recommended (ESICM Level 1, Low-quality evidence)
– for patients not responding to initial therapy, cardiac output and stroke volume measurements
recommended to evaluate uid or inotrope responsiveness (ESICM Level 1, Low-quality
evidence)
– sequential evaluation of hemodynamic status recommended during shock (ESICM Level 1, Low-
quality evidence)
– echocardiography may be used for sequential evaluation of cardiac function
– pulmonary artery catheterization
● not routinely recommended for patients with shock (ESICM Level 1, High-quality evidence)
● suggested for patients with refractory shock and right ventricular dysfunction (ESICM Level 2,
Low-quality evidence)
CLINICIANS' PRACTICE POINT
Recommendation does not appear based on published evidence in this patient

population, but mostly on expert opinion. Pulmonary artery catheter typically not used
for this purpose in United States.
● pulmonary artery catheterization or transpulmonary thermodilution suggested in patients

with severe shock, especially if accompanied by acute respiratory distress syndrome (ESICM
Level 2, Low-quality evidence)
– less invasive devices recommended for use over more invasive devices only when they have
been validated in patients with shock (ESICM Best practice point)
⚬ Reference - Intensive Care Med 2014 Dec;40(12):1795 full-text , commentary can be found in
Intensive Care Med 2015 Mar;41(3):570
● Surviving Sepsis Campaign international guidelines for management of sepsis and septic shock
recommendations on uid resuscitation
⚬ recommendations on initial resuscitation (within rst 6 hours)
– immediate resuscitation and treatment recommended in patients with sepsis or septic shock
(SCCM Best practice statement)
– for initial resuscitation of sepsis-induced hypoperfusion, give IV crystalloids ≥ 30 mL/kg within
rst 3 hours (SCCM Strong recommendation, Low-quality evidence)
– further uid resuscitation should be guided by frequent reassessment of hemodynamic status
(SCCM Best practice statement) including
● clinical examination
● physiologic variables (heart rate, blood pressure, arterial oxygen saturation, respiratory rate,
temperature, urine output)
● other invasive and noninvasive monitoring as available
– if diagnosis is not clear after clinical assessment, use further hemodynamic assessment (such as
cardiac function monitoring) to determine type of shock (SCCM Best practice statement)
– dynamic variables suggested over static variables (where available) to predict uid
responsiveness (SCCM Weak recommendation, Low-quality evidence)
– initially target mean arterial pressure of 65 mm Hg in patients with septic shock requiring
vasopressors (SCCM Strong recommendation, Moderate-quality evidence)
– resuscitation with goal of normalizing lactate levels suggested in patients with elevated lactate
as marker of tissue hypoperfusion (SCCM Weak recommendation, Low-quality evidence)
⚬ recommendations on uid therapy
– crystalloids recommended for initial uid resuscitation as well as subsequent intravascular

volume replacement (SCCM Strong recommendation, Moderate-quality evidence)
● for initial resuscitation of sepsis-induced hypoperfusion, give IV crystalloids ≥ 30 mL/kg
within rst 3 hours (SCCM Strong recommendation, Low-quality evidence)
● assess need for further uid administration using a uid challenge technique where uid is
continued as long as hemodynamic factors continue to improve (SCCM Best practice
statement)
● to predict uid responsiveness, dynamic variables suggested over static variables where
available (SCCM Weak recommendation, Low-quality evidence)
– consider either balanced crystalloids or saline for uid resuscitation (SCCM Weak
recommendation, Low-quality evidence)
– consider albumin in addition to crystalloids for uid resuscitation when patients require
substantial amounts of crystalloids (SCCM Weak recommendation, Low-quality evidence)
– do not use hydroxyethyl starches (HES) for intravascular volume replacement (SCCM Strong
recommendation, High-quality evidence)
– consider crystalloids over gelatins for resuscitation (SCCM Weak recommendation, Low-quality
evidence)
⚬ recommendations on use of blood products
– red blood cell transfusion recommended only if hemoglobin level < 7 g/dL in absence of
extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage,
or ischemic heart disease (SCCM Strong recommendation, High-quality evidence)
– prophylactic platelets suggested if (SCCM Weak recommendation, Very low-quality evidence)
● platelet counts < 10,000/mm3 (10 × 109/L) in absence of apparent bleeding

● platelet counts < 20,000/mm3 (20 × 109/L) and signi cant risk for bleeding
● platelet count < 50,000/mm3 (50 × 109/L) and active bleeding or if surgery or invasive
procedures needed
– no recommendation on use of thrombomodulin or heparin
– interventions which are not recommended
● antithrombin (SCCM Strong recommendation, Moderate-quality evidence)

● erythropoietin for sepsis-related anemia (SCCM Strong recommendation, Moderate-quality
evidence)
● fresh frozen plasma to correct clotting abnormalities in absence of planned invasive
procedures or bleeding (SCCM Weak recommendation, Very low-quality evidence)
⚬ Reference - Intensive Care Med 2017 Mar;43(3):304
● international Fluid Optimization Group statement on perioperative uid therapy
⚬ perioperative uid plans should be developed by each department, facility, or healthcare system
and used by all anesthesiologists
⚬ use individualized algorithms as part of perioperative uid plan
⚬ implementation of 2-step goal-directed therapy suggested immediately after anesthesia induction
– step 1 - determine if patient requires hemodynamic support or cardiovascular function

augmentation
– step 2 - if patient has apparent need for uid therapy and is responsive to uids, consider uid
bolus therapy guided by continual or continuous assessment of uid responsiveness
⚬ use dynamic parameters as integral part of goal-directed therapy
– consider limitations of each dynamic parameter and gray zone concept

– dynamic parameters alone should not be used as indication to start uid therapy or
measurement of uid bolus e ectiveness
– base decision to administer uids on need for hemodynamic improvement, uid
responsiveness, and associated risks
⚬ bolus therapy recommended over continuous uid administration if goal is to improve pressure,
perfusion, and oxygen delivery
– uid bolus composition, volume, and infusion rate as well as time to postbolus assessment
should be implemented as standardized protocol
– include changes in cardiac output and stroke volume in assessment of uid bolus e ectiveness
⚬ patients having major surgery (longer duration or magnitude) should receive maintenance uid at
rate of 1-2 mL/kg/hour, but patients having outpatient procedures may bene t from higher rates
of maintenance uids
⚬ uid selection
– crystalloids are recommended for routine, short duration surgery

– goal-directed uid regimens including colloids and balanced-salt solutions recommended for
major surgery
– limited data on starch solutions in perioperative uid management, though black box warning
against starch solutions exists in United States
– in patients with known renal dysfunction or sepsis, careful consideration is recommended
before administration of starch solutions
⚬ Reference - Perioper Med (Lond) 2015 Apr 10;4:3 full-text
● National Institute for Heath and Care Excellence (NICE) recommendations on IV uid therapy in adults
in hospital
⚬ initial assessment
– assess patients for hypovolemia and indicators of need for urgent uid resuscitation, including
● systolic blood pressure < 100 mm Hg

● heart rate > 90 beats per minute
● capillary re ll time > 2 seconds or peripheries cold to touch
● respiratory rate > 20 breaths per minute
● National Early Warning Score (NEWS) ≥ 5
● uid responsiveness suggested by passive leg raising
⚬ if uid resuscitation is deemed necessary
– identify uid de cit cause and begin treatment

– initiate 500-mL uid bolus of crystalloid solution containing 130-154 mmol/L sodium over < 15
minutes
● do not use tetrastarch
● in patients with severe sepsis, consider human albumin 4%-5%
– reassess patient using ABCDE approach (Airway, Breathing, Circulation, Disability, Exposure)
● continuously monitor respiratory rate, pulse, blood pressure, and perfusion

● measure venous lactate level or arterial pH and base excess
⚬ on reassessment
– if patient still requires uid resuscitation on reevaluation
● and has received < 2,000 mL total uid volume, give further uid bolus of 250-500 mL
crystalloid solution and reassess
● and has received > 2,000 mL total uid volume, consult expert
– if patient does not appear to require further uid resuscitation, evaluate for signs of shock
● seek expert help if signs of shock are present

● in absence of signs of shock, assess patient's likely uid and electrolyte needs
⚬ assess likely uid and electrolyte needs based on history, clinical exam, clinical monitoring, and
laboratory measurements
– history should include previous intake, quantity and composition of abnormal losses,
comorbidities, and thirst
– clinical exam should assess uid status and include
● pulse, blood pressure, capillary re ll and jugular venous pressure

● presence of pulmonary or peripheral edema
● presence of postural hypotension
– clinical monitoring should include
● NEWS
● uid balance chart
● weight
– laboratory measurements should include
● complete blood count

● urea, creatinine, and electrolytes
⚬ Reference - NICE 2013 Dec:CG174 PDF
Methods to Assess Fluid Responsiveness
Overview of methods for assessing fluid responsiveness
● dynamic variables to assess uid responsiveness 1 , 2 , 3 , 4
⚬ dynamic variables provide preload challenge by inducing changes in heart loading conditions
⚬ change provoked though heart-lung interactions or postural changes
– heart-lung interactions are induced by cyclic changes in intrathoracic pressure during

mechanical ventilation
– postural changes alter loading conditions by transferring blood into intrathoracic compartment
● choice of method for assessing uid responsiveness may depend on patient characteristics and
treatments 1 , 2
Table 1. Advantages and Disadvantages of Methods for Assessing Fluid

Responsiveness
Method of Mechanism of Advantages Disadvantages
Assessment Action
(Test or
Parameter)
Conventional Infusion of 250- Direct measure of Fluids given as

uid 500 mL of uid uid part of
challenge(gold over short time responsiveness assessment,
standard) period (5-30 potential for uid
minutes) overload with
repeat
assessments
Mini- uid Infusion of 100 Small volume of Fluids given as

challenge mL of uid over 1 uid part of
minute assessment,
requires precise
cardiac output
measurements
Stroke volume Heart-lung No uid infusion Cannot be used

variation or pulse interactions in in patients with
pressure mechanically spontaneous
variation ventilated breathing, low
patients tidal volume
ventilation, low
lung compliance,
cardiac
arrhythmias
Passive leg Self-volume No uid infusion, Requires direct

raising challenge reversible e ect measure of
induced by cardiac output,
shifting venous cannot be used in
blood from legs patients with
to intrathoracic intracranial
compartment hypertension
Assessment Action
(Test or
Parameter)
End-expiratory Heart-lung No uid infusion, Requires

occlusion test interactions in may be intubation,
mechanically performed in patients must be
ventilated patients with able to do 15-
patients cardiac second
arrhythmias or respiratory hold
low lung
compliance
IVC diameter Heart-lung No uid infusion Cannot be used

variation interactions in in patients with
mechanically spontaneous
ventilated breathing, low
ventilation, low
lung compliance,
preexisting
pulmonary
hypertension, or
tricuspid
regurgitation
SVC diameter Heart-lung No uid infusion Cannot be used

variation interactions in in patients with
mechanically spontaneous
ventilated breathing, low
ventilation, low
lung compliance,
preexisting
pulmonary
hypertension, or
tricuspid
regurgitation;
requires
transesophageal
Doppler
Assessment Action
(Test or
Parameter)
Abbreviations: IVC, inferior vena cava; SVC, superior vena cava.
● do not use static measures of cardiac preload to assess uid responsiveness 1 , 2 , 3 , 4
Fluid challenge
● uid challenge is gold standard for assessing uid responsiveness 1 , 2

⚬ involves giving uids over short time period and assessing cardiovascular response
⚬ dynamic test of cardiovascular system
⚬ most direct way to challenge uid responsiveness
● conventional uid challenges infuse 250- to 500-mL uid bolus (usually crystalloids) over 5-30 minutes
and positive responsiveness is indicated by increase in stroke volume or cardiac output >
10%-15% 1 , 2
● increased urine output may also suggest responsiveness to uid challenge 4
● cautions with conventional uid challenge 1
⚬ it is a treatment and may induce uid overload if indiscriminately repeated

⚬ assessing precise e ects of uid challenge often requires direct cardiac output measurement and
cannot base responsiveness on arterial pressure changes alone
● mini- uid challenge infuses 100 mL of uid over 1 minute, using high infusion rate rather than higher
volume of uid to assess responsiveness 1 , 2

⚬ has been reported using both crystalloids and colloids
⚬ small uid volumes can only induce small changes in cardiac preload, requiring very precise
monitoring systems
STUDY
● SUMMARY
mini-fluid challenge may help rule out fluid responsiveness in critically ill patients with acute
circulatory failure DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Anesthesiology 2011 Sep;115(3):541
Details
⚬ based on diagnostic cohort study without independent validation
⚬ 39 critically ill adults (median age 66 years, 77% male) with acute circulatory failure having sedation
and mechanical ventilation without spontaneous breathing were assessed for uid responsiveness
by mini- uid challenge and conventional uid challenge (reference standard)
– mini- uid challenge included 100 mL of 6% hydroxyethyl starch solution infused over 1 minute
followed by echocardiographic assessment
– additional 400 mL of 6% hydroxyethyl starch solution was infused over 14 minutes after mini-
uid challenge for conventional uid challenge (total 500-mL infusion)
– patients were excluded for cardiac arrhythmias, known tricuspid insu ciency, or
cardiopulmonary edema
⚬ circulatory failure caused by severe sepsis or septic shock in 82%, traumatic shock in 10%, and
systemic in ammatory response syndrome in 8%
⚬ 77% received norepinephrine and median tidal volume was 6.6 mL/kg
⚬ 54% had uid response de ned as ≥ 15% increase in subaortic velocity time index (VTI) after
conventional uid challenge
⚬ best cuto for increase in subaortic VTI with mini- uid challenge was 3%, but 3% is lower than
reproducibility of echocardiography and 10% cuto chosen after taking into account reproducibility
⚬ performance of mini- uid challenge for prediction of uid responsiveness with cuto 10% increase
in VTI
– sensitivity 95%
– speci city 78%
– positive predictive value 83%
– negative predictive value 93%
⚬ mini- uid challenge and pulse pressure variation had similar discrimination (c-statistics 0.92 vs. 0.9)
⚬ Reference - Anesthesiology 2011 Sep;115(3):541 , editorial can be found in Anesthesiology 2011
Sep;115(3):455
STUDY
● SUMMARY
mini-fluid challenge measured using change in pulse pressure variation or stroke volume
variation may have good discrimination for predicting fluid responsiveness in mechanically
ventilated adults with acute circulatory failure DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Br J Anaesth 2015 Sep;115(3):449
Details
⚬ 49 critically ill adults with acute circulatory failure having deep sedation and mechanical ventilation
without spontaneous breathing were assessed of uid responsiveness using mini- uid challenge
(100 mL of 4% human serum albumin solution infused over 1 minute)
– all patients had tidal volume < 8 mL/kg and had continuous monitoring with PiCCO device
– patients were excluded for cardiac arrhythmias or risk of uid-loading-induced pulmonary
edema
– 94% had acute circulatory failure due to septic shock
– median total Positive End-Expiratory Pressure (PEEP) was 8 cm H2O
⚬ reference standard was conventional uid challenge performed by addition of 400 mL of 4%

human serum albumin solution over 14 minutes after mini- uid challenge completed
⚬ 45% were uid responders de ned as ≥ 15% increase in cardiac index after conventional uid
challenge
⚬ discrimination of dynamic indices for prediction of uid responsiveness during mini- uid challenge
– moderate for change in continuous cardiac index (c-statistic 0.78)

– good for change in pulse pressure variation (c-statistic 0.92) (p = 0.04 vs. continuous cardiac
index)
– good for change in stroke volume variation (c-statistic 0.91) (p = 0.05 vs. continuous cardiac
index)
⚬ change in continuous cardiac index associated with large gray zone encompassing 67% of patients,
while change in pulse pressure variation and stroke volume variation had much smaller gray zones
(12% and 8% of patients)
⚬ baseline pulse pressure variation and stroke volume variation had poor discrimination for
predicting uid responsiveness (c-statistics 0.62 and 0.52)
⚬ Reference - Br J Anaesth 2015 Sep;115(3):449 , editorial can be found in Br J Anaesth 2015
Sep;115(3):347
⚬
DynaMed Commentary
The best cuto s were determined for change in continuous cardiac index (5.2%), pulse
pressure variation (-2), and stroke volume variation (-2%), but it is unclear if these values are
above the minimally signi cant change needed to measure a reliable di erence and if they are
outside the calculated gray zone.
● 321- to 509-mL estimated minimum uid volume needed for uid challenge to reliably identify ≥ 14%
change in transient stop ow arm arterial-venous equilibrium pressure in nonrandomized trial of 80
patients admitted to cardiothoracic intensive care unit after cardiac surgery (Crit Care Med 2017
Feb;45(2):e161 )
Pulse pressure and stroke volume variation
● stroke volume variation and its surrogates use cyclical variations in intrathoracic pressure produced
by mechanical ventilation during positive pressure ventilation as provocative test, wherein cyclic
increases and reductions are greater in patients with hypovolemia 1 , 2
⚬ insu ation increases intrathoracic and transpulmonary pressures, causing reduced preload and
increased afterload of right ventricle, and leading to decreased right ventricular stroke volume
⚬ decreased right ventricular stroke volume leads to reduced left ventricular lling after 2-3 heart
beats
⚬ left ventricular preload is decreased and may induce reduction in left ventricular stroke volume
⚬ both ventricles are considered preload dependent when left ventricular stroke volume changes in
response to cyclic positive pressure ventilation
⚬ magnitude of changes in stroke volume depend on volume status and preload dependence on
both ventricles
● pulse pressure variation uses di erences between peripheral systolic and diastolic pulse pressures to
estimate stroke volume 1 , 2
● pulse pressure variation and stroke volume variation are unreliable for assessing uid responsiveness
in patients with conditions common to intensive care unit (ICU), including 1 , 2

⚬ spontaneous breathing (even if intubated)
⚬ cardiac arrhythmias
⚬ acute respiratory distress syndrome
⚬ low tidal volume or lung compliance
⚬ open chest
⚬ intra-abdominal hypertension
⚬ very high respiratory rate
⚬ right heart failure
● stroke volume variation and pulse pressure variation monitoring may be more applicable in operating
room settings 1
● respiratory pulse pressure variations were measurable and interpretable in 17% of 566 volume
expansions in patients with systemic in ammatory response syndrome admitted to ICU (Anaesth Crit
Care Pain Med 2016 Apr;35(2):93 )
STUDY
● SUMMARY
pulse pressure variation has high sensitivity and specificity for predicting fluid responsiveness
in adults without arrhythmia receiving mechanical ventilation with tidal volume > 8 mL/kg
DynaMed Level 2
SYSTEMATIC REVIEW: Crit Care 2014 Nov 27;18(6):650 | Full Text
Details
⚬ based on systematic review of diagnostic studies limited by clinical heterogeneity
⚬ systematic review of 22 studies evaluating accuracy of pulse pressure variation (PPV) to predict
uid responsiveness in 807 adults without cardiac arrhythmia receiving mechanical ventilation with
tidal volume > 8 mL/kg in ICU
– studies were excluded for using ventilator strategies maintaining spontaneous breathing
– 10 studies included patients post surgery, 9 studies included patients with sepsis or shock, and 3
studies included mixed critically ill populations
⚬ reference standard was uid challenge in all studies, but uid type, volume, and timing varied
among studies
⚬ all but 2 studies de ned responders as patients with stroke volume or cardiac output increase ≥
15%, but methods for monitoring cardiac output varied
⚬ 58% of patients responded to uid challenge (study response rate ranged from 29% to 84%)
⚬ median PPV cuto was 12%
⚬ pooled performance of PPV for prediction of uid responsiveness
– sensitivity 88% (95% CI 81%-92%)

– speci city 89% (95% CI 84%-92%)
– positive likelihood ratio 7.7 (95% CI 5.3-11.3)
– negative likelihood ratio 0.14 (95% CI 0.08-0.23)
⚬ Reference - Crit Care 2014 Nov 27;18(6):650 full-text
STUDY
● SUMMARY
changes in pulse pressure and stroke volume variation after transient tidal volume challenge
may predict fluid responsiveness in patients with septic shock and acute circulatory failure
having controlled low tidal volume ventilation DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Crit Care Med 2017 Mar;45(3):415
Details
⚬ 20 adults (mean age 53 years) with septic shock and acute circulatory failure having controlled low
tidal volume ventilation were assessed for uid responsiveness by measurement of PPV, stroke
volume variation (SVV), end-expiratory occlusion test (EEOT) after tidal volume challenge
– patients were excluded for cardiac arrhythmias, valvular heart disease, right ventricular
dysfunction, intracardiac shunt, air leakage through chest drains, abdominal compartment
syndrome, pregnancy, or urgent need for uid bolus
– all patients were sedated and some received neuromuscular blocking agents
– patients were ventilated using tidal volume 6 mL/kg and challenged by increasing tidal volume
to 8 mL/kg
● PPV and SVV were measured before and 1 minute after challenge
● EEOT was performed before and after challenge and again after tidal volume returned to 6
mL/kg
⚬ reference standard was uid challenge with uid bolus given over 10 minutes
⚬ 10 patients had 2 tidal volume challenges performed ≥ 24 hours apart for total of 30 challenges
⚬ 53.3% of challenges had positive uid response de ned as cardiac index increase > 15% after uid
challenge
⚬ for prediction of uid responsiveness
– absolute change in PPV after increasing tidal volume from 6 to 8 mL/kg with cuto 3.5% had
● sensitivity 94%
● speci city 100%
● positive predictive value 100%
● negative predictive value 93%
– absolute change in SVV after increasing tidal volume from 6 to 8 mL/kg with cuto 2.5% had
● sensitivity 88%
● speci city 100%
– percent change in cardiac index during EEOT performed at tidal volume 8 mL/kg with cuto
4.1% had
● sensitivity 88%
● speci city 93%
⚬ at tidal volume 6 mL/kg
– PPV had modest performance (c-statistic 0.69)

– SVV and percentage change in cardiac index during EEOT had poor performance (c statistics ≤
0.56)
⚬ Reference - Crit Care Med 2017 Mar;45(3):415
● gray-zone approach determines range of values between which no conclusion about uid
responsiveness can be drawn (sensitivity or speci city < 90%)
STUDY
⚬ SUMMARY
gray-zone approach to pulse pressure variation may lead to inconclusive results in
approximately 25% of surgical patients having general anesthesia and mechanical ventilation
DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Anesthesiology 2011 Aug;115(2):231
Details
– based on retrospective diagnostic cohort study without independent validation
– 413 patients (mean age 65 years, 74% male) having surgery with general anesthesia and
mechanical ventilation were assessed for uid responsiveness using pulse pressure variation in
perioperative period
● patients were excluded for history of arrhythmia, right ventricular failure, valvular heart
disease, or intracardiac shunt; general anesthesia with muscle paralysis and mechanical
ventilation in controlled volume mode was used; or if hemodynamic measurements and
volume loading were performed in operating room or early postoperative period in closed-
chest condition
● cardiac output was measured by thermodilution (using pulmonary artery catheter), pulse
contour (PiCCO), or transesophageal echocardiography
– surgery was abdominal aortic in 49%, cardiac (before chest opening) in 39%, and abdominal
(nonvascular) in 12%
– 51% had tidal volume ≥ 8 mL/kg
– reference standard was uid challenge with 500 mL colloid infusion over 10-20 minutes with
uid responsiveness de ned as ≥ 15% increase in cardiac output
– gray zone determined as pulse pressure variation of 9%-13%, with 24% of patients falling within
gray zone
– changes in volume expansion cost ratio for di erent clinical situations where risks and harms of
uid loading might not be equilibrated shifted gray zones to
● 11%-14% for tight control where excessive uid loading is 2 times more harmful than
nonoptimal cardiac output optimization
● 8%-11% for liberal control where nonoptimal cardiac output is 2 times more harmful than
excessive uid loading
– Reference - Anesthesiology 2011 Aug;115(2):231 , editorial can be found in Anesthesiology
2011 Aug;115(2):229 , commentary can be found in Anesthesiology 2012 Mar;116(3):740 ,
Anesthesiology 2012 Mar;116(3):739 , Anesthesiology 2012 Mar;116(3):740 , and Crit Care
2015 Mar 25;19:144
STUDY
⚬ SUMMARY
pulse pressure variation may have large gray zone with inconclusive fluid responsiveness in
62% of patients with circulatory failure receiving mechanical ventilation in intensive care
units, but performance may be higher in patients with high tidal volume and driving pressure
DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Crit Care 2014 Nov 4;18(6):587 | Full Text
Details
– based on diagnostic cohort study without independent validation
– 556 adults (mean age 57 years, 65% male) with acute circulatory failure receiving mechanical
ventilation and sedation in 9 ICUs in France were assessed for uid responsiveness with pulse
pressure variation
● patients were excluded for spontaneous breathing, cardiac arrhythmias, suspected increased
intra-abdominal pressure, known tricuspid insu ciency, cardiogenic cardiopulmonary
edema, or unsatisfactory cardiac echogenicity in patients whose cardiac output was assessed
by echocardiography
● cardiac output was measured by thermodilution (PiCCO system or pulmonary artery
catheter), echocardiography, or esophageal Doppler
● 44% had ventilation with tidal volume > 8 mL/kg
– reference standard was uid challenge (most commonly 500-mL isotonic crystalloid infused over
15-30 minutes) with uid responsiveness de ned as ≥ 15% increase in stroke volume
– 48% were responded to uid challenge
– gray zone determined as pulse pressure variation of 4%-17%, with 62% of patients falling within
gray zone
– pulse pressure variation predictive performance signi cantly improved with tidal volume ≥ 8
mL/kg and driving pressure > 20 cm H2O
– Reference - Crit Care 2014 Nov 4;18(6):587 full-text , commentary can be found in Crit Care
2015 Mar 25;19:144
● conditions with low performance of pulse pressure variation or stroke volume variation for prediction
of uid responsiveness
STUDY
⚬ SUMMARY
pulse pressure variation has low performance in patients with ventilator asynchrony having
pressure support ventilation DynaMed Level 1
DIAGNOSTIC COHORT STUDY: J Crit Care 2015 Oct;30(5):1067
Details
– based on diagnostic cohort study
– 54 adults receiving pressure support ventilation were assessed for uid responsiveness using
pulse pressure variation
● all patients had clinical indication for uid challenge, positive end-expiratory pressure (PEEP)
5-10 cm H2O and inspiratory support level 10-15 cm H2O, and stable ventilatory pattern
● patients were excluded for any cardiac arrhythmia, severe valvular disease, New York Heart
Association class III or IV, moderate to severe acute respiratory distress syndrome, or
hemodialysis or hemo ltration
● 2 independent, blinded ICU physicians assessed patients for ventilator asynchrony for 3
minutes before uid challenge
– 27 patients had patient-ventilator asynchrony and 27 did not
● asynchrony group included patients with asynchronies in ≥ 10% of overall breaths counted
by both examiners
● patients with asynchronies in < 10% of overall breaths or with disagreement between
examiners were excluded
– overall uid responsiveness 42.5% on 500-mL uid challenge, de ned as ≥ 15% increase in
cardiac index (reference standard)
– performance of pulse pressure variation at cuto > 13% for assessing uid responsiveness
● in patients without asynchrony, sensitivity 78% and speci city 89%
● in patients with asynchrony, sensitivity 36% and speci city 46%
– ability of pulse pressure variation to predict uid responsiveness signi cantly a ected by
patient-ventilator asynchrony (odds ratio 8.8, 95% CI 2-38)
– correct classi cation greater in patients with tidal volume ≥ 8 mL/kg (100% for 12 patients
without asynchrony and tidal volume ≥ 8 mL/kg)
– Reference - J Crit Care 2015 Oct;30(5):1067
STUDY
⚬ SUMMARY
pulse pressure variation and stroke volume variation may have low performance for
predicting fluid responsiveness during open chest condition in patients having cardiothoracic
surgery DynaMed Level 2
SYSTEMATIC REVIEW: J Clin Monit Comput 2017 Aug;31(4):677
Details
– based on systematic review of diagnostic studies limited by heterogeneity
– systematic review of 7 diagnostic studies evaluating pulse pressure variation and stroke volume
variation for predicting uid responsiveness during open chest condition in 236 patients having
cardiothoracic surgery
– ventilator settings (tidal volume and positive end-expiratory pressure) and monitoring devices
varied among studies
– reference standard was uid challenge with hydroxyethyl starch in 6 studies (with varying
de nitions of responsiveness) and leg raise in 1 study
– 61.8% had positive uid response by reference standard
– all results limited by signi cant statistical heterogeneity
– for prediction of uid responsiveness in open chest conditions
● pulse pressure variation had modest performance (pooled c-statistic 0.663, 95% CI 0.427-
0.899) in analysis of 2 studies
● stroke volume variation had modest performance (pooled c-statistic 0.687, 95% CI 0.527-
0.847) in analysis of 4 studies
– Reference - J Clin Monit Comput 2017 Aug;31(4):677
Passive leg raising
● passive leg raising transiently and reversibly induces changes in right and left cardiac preload by
shifting venous blood from legs to intrathoracic compartment, thereby increasing venous return 1 , 2
⚬ serves as preload challenge of approximately 300 mL of blood
⚬ if ventricles are preload dependent, passive leg raise should increase stroke volume
● maximum e ect of passive leg raising occurs about 1 minute after starting maneuver 2
● advantages of passive leg raising
⚬ may be repeated as frequently as needed without risk of uid overload, as no uid is required
⚬ may be accurately performed in patients with spontaneous breathing, low tidal volume ventilation,
low lung compliance, and cardiac arrhythmias
● 5 rules for properly preforming passive leg raising
⚬ start from semirecumbent position (trunk at 45 degrees), as adding trunk lowering magni es
e ects of leg elevation and increases sensitivity
⚬ assess e ects using direct measurement of cardiac output (do not use blood pressure
measurements only)
⚬ use real-time cardiac output monitoring techniques that can detect short-term, transient changes
⚬ perform maneuver by adjusting bed, not manually raising patient legs to avoid confounding factors
such as pain, discomfort, or awakening
⚬ reassess cardiac output after maneuver (when patient back in semirecumbent position) to con rm
return to baseline values
⚬ Reference - Crit Care 2015 Jan 14;19:18 full-text , commentary can be found in Crit Care 2015
Jun 1;19:237
● limited evidence suggests passive leg raising may be less accurate in patients with intra-abdominal
hypertension 1
STUDY
● SUMMARY
passive leg raising may help identify critically ill patients responsive to fluid therapy
DynaMed Level 2
SYSTEMATIC REVIEW: Crit Care Med 2016 May;44(5):981
Details
⚬ systematic review of 23 diagnostic studies evaluating passive leg raising for prediction of uid
responsiveness in 1,013 patients (mean age 59 years)
– passive leg raising consisted of lifting straightened lower limbs to a 45-degree angle, mostly
from semirecumbent starting position
– uid response de ned as ≥ 15% increase in cardiac output or its direct derivatives (aortic blood
ow, stroke volume index, stroke volume, or cardiac index) in most studies
– 57% of patients had sepsis
⚬ reference standard was uid challenge

⚬ cuto values, measurement techniques, and outcome variables to determine uid response
di ered among studies
⚬ ventilation modes included controlled mechanical ventilation in 8 studies, spontaneous breathing
in 7 studies, and mixed modes in 8 studies
⚬ measurement of uid response (to both passive leg raising and uid challenge) included
esophageal Doppler, transthoracic echocardiography, calibrated pulse contour analysis, and
bioreactance
⚬ mean 53% of patients (range 29%-88%) responded to uid challenge
⚬ pooled diagnostic performance of uid response after passive leg raising
– sensitivity 86% (95% CI 79%-92%)

– speci city 92% (95% CI 88%-96%)
⚬ Reference - Crit Care Med 2016 May;44(5):981 , editorial can be found in Crit Care Med 2016
May;44(5):1020
STUDY
● SUMMARY
passive leg raising evaluated by changes in cardiac output, but not by changes in arterial pulse
pressure, may predict fluid responsiveness in critically ill patients DynaMed Level 2
SYSTEMATIC REVIEW: Intensive Care Med 2016 Dec;42(12):1935
Details
⚬ systematic review of 21 studies evaluating passive leg raising for prediction of uid responsiveness
in 991 adults
– passive leg raising was initiated from supine position at 0 degrees in 4 studies and
semirecumbent position in 17 studies
– uid responsiveness de ned as ≥ 15% increase in cardiac output (or surrogate) in 16 studies,
with range of ≥ 7% to ≥ 12% increase in cardiac output in remaining studies
– cardiac output measured by echocardiography, calibrated pulse contour analysis, bioreactance,
esophageal Doppler, transpulmonary thermodilution or pulmonary artery catheter, and
suprasternal Doppler
– 8 studies also evaluated changes in arterial pulse pressure with passive leg raising
⚬ reference standard was uid challenge

⚬ 54% of 995 uid challenges had positive response
⚬ for prediction of uid responsiveness, pooled performance of
– passive leg raising-induced changes in cardiac output in analysis of all studies
● sensitivity 85% (95% CI 81%-88%)

● speci city 91% (95% CI 88%-93%)
– passive leg raising-induced changes in arterial pulse pressure in analysis of 8 studies with 432
uid challenges
● sensitivity 56% (95% CI 49%-53%)
● speci city 83% (95% CI 77%-88%)
⚬ Reference - Intensive Care Med 2016 Dec;42(12):1935
STUDY
● SUMMARY
increased cardiac output in response to passive leg raising may help predict response to fluid
administration in patients with hemodynamic instability presenting to emergency room
DynaMed Level 2
SYSTEMATIC REVIEW: JAMA 2016 Sep 27;316(12):1298
Details
⚬ based on systematic review of diagnosis studies limited by heterogeneity
⚬ systematic review of 50 studies evaluating tests to predict uid responsiveness in 2,260 patients
presenting to emergency department or intensive care unit with hemodynamic instability
– hemodynamic instability most commonly due to sepsis (median 71%) and nonseptic systemic
in ammatory response (median 23%)
– 66% were treated with vasopressors at inclusion
– patients received uid resuscitation prior to enrollment in 43 out of 50 studies, but indices were
measured before assessment of uid responsiveness in all studies
⚬ uid responsiveness de ned as increase in cardiac output ≥ 15% in 39 studies and ≥ 10% in 11
studies following IV uid administration measured by noninvasive or invasive methods (reference
standard)
⚬ mean prevalence of uid responsiveness 50% (95% CI 42%-56%)
⚬ dynamic measures associated with highest pooled performance for prediction of uid
responsiveness include
– cardiac output increase in response to passive leg raising at mean cuto 11% in analysis of 17
studies with 788 patients
● sensitivity 88% (95% CI 80%-93%)
● speci city 92% (95% CI 89%-95%)
● positive likelihood ratio 11 (95% CI 7.6-17)
● negative likelihood ratio 0.13 (95% CI 0.07-0.22)
● similar results during controlled ventilation or spontaneous breathing
– pulse pressure variation with high tidal volume (≥ 7 mL/kg) controlled ventilation at mean cuto
11% in analysis of 17 studies with 768 patients
● sensitivity 84% (95% CI 75%-90%)
● speci city 84% (95% CI 77%-90%)
● positive likelihood ratio 5.3 (95% CI 3.5-8.1)
– pulse pressure variation with low tidal volume (< 7 mL/kg) controlled ventilation at mean cuto
8% in analysis of 5 studies with 219 patients
● sensitivity 72% (95% CI 61%-81%)
● speci city 91% (95% CI 83%-95%)
● positive likelihood ratio 7.9 (95% CI 4.1-16)
⚬ Reference - JAMA 2016 Sep 27;316(12):1298
STUDY
● SUMMARY
fluid management based on passive leg raise-guided stroke volume responsiveness reduces need
for renal replacement therapy and mechanical ventilation in adults presenting to emergency
department with sepsis-associated hypotension DynaMed Level 1
RANDOMIZED TRIAL: Chest 2020 Apr 27 early online
Details
⚬ based on randomized trial
⚬ 152 adults presenting to emergency department with sepsis-associated hypotension and enrolled
within 24 hours after hospital arrival were randomized to uid management based on passive leg
raise-guided stroke volume responsiveness vs. usual care and followed for 30 days
⚬ all patients had sepsis or septic shock (≥ 2 criteria of systemic in ammatory response syndrome
and suspected or documented infection) and were expected to be admitted to intensive care unit
(ICU)
⚬ stroke volume was assessed with continuous noninvasive surface electrode bioreactance
⚬ stroke volume-guided uid and vasopressor management was based on algorithm using change in
stroke volume of < 10% to initiate titration of pressors and > 10% to give uids; treatment was
continued for rst 72 hours of ICU admission or until ICU discharge, whichever occurred rst
⚬ primary outcome was positive uid balance at 72 hours or ICU discharge
⚬ 82% included in e cacy analyses, 99% in safety analysis
⚬ comparing stroke volume-guided uid management vs. usual care
– requirement for renal replacement therapy in 5.1% vs. 17.5% (p = 0.042, NNT 8)
– requirement for mechanical ventilation in 17.7% vs. 34.1% (p = 0.044, NNT 6)
– mean uid balance at 72 hours or at ICU discharge 0.65 L vs. 2.02 L (p = 0.021)
– mean duration of ventilator use 47 hours vs. 119.42 hours (p = 0.079)
– overall mortality 19.6% vs. 20.8% (not signi cant)
– 3-point major adverse cardiac event in 6% vs. 12.2% (not signi cant)
– discharge home in 63.9% vs. 43.9% (p = 0.035, NNT 5)
– treatment-emergent serious adverse event in 10.2% vs. 15.6% (not signi cant)
⚬ no signi cant di erences in ICU length of stay, duration of vasopressor use, or change from
baseline in serum creatinine
⚬ Reference - FRESH trial (Chest 2020 Apr 27 early online )
End-expiratory occlusion test
● end-expiratory occlusion test is a functional test for uid responsiveness performed on patients
receiving mechanical ventilation 1 , 2

⚬ intrathoracic pressure during insu ation decreases venous return and cardiac preload
⚬ interrupting mechanical ventilation with short (≥ 15 seconds) end-expiratory occlusion stops cyclic
impediment of venous return and left cardiac preload
⚬ cardiac preload increase during end-expiratory occlusion test indicates both ventricles are preload
responsive
● patients must be intubated and able to tolerate respiratory hold for ≥ 15 seconds 1
● techniques used for assessing end-expiratory occlusion test's e ect on cardiac output must be able to
detect small changes (pulse contour analysis most commonly reported) 1
● advantages of end-expiratory occlusion test 1 , 2
⚬ easy to perform - stop ventilator as when measuring change in cardiac output or positive end-
expiratory pressure
⚬ independent of cardiac arrhythmias
⚬ may be used in patients with acute respiratory distress syndrome
STUDY
● SUMMARY
end-expiratory occlusion test and passive leg raising may predict fluid responsiveness in
patients with circulatory failure regardless of respiratory compliance, while pulse pressure
variation has poor performance in patients with low respiratory compliance DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Crit Care Med 2012 Jan;40(1):152
Details
⚬ 54 adults (mean age 63 years) with circulatory failure (mostly due to sepsis) having mechanical
ventilation in assist control mode were assessed for uid responsiveness by end-expiratory
occlusion test, passive leg raising, and baseline pulse pressure variation
– all patients were sedated (5 received paralytics) and monitored by PiCCO2 device
– patients were excluded for spontaneous breathing, cardiac arrhythmias, or contraindication to
passive leg raising (head trauma or compression stockings)
– 27 patients (50%) had acute respiratory distress syndrome (mean respiratory system
compliance 22 mL/cm H2O)
– mean total positive end-expiratory pressure was 7 cm H2O in 28 patients with compliance ≤ 30
cm H2O and 6 cm H2O in 26 patients with compliance > 30 cm H2O
⚬ reference standard was uid challenge with 500 mL of saline infused over 20 minutes
⚬ 56% responded to uid challenge, de ned as ≥ 15% increase in cardiac index
⚬ performance for identifying uid responsiveness in patients based on respiratory system
compliance
Test Compli Best Sensiti Speci PPV NPV

ance Cuto vity city
(mL/c
m H2O)
End- > 30 5% 93% 91% 93% 91%

expirat
ory
occlusi ≤ 30 5% 93% 92% 93% 92%
on test
Passive > 30 10% 93% 91% 93% 91%

leg
raising ≤ 30 10% 94% 100% 100% 93%
Pulse > 30 12% 85% 100% 100% 84%

pressur
e
variatio ≤ 30 4% 100% 31% 64% 100%
n
Abbreviations: NPV, negative

predictive value; PPV, positive predictive
value.
⚬ Reference - Crit Care Med 2012 Jan;40(1):152 , editorial can be found in Crit Care Med 2012
Jan;40(1):327 , commentary can be found in Crit Care Med 2012 May;40(5):1691
STUDY
● SUMMARY
15-second end-expiratory occlusion test has high sensitivity and specificity for fluid
responsiveness in patients with acute respiratory distress syndrome and acute circulatory
failure, regardless of PEEP setting DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Crit Care Med 2013 Jul;41(7):1692
Details
⚬ based on diagnostic cohort study with unclear blinding of test under investigation
⚬ 34 adults with acute respiratory distress syndrome and acute circulatory failure were assessed for
uid responsiveness by 15-second end-expiratory occlusion test and passive leg raising (reference
standard)
– all patients were sedated and mechanically ventilated in volume assist-controlled mode with
tidal volume 6-7 mL/kg
– baseline positive end-expiratory pressure (PEEP) 5 cm H2O and initial end-expiratory occlusion
test was performed after at 15 minutes baseline hemodynamic measurements, followed by
passive leg raising 1 minute later
– after rst passive leg raising, PEEP was increased to obtain plateau pressure of 30 cm H2O;
hemodynamic measurements were obtained after stabilization, followed by second end-
expiratory occlusion test and passive leg raising
⚬ at presentation, 18% had atrial brillation, 35% had spontaneous triggering of ventilator and all
patients had extravascular lung water ≥ 7 mL/kg
⚬ uid responsiveness was de ned as ≥ 10% increase in cardiac index during passive leg raising
⚬ at PEEP of 5 cm H2O
– 29% were uid responsive

– performance of end-expiratory occlusion test with cuto ≥ 5% increase in cardiac index
● sensitivity 90%
● speci city 88%
⚬ at increased PEEP (plateau pressure of 30 cm H2O)
– 38% were uid responsive (all patients responding at PEEP 5 cm H2O plus 3 previous
nonresponders)
– performance of end-expiratory occlusion test with cuto ≥ 6% increase in cardiac index
● sensitivity 100%
● speci city 90%
⚬ 20 patients had uid challenge after all testing
– 65% were responsive to uid challenge, de ned as ≥ 15% increase in cardiac index
– all responders to uid challenge were responders on passive leg raising and all uid challenge
nonresponders had negative passive leg raising
⚬ Reference - Crit Care Med 2013 Jul;41(7):1692
Vena caval dimension variations
● variations in diameter of inferior vena cava (IVC) or superior vena cava (SVC) over respiratory cycles
are associated with uid responsiveness 1 , 2 , 3

⚬ when blood volume is low, mechanical ventilation-induced changes in intrathoracic pressure may
cause variations in vena caval dimensions at points close to the heart
⚬ absence of respiratory variations suggests patients are not uid responsive
● transthoracic echocardiography may be used for IVC measurements, but transesophageal
echocardiography is needed for SVC measurements 1 , 3

⚬ vessel walls must be kept clearly visible throughout respiratory cycle and bright edges must be
kept in view
⚬ IVC can move out of ultrasound beam plane during respiration, mimicking changes in diameter
⚬ spontaneous breathing can signi cantly a ect vessel size and leads to less accuracy
● IVC variations can be assessed in M-mode, but are better viewed in 2-dimensional mode (2-D) 3
● commonly used calculations include 3
⚬ IVC diameter variability = ([maximum IVC diameter - minimum IVC diameter] ÷ mean IVC diameter)
× 100
⚬ IVC distensibility index = (maximum IVC diameter - minimum IVC diameter) ÷ minimum IVC
diameter
⚬ SVC collapsibility index = ([maximum SVC diameter - minimum SVC diameter] ÷ minimum SVC
diameter) × 100
● reported cuto s vary 1
● variations in caval dimensions may predict uid responsiveness in patients with cardiac arrhythmias 1
STUDY
● SUMMARY
changes in IVC dimensions may help identify fluid responsiveness in critically ill patients
DynaMed Level 2
SYSTEMATIC REVIEW: Ultrasound Med Biol 2014 May;40(5):845 | Full Text
Details
⚬ systematic review of 8 studies evaluating ultrasound-measured changes in IVC dimensions for
predicting uid responsiveness in 235 critically ill patients
– 5 studies evaluated patients on mechanical ventilation, 2 evaluated spontaneously breathing
patients, and 1 did not report respiratory pattern
– reference for IVC measurements sites was right atrium 6 studies and suprahepatic vein in 2
studies
– reference standard was uid challenge (with varying uids) in 6 studies and passive leg raising in
1 study, with varied de nitions of positive response
⚬ cuto values for determining uid responsiveness with change in IVC ranged from 12% to 40%
⚬ pooled performance of change in IVC dimensions for predicting uid responsiveness
– in overall analysis of 6 studies with 179 patients
● sensitivity 76% (95% CI 61%-86%)

● speci city 86% (95% CI 69%-95%)
– in analysis of 4 studies with 116 patients receiving mechanical ventilation
● sensitivity 81% (95% CI 67%-91%)

● speci city 87% (95% CI 63%-97%)
⚬ Reference - Ultrasound Med Biol 2014 May;40(5):845 full-text
● performance of IVC collapsibility in patients with spontaneous breathing
STUDY
⚬ SUMMARY
IVC collapsibility index during standardized breathing helps predict responders to volume
expansion in nonintubated patients with sepsis-induced acute circulatory failure
DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Crit Care Med 2017 Mar;45(3):e290

Details
– 112 consecutive patients (64% male) presenting to 2 intensive care units with sepsis-induced
acute circulatory failure and who were not intubated were assessed for uid responsiveness by
IVC collapsibility index and changes in stroke volume index after volume expansion (reference
standard)
● all patients were spontaneously breathing without mechanical assistance, had regular sinus
cardiac rhythm, and ≥ 1 sign of acute circulatory failure including systemic arterial
hypotension, oliguria, tachycardia, and mottled skin
● patients assessed at baseline and after volume expansion with 4% gelatin 500-mL infusion
over 30 minutes
– 22 patients were excluded due to nonmeasurable parameters
– 16% received norepinephrine IV continuously
– measurements to calculate IVC collapsibility index and stroke volume index obtained during
standardized and spontaneous breathing using transthoracic echocardiography
● standardized breathing included deep standardized inspirations (brief continuous inspiration
strain not surpassing maximum inhalation, with patients guided to generated a minimum
buccal pressure from -5 to -10 mm H2O without any respiratory resistor) followed by passive
exhalation
● IVC collapsibility index de ned as 100 × ([end-expiratory IVC diameter - minimum-inspiratory
IVC diameter] ÷ end-expiratory IVC diameter)
– 56% responded to volume expansion (de ned as ≥ 10% increase in stroke volume index)
– performance of IVC collapsibility index for prediction of uid responsiveness
● during standardized breathing with cuto ≥ 48%

⚬ sensitivity 84%
⚬ speci city 90%
● during spontaneous breathing with cuto ≥ 31%

⚬ sensitivity 76%
⚬ speci city 88%
– Reference - Crit Care Med 2017 Mar;45(3):e290
STUDY
⚬ SUMMARY
IVC collapsibility index may have high specificity, but low sensitivity, for fluid responsiveness
in nonventilated, spontaneously breathing patients in intensive care unit DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Crit Care 2015 Nov 13;19:400 | Full Text
Details
– 59 nonintubated, nonventilated, spontaneous breathing patients (mean age 57 years) in
intensive care unit having uid expansion were assessed for uid responsiveness using changes
in IVC diameter at baseline, after passive leg raising, and uid challenge (reference standard)
● patients were excluded for clinical signs of hemorrhage, arrhythmia, inability to delay uid
challenge for responsiveness testing, compression stocking use, or contraindication to
passive leg raising
● patients had invasive arterial pressure monitoring; cardiac output and IVC diameter were
measured with echocardiography
– 39% had clinical or laboratory signs of dehydration, 34% had oligoanuria or acute kidney failure,
and 27% had hypotension or acute circulatory failure
– reference standard was uid challenge with positive response de ned as ≥ 10% increase in
cardiac output after uid expansion
– 49% were uid responsive de ned as ≥ 10% increase in cardiac output after uid challenge
– IVC collapsibility index calculates respiratory decreases in IVC diameter and is de ned as
(maximum IVC diameter on expiration - minimum IVC diameter on inspiration) ÷ maximum IVC
diameter on expiration
– performance of IVC measurements for prediction of uid responsiveness
● IVC collapsibility index at cuto > 42%

⚬ sensitivity 31%
⚬ speci city 97%
⚬ positive predictive value 90%
⚬ negative predictive value 59%
● baseline maximum IVC diameter at baseline < 2.1 cm
⚬ sensitivity 93%
⚬ speci city 33%
⚬ positive predictive value 57%
⚬ negative predictive value 83%
– Reference - Crit Care 2015 Nov 13;19:400 full-text
STUDY
● SUMMARY
superior vena cava collapsibility ≥ 36% may be associated with positive response to blood
volume expansion in patients receiving mechanical ventilation for septic shock with associated
acute lung injury
COHORT STUDY: Intensive Care Med 2004 Sep;30(9):1734
Details
⚬ based on prospective cohort study without independent validation
⚬ 66 patients receiving mechanical ventilation for septic shock with associated acute lung injury had
simultaneously measured superior vena caval collapsibility by echocardiography and cardiac index
by Doppler echocardiography at baseline and after blood volume expansion
⚬ rapid blood volume expansion therapy included IV hydroxyethyl starch 6% dose of 10 mL/kg over
30 minutes
⚬ superior vena cava collapsibility was calculated as
(maximum diameter on expiration - minimum diameter on inspiration)/maximum

diameter on expiration
⚬ mean superior vena cava collapsibility was 30% at baseline and 14% after blood volume expansion
(p < 0.05)
⚬ 20 patients (30%) responded to blood volume expansion (de ned as increase in cardiac index ≥
11%)
⚬ mean superior vena cava collapsibility at baseline was signi cantly higher in patients who
responded to blood volume expansion compared to patients who did not response (64% vs. 17%, p
< 0.05)
⚬ compared to baseline, mean superior vena cava collapsibility was signi cantly reduced after blood
volume expansion in patients who responded to therapy, but not in patients who did not respond
to therapy
⚬ for predicting positive response to blood volume expansion, superior vena cava collapsibility ≥ 36%
at baseline had sensitivity 90% and speci city 100%
⚬ Reference - Intensive Care Med 2004 Sep;30(9):1734 , editorial can be found in Intensive Care
Med 2004 Sep;30(9):1699 , commentary can be found in Intensive Care Med 2004
Dec;30(12):2282
● respiratory variations in SVC diameter may have higher performance for predicting uid
responsiveness than variations in IVC diameter, but measurements of SVC diameter require use of
more invasive transesophageal echocardiography
STUDY
⚬ SUMMARY
respiratory variations of SVC diameter may have higher performance than respiratory
variations of IVC diameter or pulse pressure variations in patients with acute circulatory
failure having mechanical ventilation DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Am J Respir Crit Care Med 2017 Apr 15;195(8):1022
Details
– based on diagnostic cohort study without independent reference standard
– 540 adults (mean age 65 years, 70% male) with acute circulatory failure having mechanical
ventilation with sedation and with inserted central venous and arterial catheters were assessed
for uid responsiveness by
● respiratory variations of SVC diameter (ΔSVC) by transesophageal echocardiography
● respiratory variations of IVC diameter (ΔIVC) by transthoracic echocardiography
● pulse pressure variations (PPV) in the semirecumbent position
● left ventricular out ow tract maximal Doppler velocity (ΔVmaxAo) by either
echocardiographic approach
– 66% had tidal volume < 8 mL/kg, 32% had intra-abdominal pressure ≥ 12 mm Hg, and 14% had
nonsinus rhythm
– only 15.6% had tidal volume ≥ 8 mL/kg, intra-abdominal pressure < 12 cm Hg, and sinus rhythm
– 85% were receiving catecholamines at time of echocardiographic assessment
– reference standard was passive leg raising with responsiveness de ned as ≥ 10% increase in
aortic ow velocity time integral
– 42% were uid responsive by reference standard
– performance of dynamic measures for identi cation of uid responsiveness
● in analysis of all patient
Parameter Patients Cuto Sensitivity Speci city

assessed
ΔSVC 538 ≥ 21% 61% 84%
ΔIVC 422 ≥ 8% 55% 70%

Parameter Patients Cuto Sensitivity Speci city
assessed
PPV 424 ≥ 11% 58% 72%
ΔVmaxAo 421 ≥ 10% 79% 64%
● in analysis of 319 patients assessed by all parameters
Parameter Cuto Sensitivity Speci city
ΔSVC ≥ 21% 63% 81%
ΔIVC ≥ 13 44% 85%
PPV ≥ 11% 55% 73%
ΔVmaxAo ≥ 9.4% 78% 60%
– ΔSVC had signi cantly higher discrimination than PPV or ΔIVC

– Reference - Am J Respir Crit Care Med 2017 Apr 15;195(8):1022
STUDY
⚬ SUMMARY
SVC collapsibility index helps identify fluid responsiveness and has higher performance than
IVC distensibility in patients with sepsis or septic shock having mechanical ventilation
DynaMed Level 1
DIAGNOSTIC COHORT STUDY: Crit Care 2014 Sep 5;18(5):473 | Full Text
Details
– based on diagnostic cohort study
– 44 patients with sepsis or septic shock having mechanical ventilation were assessed for uid
responsiveness by IVC variations, SVC variations, and change in cardiac output after uid
challenge (reference standard)
● all patients had volume controlled mechanical ventilation with tidal volume 8-10 mL/kg while
under sedation
● patients were excluded for spontaneous breathing, cardiac arrhythmias, or contraindication
to transesophageal echocardiography
– IVC distensibility index was calculated during mechanical insu ation and de ned as (maximum
IVC diameter - minimum IVC diameter) ÷ minimum IVC diameter
– SVC collapsibility index was calculated from measurements over 1 respiratory cycle and de ned
as (maximum SVC diameter - minimum SVC diameter) ÷ maximum SVC diameter
– 59% were uid responsive de ned as ≥ 15% increase in cardiac output on uid challenge
– performance of vena cava measurements for prediction of uid responsiveness using previously
published cuto s
Measure Cuto Sensitivi Speci ci PPV NPV
ty ty
SVC > 36% 42% 100% 100% 55%

collapsibility
IVC ≥ 18% 42% 39% 48% 33%

distensibility
Abbreviations: NPV, negative

predictive value; PPV, positive predictive
value.
– performance of vena cava measurements for prediction of uid responsiveness using study
de ned best cuto s
● SVC collapsibility > 29% had sensitivity 54% and speci city 94%
● IVC distensibility > 21% had sensitivity 38% and speci city 61%
– SVC collapsibility had signi cantly higher discrimination compared to IVC distensibility (c-
statistics 0.74 vs. 0.43) (p = 0.012)
– Reference - Crit Care 2014 Sep 5;18(5):473 full-text
–
DynaMed Commentary
The authors indicate that tidal volumes of 8-10 ml/kg were used for all patients, but later
discuss their analysis excluding patients with a tidal volume < 8 mL/kg (18 patients). This
discrepancy is never addressed.
Other methods of fluid assessment
STUDY
● SUMMARY
pleth variability index may have low sensitivity but moderate specificity for predicting fluid
responsiveness in mechanically ventilated patients DynaMed Level 2
SYSTEMATIC REVIEW: J Clin Monit Comput 2016 Jun;30(3):265
Details
⚬ based on systematic review of diagnostic studies with unclear blinding of reference standard or
test under investigation
⚬ systematic review of 18 studies evaluating pleth variability index for predicting uid responsiveness
in 665 children and adults on mechanical ventilation in operating room or intensive care unit
– 13 studies were conducted in operating rooms and 5 studies in intensive care units
– 16 studies included adults and 2 studies included children
– all patients had closed chest conditions, normal sinus rhythm, and mechanical ventilation
⚬ reference standard was uid challenge in all studies, but de nitions of uid responsiveness varied
⚬ best pleth variability index threshold for predicting uid responsiveness varied from 8% to 20%
⚬ pooled performance of pleth variability index for predicting uid responsiveness in analysis of all
studies
– sensitivity 73% (95% CI 68%-78%)
– speci city 82% (95% CI 77%-86%)
– positive likelihood ratio 4.16 (95% CI 3.22-5.38)
– negative likelihood ratio 0.3 (95% CI 0.24-0.36)
⚬ comparing studies conducted in operating room vs. intensive care unit, pleth variability index had
– sensitivity 84% vs. 56% (p < 0.0001)

– speci city 84% vs. 84% (not signi cant)
⚬ Reference - J Clin Monit Comput 2016 Jun;30(3):265
STUDY
● SUMMARY
internal jugular vein distensibility may help predict fluid responsiveness in mechanically
ventilated patients with sepsis, especially when combined with pulse pressure variation
DynaMed Level 2
DIAGNOSTIC COHORT STUDY: Crit Care 2014 Dec 5;18(6):647 | Full Text
Details
⚬ 50 adults (median age 67, 64% male) with sepsis having mechanical ventilation were assessed for
uid responsiveness by internal jugular vein (IJV) distensibility, arterial pulse pressure variation
(PPV), and change in cardiac index after volume expansion (reference standard)
– mechanical ventilation parameters adjusted to maintain airway plateau pressure < 30 cm H2O,
partial pressure of carbon dioxide (PCO2) < 40 mm Hg, and oxygen saturation (SaO2) > 96% with
tidal volume 6-8 mL/kg, positive end-expiratory pressure (PEEP) of 6 cm H2O, and inspired
oxygen fraction (FiO2) 0.4
– patients were excluded for history of cardiac disease, jugular vein thrombosis, or atrial
brillation
– volume expansion included crystalloid 7 mL/kg infused over 30 minutes
– hemodynamic measurements were obtained via radial arterial indwelling catheter
⚬ IJV was visualized at level of cricoid cartilage with patient in semirecumbent position and head
elevated 30 degrees and recognized by compression, color Doppler, and pulsed-wave Doppler
sampling
⚬ IJV distensibility de ned as ([IJV maximal anteroposterior diameter during inspiration - minimum
expiratory diameter] ÷ minimum expiratory diameter) × 100
⚬ PPV measured over 3 respiratory cycles and de ned (maximum pulse pressure - minimum pulse
pressure) ÷ ([maximum pulse pressure + minimum pulse pressure] ÷ 2)
⚬ 60% were uid responders de ned as cardiac index increase ≥ 15% after volume expansion
⚬ for prediction of uid responsiveness
– IJV distensibility with cuto > 18% had sensitivity 80% and speci city 85%
– PPV with cuto > 12.5% had sensitivity 96% and speci city 55%
– IJV distensibility with cuto > 9.9% plus PPV > 12% had sensitivity 100% and speci city 95%
⚬ IJV alone and PPV alone had similar discrimination for prediction of uid responsiveness (c-statistics
0.915 vs. 0.852)
⚬ Reference - Crit Care 2014 Dec 5;18(6):647 full-text
STUDY
● SUMMARY
respiratory changes in peak velocity of aortic blood (ΔVpeak) > 12% may be associated with
positive response to volume expansion in patients with septic shock receiving mechanical
ventilation DynaMed Level 2
PREDICTION RULE: Chest 2001 Mar;119(3):867
Details
⚬ based on prospective prognostic cohort study without independent validation
⚬ 19 patients (mean age 58 years) with septic shock receiving mechanical ventilation had
transesophageal echocardiography beat-to-beat measurement of aortic blood ow before and
after volume expansion
– all patients were hemodynamically stable and had left ventricular ejection fraction ≥ 30%
– patients were excluded if arrhythmia, severe hypoxemia, aortic valvulopathy, or Doppler left
ventricular output measurement in transgastric view could not be obtained
– drug therapy included inotropic and vasopressor drugs in all patients, epinephrine in 13
patients, dopamine in 6 patients, and dobutamine in 11 patients
⚬ 8 patients (42%) survived
⚬ 10 patients (53%) responded to volume expansion (de ned as increase in cardiac index ≥ 15%)
⚬ respiratory changes in peak velocity of aortic blood (ΔVpeak) was calculated as
ΔVpeak (%) = 100 × (Vpeakmax - Vpeakmin)/ [(Vpeakmax + Vpeakmin)/2]
⚬ mean ΔVpeak at baseline was signi cantly higher in patients who responded to volume expansion
compared to patients who did not response (20% vs. 10%, p < 0.001)
⚬ for predicting positive response to blood volume expansion, ΔVpeak > 12% had sensitivity 100%
and speci city 89%
⚬ Reference - Chest 2001 Mar;119(3):867
Static variables
● central venous pressure and other static measures do not adequately predict uid responsiveness
and should not be used 1 , 2

⚬ shape of Frank-Starling curve varies for every patient and static measures cannot di erentiate uid
responsiveness from unresponsiveness due to this variability
⚬ other static measurements include pulmonary artery occlusion pressure, global end-diastolic
volume measured by transpulmonary thermodilution, aortic ow time by esophageal Doppler, and
left ventricular end-diastolic dimensions on echocardiography
● central venous pressure should still be measured for other clinical indications 1
⚬ marker of preload, but not preload responsiveness, and key determinant of cardiac function
⚬ required for determining pressure gradient for organ perfusion
⚬ high central venous pressure associated with impaired renal perfusion, acute kidney injury, or pre-
existing pulmonary hypertension
● static variables may only be useful at extremely low and high values (not seen in most critically ill
patients) to guide therapy in combination with clinical features (Crit Care Clin 2015 Jan;31(1):89 full-
text )
STUDY
● SUMMARY
central venous pressure may not predict fluid responsiveness in critically ill patients
DynaMed Level 2
SYSTEMATIC REVIEW: Intensive Care Med 2016 Mar;42(3):324
Details
⚬ based on systematic review of diagnostic cohort study limited by clinical heterogeneity
⚬ systematic review of 51 studies evaluating use of central venous pressure (CVP) for predicting uid
responsiveness
⚬ studies varied in patient population, use of mechanical ventilation, methods and parameters for
de ning uid responsiveness (reference standards), and preload uid protocols
⚬ raw baseline CVP data was available for 982 critically ill patients (1,148 individual responsiveness
assessments) from 22 studies
– 48% of all assessments were from patients responsive to uid
– performance of CVP for prediction of uid responsiveness was low across all patient subgroups
(c-statistic range 0.5-0.59)
– no calculated positive or negative predictive value above 66% for any central venous pressure
cuto from 0 to 20 mm Hg
⚬ Reference - Intensive Care Med 2016 Mar;42(3):324 , editorial can be found in Intensive Care Med
2016 Mar;42(3):458
Fluid Resuscitation Strategies
Goal-directed therapy
● inconsistent evidence for e cacy of protocol-based strategies
STUDY
⚬ SUMMARY
protocol-based early goal-directed therapy is similar to usual care for mortality in patients
with early septic shock, but reduces mortality in subgroup of patients with coexisting
respiratory condition DynaMed Level 1
RANDOMIZED TRIAL: N Engl J Med 2017 Jun 8;376(23):2223
Details
– based on collaborative meta-analysis of individual patient data from 3 randomized trials
– individual patient data from 3,723 patients (median age 65 years, 58% male) with septic shock
randomized to early goal-directed therapy vs. usual care in ARISE, ProCESS, and ProMISe
randomized trials were assessed
– protocol-based standard therapy arm of ProCESS trial (448 patients) were not included in
analysis
– 98.9% included in primary analysis and 93.3% were followed for 1 year
– comparing early goal-directed therapy vs. usual care
● 90-day mortality 24.9% vs. 25.4% (not signi cant)

● mean intensive care unit stay (including readmissions) 5.3 days vs. 4.9 days (p = 0.04)
● cardiovascular support received by 56.1% vs. 49.3% (p < 0.001)
● mean duration of cardiovascular support 1.9 days vs. 1.6 days (p = 0.01)
– no signi cant di erences in 28-day mortality, 1-year mortality, length of hospital stay, receipt of
respiratory or renal support, and quality of life at 90 days
– in prespeci ed subgroup analyses, early goal-directed therapy associated with
● increased 90-day mortality in 117 patients with coexisting liver condition (odds ratio 2.51,
95% CI 1.12-5.63)
● decreased 90-day mortality in 370 patients with coexisting respiratory condition (odds ratio
0.54, 95% CI 0.34-0.85)
– no signi cant di erences in other subgroups including those assessing severity of septic shock,
lactate levels, vasopressor use, invasive mechanical ventilation use, or volume of uid use
– Reference - N Engl J Med 2017 Jun 8;376(23):2223
– 3 trials (ARISE, ProCESS, and ProMISe) included in pooled analysis
● 1,600 patients (mean age 63 years) with septic shock in emergency department for ≤ 6 hours
randomized to early goal-directed therapy (EGDT) vs. usual care for 6 hours and followed for
90 days
⚬ early goal-directed therapy included supplemental oxygen, crystalloids or colloids until
desired central venous pressure obtained, vasopressors and/or vasodilators, red blood
cell transfusion, and dobutamine administered in emergency department and/or
intensive care unit
⚬ early goal-directed therapy group received larger volume of IV uids and had higher rate
of vasopressor infusions, red blood cell transfusions, and dobutamine (p < 0.001 for each)
⚬ comparing early goal-directed therapy vs. usual care
– 90-day mortality 18.6% vs. 18.8% (not signi cant)

– median length of stay in emergency department 1.4 hours vs. 2 hours (p < 0.001)
– median hospital stay 8.2 days vs. 8.5 days (not signi cant)
⚬ no signi cant di erences in in-hospital mortality, duration of organ support with

mechanical ventilation, vasopressors, renal replacement therapy, or adverse events
⚬ Reference - ARISE trial (N Engl J Med 2014 Oct 16;371(16):1496 full-text ), commentary
can be found in Acta Anaesthesiol Scand 2016 Aug;60(7):925
● 1,341 patients ≥ 18 years old with severe sepsis and septic shock at 31 hospitals in the United
States were randomized to 1 of 3 treatment strategies
⚬ treatment strategies
– protocol-based EGDT, with placement of central venous catheter, monitoring of

pressure and central venous oxygen saturation (ScvO2), and administration of IV uids,
vasopressors, packed red blood cell transfusions, or dobutamine, or as directed
– protocol-based standard therapy, with 6-hour resuscitation instructions that did not
specify placement of central venous catheter, administration of inotropes, or blood
transfusions
– usual care
⚬ eligible sites used serum lactate level measurements to screen for cryptogenic shock and
adhered to Surviving Sepsis Campaign guidelines for nonresuscitation aspects of care
⚬ nonadherence to protocol occurred with 11.9% of patients in EGDT group and 4.4% of
patients in protocol-based standard therapy group
⚬ 60-day mortality (not signi cant)
– 21% with protocol-based EGDT

– 18.2% with protocol-based standard therapy
– 18.9% with usual care
⚬ no signi cant di erence in 60-day mortality comparing combined protocol groups vs.
usual care
⚬ no signi cant di erence in severe adverse events, which were uncommon
⚬ Reference - ProCESS trial (N Engl J Med 2014 May;370(18):1683 full-text ), also
published in Crit Care 2015 Jun 19;19:260 full-text , editorial can be found in N Engl J
Med 2014 May 1;370(18):1750 , commentary can be found in Acta Anaesthesiol Scand
2016 Aug;60(7):925
● 1,260 patients ≥ 18 years old with septic shock in emergency department in England for ≤ 6
hours randomized to early goal-directed therapy vs. usual care for 6 hours and followed for
90 days
⚬ early goal-directed therapy included placement of central venous catheter,
recommendation for placement of arterial catheter, supplemental oxygen, uid
resuscitation, vasopressors and/or vasodilators, red blood cell transfusion, and
dobutamine administered in emergency department and/or intensive care unit
⚬ early goal-directed therapy associated with increased use of IV uids, vasoactive drugs,
and red-cell transfusions
⚬ comparing early goal-directed therapy vs. usual care

– mean Sequential Organ Failure Assessment (SOFA) score at 6 hours 6.4 vs. 5.6 (p <
0.001)
– cardiovascular support received by 37% vs. 30.9% (p = 0.026)
– median intensive care unit stay 2.6 days vs. 2.2 days (p = 0.005)
⚬ no signi cant di erence in SOFA score at 72 hours, receipt of advanced respiratory

support, receipt of renal support, median hospital stay, or mean cost
⚬ Reference - ProMISe trial (N Engl J Med 2015 Apr 2;372(14):1301 full-text ), also
published in Health Technol Assess 2015 Nov;19(97):1 full-text , commentary can be
found in Acta Anaesthesiol Scand 2016 Aug;60(7):925
STUDY
⚬ SUMMARY
early goal-directed therapy may not decrease mortality compared to standard therapy or
other resuscitation methods in patients with septic shock DynaMed Level 2
SYSTEMATIC REVIEW: Intensive Care Med 2015 Sep;41(9):1549
Details
– based on systematic review of trials limited by heterogeneity
– systematic review of 11 randomized trials evaluating EGDT in 5,416 patients with septic shock
● 5 trials included patients presenting to emergency department

● 6 trials included patients from emergency department, general ward, or intensive care unit
– EGDT included optimization of hemodynamic goals, such as arterial and central venous
pressures and central venous oxygenation saturation ≥ 70%
– comparing EGDT vs. standard care or other resuscitation method, no signi cant di erences in
● overall mortality (odds ratio 1.01, 95% CI 0.88-1.16) in analysis of 5 trials with 4,735 patients
presenting to emergency department
● overall mortality in analysis of all trials
● both results limited by signi cant heterogeneity
– Reference - Intensive Care Med 2015 Sep;41(9):1549 , editorial can be found in Intensive Care
Med 2015 Sep;41(9):1723
STUDY
⚬ SUMMARY
early resuscitation protocol increases mortality in adults with sepsis and hypotension in
resource-limited setting
RANDOMIZED TRIAL: JAMA 2017 Oct 3;318(13):1233
Details
– based on randomized trial
– 212 adults (mean age 36 years) with sepsis and hypotension presenting to emergency
department in Zambia were randomized to early resuscitation protocol vs. usual care and
followed for 28 days
● early resuscitation protocol included IV uid bolus (2 L over rst hour then 2 L over next 4
hours) with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen
saturation, plus vasopressors 10 mcg/kg/minute with mean arterial pressure target ≥ 65 mm
Hg, and blood transfusion if hemoglobin < 7 g/dL or severe pallor
● usual care was clinician-determined hemodynamic management
– 89% were HIV positive, diagnosis at admission was suspected tuberculosis in 63% and
pneumonia in 49%
– 99.5% treated in regular medical wards without mechanical ventilation available
– comparing early resuscitation protocol vs. usual care
● in-hospital mortality 48.1% vs. 33% (p = 0.03, NNH 6)

● 28-day mortality 67% vs. 45.3% (p = 0.01, NNH 4)
● vasopressors used in 14.2% vs. 1.9% (p < 0.001)
– no transfusion reactions, dopamine extravasation, tissue ischemia, or necrosis reported in

either group
– 2 patients in early resuscitation protocol group had iatrogenic pulmonary edema
– Reference - JAMA 2017 Oct 3;318(13):1233 , editorial can be found in JAMA 2017 Oct
3;318(13):1225
STUDY
⚬ SUMMARY
goal-directed therapy associated with reduced mortality in adults with sepsis
DynaMed Level 2
SYSTEMATIC REVIEW: Crit Care 2014 Oct 20;18(5):570 | Full Text
Details
– based on systematic review limited by signi cant heterogeneity
– systematic review of 13 randomized trials comparing goal-directed therapy vs. standard therapy
or usual care in 2,525 adults with sepsis
– goal-directed therapy de ned as speci c protocol using hemodynamic monitoring and
manipulation of hemodynamic parameters to reach predetermined hemodynamic endpoints
– goal-directed therapy associated with reduced risk of mortality in analysis of all trials, results
limited by signi cant heterogeneity
● relative risk 0.83 (CI 95% 0.71-0.96)
● NNT 9-60 with 42% mortality in control group
– early administration (within 6 hours of admission) of goal-directed therapy associated with
reduced risk of mortality in analysis of 7 trials with 2,062 patients
● relative risk 0.77 (CI 95% 0.67-0.89)
● NNT 8-23 with 40% mortality in control group
● 1 high-quality trial found no signi cant di erence between early administration of goal-
directed therapy and standard care
– Reference - Crit Care 2014 Oct 20;18(5):570 full-text , commentary can be found in Crit Care
2014 Dec 29;18(6):705
STUDY
⚬ SUMMARY
early goal-directed therapy (emergency department protocol for initial 6 hours) may reduce
in-hospital mortality and organ dysfunction DynaMed Level 2
RANDOMIZED TRIAL: N Engl J Med 2001 Nov 8;345(19):1368 | Full Text
Details
– based on randomized trial with postpublication concerns
– 263 patients with severe sepsis or septic shock randomized to 6 hours of early goal-directed
therapy vs. standard therapy prior to admission to ICU
– goal-directed therapy included
● central vein catheter (CVC) that measured ScvO2

● crystalloid 500 mg every 30 minutes as needed to maintain central venous pressure 8-12 mm
Hg
● vasopressors or vasodilators as needed to maintain mean arterial pressure 65-90 mm Hg
● if ScvO2 < 70% and hematocrit < 30%, transfusion of red cells until hematocrit ≥ 30%
● if ScvO2 < 70% remained despite hematocrit ≥ 30% or transfusion to that goal, dobutamine
initiated
– study assignment blinded to clinicians assuming care in ICU
– in-hospital mortality was 30.5% with early goal-directed therapy vs. 46.5% with standard therapy
(p = 0.009, NNT 7)
– Reference - N Engl J Med 2001 Nov 8;345(19):1368 full-text , editorial can be found in N Engl
J Med 2001 Nov 8;345(19):1417 , commentaries can be found in N Engl J Med 2002 Mar
28;346(13):1025 , ACP J Club 2002 May-Jun;136(3):90 , N Engl J Med 2007 Mar
15;356(11):1178
–
DynaMed Commentary
Since publication, concerns have been raised about the validity of these data, including the
high rate of mortality with conventional therapy compared to other published studies, the
possibility that an additional 25 patients were randomized but excluded from analysis, and
author funding by the makers of the catheter used in the trial.
STUDY
⚬ SUMMARY
protocol of combined therapies associated with increased survival compared with
nonprotocolized care in adults with sepsis, likely due to decreased time to antibiotics and
increased appropriateness of antibiotics DynaMed Level 2
SYSTEMATIC REVIEW: Crit Care Med 2010 Feb;38(2):668 | Full Text
Details
– based on systematic review of mostly observational studies with clinical heterogeneity
– systematic review of 8 studies (1 randomized trial without blinding and 7 before-and-after
studies) evaluating e cacy of protocol of combined therapies vs. nonprotocolized care for
adults with sepsis
– studies varied in use of antibiotics within speci c time period, agents used to meet
hemodynamic goals ( uids, vasopressors, inotropes, and blood transfusion), use of
corticosteroids, and use of human recombinant activated protein C
– combined therapies protocols
● 6-hour acute sepsis management
⚬ acquisition of microbiology samples and lactate measures

⚬ administration of appropriate antibiotics
⚬ early goal-directed therapy of uids (central venous pressure 8-12 mm Hg), vasopressors
(mean arterial blood pressure > 65 mm Hg), and maintenance of ScvO2 (> 70% with
packed red blood cells or inotrope therapy)
● 24-hour sepsis management
⚬ administration of low-dose corticosteroids and recombinant human activated protein C

(drotrecogin alfa) based on hospital policy
⚬ maintenance of glycemic control (120-150 mg/dL)
⚬ maintenance of plateau airway pressures ≤ 30 cm H2O in mechanically vented patients
– protocol of combined therapies associated with
● increased survival (odds ratio [OR] 1.91, 95% CI 1.49-2.45) in analysis of 8 studies
● decrease in time to antibiotic administration (p < 0.0001) in analysis of 4 studies
● increase in appropriateness of antibiotics (OR 3.06, 95% CI 1.69-5.53) in analysis of 5 studies
– Reference - Crit Care Med 2010 Feb;38(2):668 full-text , editorial can be found in Crit Care
Med 2010 Feb;38(2):733
– drotrecogin alfa (activated protein C) (Xigris) has been withdrawn from all markets due to failure
to show survival bene t for patients with severe sepsis and septic shock (FDA MedWatch 2011
Oct 25 )
STUDY
⚬ SUMMARY
early goal-directed therapy may improve 28-day survival in patients with severe
sepsis/septic shock DynaMed Level 2
RANDOMIZED TRIAL: Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2010 Jun;22(6):331
Details
– based on randomized trial without intention-to-treat analysis
– 314 patients with severe sepsis/septic shock randomized to early goal-directed therapy vs.
conventional treatment
– 303 patients were available for analysis at end of study
– comparing early goal-directed therapy vs. conventional treatment
● 28-day survival 75.2% vs. 57.5% (p = 0.001, NNT 6)

ICU mortality 30.5% vs. 50.7% (p = 0.035, NNT 5)
●
– Reference - Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2010 Jun;22(6):331 [Chinese]
–
DynaMed Commentary
Mortality with conventional treatment is higher than reported in other studies.
STUDY
⚬ SUMMARY
in patients with severe sepsis, differences in mortality observed with early goal directed
therapy may be influenced by factors associated with antibiotic administration
SYSTEMATIC REVIEW: Crit Care Med 2017 Apr;45(4):607
Details
– based on systematic review with trial-speci c quality measures not reported
– systematic review of 6 randomized trials and 31 observational studies evaluating early goal-
directed therapy in 19,998 patients with severe sepsis and/or septic shock
– comparing early goal-directed therapy to control
● early goal-directed therapy associated with reduced mortality (risk ratio 0.73, 95% CI 0.67-0.8)
in analysis of 31 observational studies with 15,656 patients
● no signi cant di erences in mortality in analysis of 6 randomized trials with 4,342 patients
– factors associated with increased mortality with early goal-directed therapy included
randomized trial design, higher disease severity, presence of shock, and longer time to
antibiotics
– signi cant di erence in mortality between observational studies and randomized trials were
eliminated when analysis adjusted for any of
● time-to- rst antibiotic
● antibiotics administered within speci c time (3, 4, or 6 hours)
● appropriate antibiotic usage
– Reference - Crit Care Med 2017 Apr;45(4):607
● lactate-guided therapy
STUDY
⚬ SUMMARY
goal-directed resuscitation based on lactate clearance or central venous oxygen saturation
appear similar for in-hospital mortality in patients with septic shock DynaMed Level 2
RANDOMIZED TRIAL: JAMA 2010 Feb 24;303(8):739 | Full Text
Details
– based on randomized trial without blinding
– 300 patients with severe sepsis and evidence of hypoperfusion or septic shock randomized to 1
of 2 resuscitation protocols
● ScvO2 group resuscitated to normalize central venous pressure, mean arterial pressure, and
ScvO2 ≥ 70%
● lactate clearance group resuscitated to normalize central venous pressure, mean arterial
pressure, and lactate clearance ≥ 10%
– treatments continued until all goals achieved or up to 6 hours
– in-hospital mortality in 23% with ScvO2 group vs. 17% with lactate clearance group (not
signi cant)
– no signi cant di erences in
● mechanical ventilation
● parenteral corticosteroids
● blood pressure
● heart rate
● lactate levels
● crystalloid volume
● vasopressor administration
● SOFA score
● Glasgow coma score
– Reference - EMShockNet trial (JAMA 2010 Feb 24;303(8):739 full-text ), editorial can be
found in JAMA 2010 Feb 24;303(8):777 , commentary can be found in JAMA 2010 May
26;303(20):2031
STUDY
⚬ SUMMARY
lactate-guided therapy in intensive care unit patients with high lactate levels might reduce
hospital mortality DynaMed Level 2
RANDOMIZED TRIAL: Am J Respir Crit Care Med 2010 Sep 15;182(6):752
Details
– based on randomized trial with borderline statistical signi cance
– 348 patients admitted to the ICU with lactate level ≥ 3 mEq/L (3 mmol/L) were randomized to
lactate-guided treatment vs. usual treatment without information about lactate levels
– treatment objective was to decrease lactate levels ≥ 20% every 2 hours for the initial 8 hours
– 39% of patients admitted to ICU for sepsis
– hospital mortality 33.9% in lactate-guided therapy group vs. 43.5% in usual care group (p =
0.067)
– lactate-guided therapy group received more uids in the rst 8 hours and received more
vasodilators
– Reference - Am J Respir Crit Care Med 2010 Sep 15;182(6):752 , commentary can be found in
Am J Respir Crit Care Med 2011 Mar 1;183(5):681
Delayed resuscitation
● delayed infusion of uid may increase survival compared to immediate uid resuscitation in trauma
patients having imminent surgical intervention to control bleeding
STUDY
⚬ SUMMARY
delayed resuscitation associated with increased survival to discharge in patients with
penetrating torso injury having surgery within 80 minutes of medical response
DynaMed Level 2
RANDOMIZED TRIAL: N Engl J Med 1994 Oct 27;331(17):1105 | Full Text
Details
– based on quasi-randomized trial
– 598 adults with penetrating torso injury and systolic blood pressure ≤ 90 mm Hg were
randomized to delayed vs. immediate resuscitation
● 289 patients in delayed resuscitation group were cannulated but did not have uid
resuscitation until operative intervention
● 309 patients in immediate resuscitation group had Ringer's acetate solution in prehospital
and trauma center settings
– comparing delayed resuscitation vs. immediate resuscitation
● survival to discharge 70% vs. 62% (p = 0.04)

● mean time between response and surgery 79 minutes vs. 74 minutes (not signi cant)
– Reference - N Engl J Med 1994 Oct 27;331(17):1105 full-text , editorial can be found in N
Engl J Med 1994 Oct 27;331(17):1153 , commentary can be found in N Engl J Med 1995 Mar
9;332(10):681
STUDY
⚬ SUMMARY
immediate and delayed fluid resuscitation appear to have similar mortality rates in trauma
patients DynaMed Level 2
RANDOMIZED TRIAL: Health Technol Assess 2000;4(31):1
Details
– based on randomized trial with low adherence
– 1,309 trauma patients (aged ≥ 16 years) treated by paramedics were randomized to 1 of 2 uid
resuscitation protocols
● IV uids were given to patients at the scene (immediate resuscitation)
● IV uids were given to patients at hospital arrival unless time to hospital likely > 1 hour
(delayed resuscitation)
– poor protocol compliance
● 31% of patients randomized to immediate resuscitation received prehospital uids

● 80% of patients randomized to delayed resuscitation did not receive any uids
– no signi cant di erence in mortality at 6 months (10.4% among immediate resuscitation group
vs. 9.8% among delayed group)
– Reference - Health Technol Assess 2000;4(31):1
⚬ no additional trials identi ed in Cochrane review (Cochrane Database Syst Rev 2014 Mar 5;
(3):CD002245 )
Other resuscitation strategies
● after rescue therapy with boluses
⚬ titrate intravenous uid infusion rate based on clinical context to achieve optimization of tissue
perfusion
⚬ de-escalate uid infusion as clinical condition improves to avoid uid overload
⚬ Reference - Br J Anaesth 2014 Nov;113(5):740
STUDY
● SUMMARY
conservative or deresuscitative fluid strategy following resuscitation phase might increase
ventilator-free days and decrease length of intensive care unit stay compared to standard care
or liberal fluid strategy in patients with acute respiratory distress syndrome or sepsis
DynaMed Level 2
SYSTEMATIC REVIEW: Intensive Care Med 2017 Feb;43(2):155
Details
⚬ based on systematic review limited by clinical heterogeneity
⚬ systematic review of 11 randomized trials and 38 observational studies evaluating conservative or
deresuscitative uid strategies (active uid removal using diuretic [with or without albumin
infusion] or renal replacement therapy) in adults and children with acute respiratory distress
syndrome, sepsis, or systemic in ammatory response syndrome
⚬ meta-analysis only included 11 randomized trials comparing conservative or deresuscitative uid
strategies vs. liberal uid strategies or standard care in 2,051 patients
⚬ timing and duration of strategies following resuscitation phase, patient population, and duration of
follow-up varied among trials
– conservative or deresuscitative strategies included diuretics (with or without albumin infusion)
in 3 trials, protocolized uid restriction or minimization in 4 trials, and uid management based
on alternative hemodynamic targets in 5 trials (1 trial included both diuretics and protocolized
restriction)
– liberal uid strategies or standard care included protocolized liberal uid administration in 1
trial, protocolized diuretic use without albumin infusion in 1 trial, central venous pressure or
pulmonary capillary wedge pressure-guided uid administration in 4 trials, and usual care or
unclear regimens in 5 trials
⚬ compared to liberal uid strategies or standard care, conservative or deresuscitative strategies
associated with
– increased ventilator-free days (weighted mean di erence 1.82 days, 95% CI 0.53-3.1 days) in
analysis of 7 trials with 1,784 patients
– reduced length of stay in intensive care unit (weighted mean di erence 1.88 days, 95% CI 0.12-
3.64 days) in analysis of 7 trials with 892 patients, results limited by signi cant heterogeneity
– nonsigni cant decrease in mortality (risk ratio 0.92, 95% CI 0.82-1.02) in analysis of all trials
⚬ no signi cant di erences in rate of renal replacement therapy in analysis of 3 trials with 1,233
patients
⚬ Reference - Intensive Care Med 2017 Feb;43(2):155
● largest randomized trial included in above systematic review
STUDY
⚬ SUMMARY
conservative fluid management in patients with acute lung injury improves fluid balance,
reduces need for mechanical ventilation and shortens intensive care unit stay
DynaMed Level 1
RANDOMIZED TRIAL: N Engl J Med 2006 Jun 15;354(24):2564 | Full Text
Details
– based on randomized trial
– 1,000 intubated patients with acute lung injury (ALI, de ned as partial pressure of oxygen in
arterial blood [PaO2]/Fraction of inspired Oxygen [FiO2] < 300 mm Hg and bilateral in ltrates on
chest x-ray without evidence of left atrial hypertension) were randomized to conservative vs.
liberal uid management after achievement of hemodynamic stability
– detailed algorithm for uid management provided based on random group assignment and
analysis of
● central venous pressure or pulmonary-artery occlusion pressure (depending on catheter
assignment)
● presence or absence of shock de ned as mean arterial pressure ≤ 60 mm Hg or need for
pressure support
● presence or absence of oliguria (urinary output < 0.5 mL/kg/hour)
● presence or absence of ine ective circulation de ned as cardiac index < 2.5 L/minute/m2 or
cold, mottled skin with decreased capillary re ll time
– no signi cant baseline di erences between groups, but borderline greater use of systemic
steroids in liberal-strategy group (p = 0.09)
– comparing conservative vs. liberal uid management
● 7-day cumulative uid balance -136 mL vs. 6,992 mL (p < 0.001)

● percentage of patients who received ≥ 1 blood transfusion 29% vs. 39% (p < 0.001)
● mean ventilator-free days 14.6 vs. 12.1 (p < 0.001)
● mean number of intensive care unit-free days during rst 28 days of hospitalization 13.4 vs.
11.2 (p < 0.001)
● no signi cant di erences in
⚬ incidence of renal failure, hepatic failure or coagulation abnormalities

⚬ overall mortality (25.5% vs. 28.4% after 60 days)
– Reference - Fluid and Catheter Treatment (FACTT) trial (N Engl J Med 2006 Jun 15;354(24):2564
full-text ), editorial can be found in N Engl J Med 2006 Jun 15;354(24):2598 , commentary
can be found in N Engl J Med 2006 Sep 14;355(11):1175 full-text , ACP J Club 2006 Nov-
Dec;145(3):69 , Lancet 2007 Jun 16;369(9578):1984 , Ann Intern Med 2007 Sep 18;147(6):412
STUDY
● SUMMARY
quantitative resuscitation strategy may reduce mortality in sepsis if applied early
DynaMed Level 2
SYSTEMATIC REVIEW: Crit Care Med 2008 Oct;36(10):2734 | Full Text
Details
⚬ based on systematic review with incomplete assessment of trial quality
⚬ systematic review of 9 randomized trials comparing quantitative vs. standard resuscitation
strategies in 1,001 adults with presumed or con rmed sepsis
⚬ quantitative resuscitation strategy de ned as structured cardiovascular resuscitation protocol to
achieve prede ned hemodynamic endpoints
– early quantitative resuscitation de ned as therapy started at time of recognition of sepsis or
within 24 hours
– late quantitative resuscitation de ned as therapy started after 24 hours or unknown or
unreported timing
⚬ study quality assessment evaluated only patient selection and allocation concealment
⚬ quantitative strategy associated with reduced mortality in 9 trials with 1,001 patients
– mortality ranged from 13% to 74% in quantitative resuscitation strategy groups (mean 47%) and
from 27% to 72% in control groups (mean 57%)
– odds ratio (OR) 0.64 (95% CI 0.43-0.96)
– results limited by heterogeneity (p = 0.07)
⚬ early quantitative resuscitation associated with decreased mortality (OR 0.5, 95% CI 0.37-0.69) in
analysis of 6 trials with 740 patients
⚬ late quantitative resuscitation strategy associated with no signi cant di erence in mortality (OR
1.16, 95% CI 0.6-2.22) in analysis of 3 trials with 261 patients
⚬ Reference - Crit Care Med 2008 Oct;36(10):2734 full-text , editorial can be found in Crit Care
Med 2008 Oct;36(10):2932 , commentary can be found in CJEM 2010 Mar;12(2):150
STUDY
● SUMMARY
plethysmogram variability index-directed fluid management may reduce volume of
intraoperative fluids and postoperative lactate levels in patients having major abdominal surgery
DynaMed Level 2
RANDOMIZED TRIAL: Anesth Analg 2010 Oct;111(4):910
Details
⚬ based on randomized trial with allocation concealment not stated
⚬ 82 adults (mean age 60 years, 61% male) having major abdominal surgery were randomized to
intraoperative plethysmogram variability index (PVI)-directed uid management vs. standard care
and followed for 48 hours
– patients were excluded for cardiac arrhythmias, cardiac ejection fraction < 30% by ultrasound,
lung pathology prohibiting mechanical ventilation with tidal volume > 6 mL/kg, or dialysis
– PVI-directed uid management included
● 500-mL crystalloid infusion during induction, followed by 2 mL/kg/hour continuous infusion

● 250-mL bolus of colloid if PVI > 13% for > 5 minutes with repeated dosing every 5 minutes if
PVI remained > 13%
● norepinephrine as needed to maintain arterial blood pressure > 65 mm Hg
– standard care included
● 500-mL crystalloid infusion during induction, followed by 4-8 mL/kg/hour continuous infusion
● colloid bolus given if acute blood loss > 50 mL, mean arterial blood pressure < 65 mm Hg, or
central venous pressure < 6 mm Hg, with repeat bolus after 5 minutes if any condition still
met
● norepinephrine if mean arterial blood pressure < 65 mm Hg and unresponsive to uids
⚬ 94% were included in analysis

⚬ comparing PVI-directed uid management vs. standard care
– mean volume of total intraoperative uids 2,394 mL vs. 2,918 mL (p = 0.049)

– mean volume of intraoperative crystalloids 1,363 vs. 1,815 (p = 0.004)
– lactate level > 1.7 mmol/L at 24 hours in 5% vs. 68% (p < 0.0001)
– lactate level > 1.7 mmol/L at 48 hours in 0% vs. 20% (p = 0.003)
⚬ no signi cant di erences in postoperative uid volumes, rate of patients with lactate levels > 5
mmol/L, use of continuous norepinephrine infusion, renal function, serum creatinine, or initiation
of dialysis
⚬ Reference - Anesth Analg 2010 Oct;111(4):910
STUDY
● SUMMARY
hypotensive fluid resuscitation strategy (targeting mean arterial pressure of 50 mm Hg) before
emergency surgery in patients with hemorrhagic shock may reduce transfusions
DynaMed Level 2
RANDOMIZED TRIAL: J Trauma 2011 Mar;70(3):652
Details
⚬ based on randomized trial with allocation concealment not stated
⚬ 90 patients with traumatic injury to chest or abdomen requiring emergency laparotomy or
thoracotomy and in hemorrhagic shock were randomized to uid resuscitation targeting mean
arterial pressure of 50 mm Hg vs. mean arterial pressure of 65 mm Hg
⚬ comparing mean arterial pressure of 50 mm Hg vs. 65 mm Hg

– coagulopathy in 60.5% vs. 61.1% (not signi cant)
– mean volume of blood products transfused 1,594 mL vs. 2,898 mL (p = 0.03)
⚬ Reference - J Trauma 2011 Mar;70(3):652
Guidelines and Resources
Guidelines
International guidelines
● Surviving sepsis campaign: international guideline on management of sepsis and septic shock can be
found in Intensive Care Med 2017 Mar;43(3):304
● Prevention and Management of Acute Renal Failure in the ICU Patient: an international consensus
conference in intensive care medicine can be found in Am J Respir Crit Care Med 2010 May
15;181(10):1128
● International Society of Nephrology Kidney Disease: Improving Global Outcomes (KDIGO) clinical
practice guideline on acute kidney injury can be found at KDIGO 2012 Mar PDF
United States guidelines
● Eastern Association for the Surgery of Trauma (EAST) practice management guidelines on
⚬ prehospital uid resuscitation for the injured patient can be found in J Trauma 2009 Aug;67(2):389
⚬ monitoring modalities and assessment of uid status can be found in J Trauma Acute Care Surg
2018 Jan;84(1):37
United Kingdom guidelines
● National Institute for Health and Care Excellence (NICE) guideline on intravenous uid therapy in
adults in hospital can be found at NICE 2013 Dec:CG174 (updated May 2017) PDF
● National Institute for Health and Care Excellence (NICE) guidance on prehospital initiation of uid
replacement therapy in trauma can be found at NICE 2004 Jan:TA74 PDF
● British Consensus Guideline on intravenous uid therapy for adult surgical patients (GIFTASUP) can be
found at GIFTASUP 2012 PDF
European guidelines
● European guideline on management of major bleeding and coagulopathy following trauma: fourth
edition can be found in Crit Care 2016 Apr 12;20:100 full-text
● S3 Leitlinie Volumentherapie beim Erwachsenen nden Sie unter AWMF 2014 Jul PDF [Deutsch]
Australian and New Zealand guidelines
● New South Wales (NSW) Ministry of Health standards on paediatric intravenous uids can be found at
NSW 2015 Aug 31 PDF
Review articles
● review can be found in Curr Opin Crit Care 2016 Oct;22(5):424
● review of uid management in critically ill patients can be found in Kidney Dis (Basel) 2016 Jun;2(2):64
● review of echocardiography for guiding uid management can be found in Crit Care. 2016 Sep
4;20:274 full-text
● review of early uid resuscitation in severe trauma can be found in BMJ 2012 Sep 11;345:e5752 ,
commentary can be found in BMJ 2012 Oct 30;345:e7205
● review of shock resuscitation can be found in Lancet 2004 Jun 12;363(9425):1988
● review of arterial pulse pressure variation with mechanical ventilation can be found in Am J Respir Crit
Care Med 2018 Aug 23 early online
● review of initial resuscitation of hemorrhagic shock can be found in World J Emerg Surg 2006 Apr
27;1:14 full-text
● review of intravenous uids for surgical patients can be found in Curr Opin Crit Care 2015
Aug;21(4):358
● review of approach to uid therapy in patients with sepsis can be found in Br J Anaesth 2016
Mar;116(3):339
● review of uid and hemodynamic management in severe dengue can be found in Southeast Asian J
Trop Med Public Health 2015;46 Suppl 1:123
● review of human serum albumin and albumin solutions in patients with critical illness, sepsis, or
cirrhosis can be found in World J Hepatol 2016 Mar 8;8(7):345 full-text
MEDLINE search
● to search MEDLINE for (Assessment of adequate uid resuscitation) with targeted search (Clinical
Queries), click therapy , diagnosis , or prognosis
Patient Information
● information on managing the intensive care unit experience from American Thoracic Society PDF
ICD Codes
ICD-10 codes
● E87.0 hyperosmolality and hypernatraemia
● E86 volume depletion
⚬ ICD-10-CA modi cation in Canada
– E86.0 dehydration
– E86.8 other volume depletion (hypovolemia)
● R57.1 hypovolemic shock
● R57.9 shock, unspeci c
● T79.4 traumatic shock
References
General references used
1. Monnet X, Marik PE, Teboul JL. Prediction of uid responsiveness: an update. Ann Intensive Care. 2016
Dec;6(1):111 full-text
2. Carsetti A, Cecconi M, Rhodes A. Fluid bolus therapy: monitoring and predicting uid responsiveness.
Curr Opin Crit Care. 2015 Oct;21(5):388-94
3. Miller A, Mandeville J. Predicting and measuring uid responsiveness with echocardiography. Echo Res
Pract. 2016 Jun;3(2):G1-G12 full-text
4. Marik PE. Fluid Responsiveness and the Six Guiding Principles of Fluid Resuscitation. Crit Care Med.
2016 Oct;44(10):1920-2
Recommendation grading systems used
● Society of Critical Care Medicine (SCCM) uses Grading of Recommendations, Assessment,

Development, and Evaluation (GRADE)
⚬ strength of recommendation
– Strong - bene ts clearly outweigh risks and burdens (or vice versa) for most, if not all, patients
– Weak - bene ts and risks closely balanced and/or uncertain
– Best practice statement - recommendation not conducive to GRADE process
⚬ quality of evidence
– High - randomized trials without factors that reduce quality of evidence, or well-done
observational studies with very large magnitude of e ect
– Moderate - downgraded randomized trials or upgraded observational studies
– Low - well-done observational studies, or randomized trials with many limitations
– Very low - case series or expert opinion
⚬ Reference - SCCM Surviving Sepsis Campaign 2016 international guideline on management of

severe sepsis and septic shock (Intensive Care Med 2017 Mar;43(3):304 )
● European Society of Intensive Care Medicine (ESICM) grading system
⚬ strength of recommendation
– Level 1 (strong) recommendation - desirable e ects of an intervention clearly outweigh the

undesirable e ects
– Level 2 (weak) recommendation - uncertainty about trade-o s between desirable and
undesirable e ects of an intervention
– Best practice point - panel judgment recommendation should be issued
⚬ quality of evidence
– High-quality evidence - further research unlikely to change con dence in estimate of e ect
– Moderate-quality evidence - further research likely to have impact on con dence in estimate of
e ect
– Low-quality evidence - further research expected to have important impact on con dence in
estimate of e ect and is likely to change estimate
⚬ Reference - ESICM consensus on circulatory shock and hemodynamic monitoring (Intensive Care
Med 2014 Dec;40(12):1795 full-text ), commentary can be found in Intensive Care Med 2015
Mar;41(3):570
Synthesized Recommendation Grading System for DynaMed Content
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where guidelines agree and where guidelines di er from each other and from the current evidence.
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and clinical expertise to provide recommendations to support clinical decision-making in the Overview
& Recommendations section.
● We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to

classify synthesized recommendations as Strong or Weak.
⚬ Strong recommendations are used when, based on the available evidence, clinicians (without
con icts of interest) consistently have a high degree of con dence that the desirable consequences
(health bene ts, decreased costs and burdens) outweigh the undesirable consequences (harms,
costs, burdens).
⚬ Weak recommendations are used when, based on the available evidence, clinicians believe that
desirable and undesirable consequences are nely balanced, or appreciable uncertainty exists
about the magnitude of expected consequences (bene ts and harms). Weak recommendations are
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Assessment of Adequate Fluid Resuscitation

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Assessment of Adequate Fluid Resuscitation

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Assessment of Adequate Fluid Resuscitation

Overview and Recommendations

● Dynamic variables may be superior to static variables to assess uid responsiveness.

● In patients with sepsis:

⚬ Immediate resuscitation and treatment is recommended (Strong recommendation).

● Fluid selection for IV uid resuscitation

● Vasopressor and inotrope use in the intensive care unit

● Sepsis treatment in adults

General Considerations for Fluid Resuscitation

output and signs of tissue hypoperfusion 1

● only about 50% of critically ill patients are uid responsive 1 , 2 , 3 , 4

● uid boluses have small and short-lived hemodynamic e ects 4

COHORT STUDY: Ann Intensive Care 2014;4:25 | Full Text

● 2.84 L/minute/m2 at baseline

● avoid uid overload

⚬ volume expansion in unresponsive patients causes hemodilution, increased cardiac lling

pressure, and uid overload 1

● high positive uid balance associated with increased mortality

COHORT STUDY: Am J Emerg Med 2015 Feb;33(2):186

● higher admission Simpli ed Acute Physiology Score (SAPS) II score (p = 0.016)

COHORT STUDY: J Intern Med 2015 Apr;277(4):468 | Full Text

– mortality within 90 days of hospital discharge 11.9%

– no signi cant association with death after 90 days

COHORT STUDY: Shock 2015 Jan;43(1):68 | Full Text

● uid overload on day 1 associated with increased

● persistent uid overload associated with increased

⚬ use of thoracentesis (OR 3.81, 95% CI 1.74-9.15)

● persistent uid overload associated with nonsigni cant increase in

⚬ use of ultra ltration (OR 1.9, 95% CI 0.9-4.19)

– Reference - Shock 2015 Jan;43(1):68 full-text

Recommendations from Professional Organizations

● volumetric parameters (evaluated using transpulmonary thermodilution methods)

CLINICIANS' PRACTICE POINT

Recommendation does not appear based on published evidence in this patient

● pulmonary artery catheterization or transpulmonary thermodilution suggested in patients

– crystalloids recommended for initial uid resuscitation as well as subsequent intravascular

● platelet counts < 10,000/mm3 (10 × 109/L) in absence of apparent bleeding

● antithrombin (SCCM Strong recommendation, Moderate-quality evidence)

● international Fluid Optimization Group statement on perioperative uid therapy

– step 1 - determine if patient requires hemodynamic support or cardiovascular function

– consider limitations of each dynamic parameter and gray zone concept

– crystalloids are recommended for routine, short duration surgery

● systolic blood pressure < 100 mm Hg

– identify uid de cit cause and begin treatment

● continuously monitor respiratory rate, pulse, blood pressure, and perfusion

● seek expert help if signs of shock are present

● pulse, blood pressure, capillary re ll and jugular venous pressure

– clinical monitoring should include

– laboratory measurements should include

● complete blood count

⚬ Reference - NICE 2013 Dec:CG174 PDF

Methods to Assess Fluid Responsiveness

Overview of methods for assessing fluid responsiveness

● dynamic variables to assess uid responsiveness 1 , 2 , 3 , 4

– heart-lung interactions are induced by cyclic changes in intrathoracic pressure during

Table 1. Advantages and Disadvantages of Methods for Assessing Fluid

Conventional Infusion of 250- Direct measure of Fluids given as

Mini- uid Infusion of 100 Small volume of Fluids given as

Stroke volume Heart-lung No uid infusion Cannot be used

Passive leg Self-volume No uid infusion, Requires direct

End-expiratory Heart-lung No uid infusion, Requires

IVC diameter Heart-lung No uid infusion Cannot be used

SVC diameter Heart-lung No uid infusion Cannot be used

Abbreviations: IVC, inferior vena cava; SVC, superior vena cava.