Acute Liver Failure:Supporting Other Organs
Michael A. Gropper, MD, PhDProfessor of Anesthesia and Physiology
Director, Critical Care MedicineUniversity of California San Francisco
UCSF Department of Anesthesia and Perioperative Care
Acute Liver Failure
• Circulatory abnormalities and shock• Management of renal failure• Management of respiratory failure
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Circulatory Abnormalities
• Diagnosis of shock• Resuscitation Goals• Choice of vasopressors• Goal directed therapy
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Differentiation of Shock
SepticCardiogenic
andHypovolemic
Cardiac output Normal or high Low
Pulse pressure Decreased Decreased
SVR Decreased Increased
Temperature Up or down Unchanged or
Peripheralperfusion
Increased Decreased
WBC count Up or down Unchanged
Infection Suspected ordocumented
none
A-V DO2 Decreased Increased
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• Increase O2 delivery• Optimize O2 content of blood• Improve cardiac output and
blood pressure• Match systemic O2 needs with O2
delivery• Reverse/prevent organ hypoperfusion
Therapeutic Goals in Shock
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First, fill the tank…
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PAOP versus CVP
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CV Mechanics in Shock
cardiogenic shocknormal
End Diastolic Pressure
Car
diac
Out
put
hypovolemic
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Schierhout, BMJ 1998
Crystalloid or
Colloid?
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• Randomized, prospective trial of 4%albumin versus normal saline for fluidresuscitation
• 6997 patients randomized• Primary outcome was 28-day mortality
NEJM 2004
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Albumin vs SalineSAFE Study: NEJM, 2004
• Prospective, randomized study of 6997 patients• Objective need (one): tachycardia, hypotension,
low PCWP, low Urine Output• Normal saline vs 4% albumin for resuscitation• All other management the same• Primary outcome: 28d mortality• Secondary outcomes: Survival time, new organ
failures, duration of mechanical ventilation, ICULOS
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Albumin vs SalineSAFE Study: NEJM, 2004
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Albumin vs SalineSAFE Study: NEJM, 2004
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FDA Medwatch on Albumin
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If still hypotensive after fluidresuscitation, start pressors
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Best Pressor: Dopamine?• No evidence of increased renal perfusion
at low doses• Tachycardia more common than with
norepinephrine• May impair splanchnic blood flow• Stimulates vasopressin secretion• Does not confer clinically significant
protection against renal dysfunction
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Best Pressor: Norepinephrine?
• No evidence of worsening renalfunction
• Less tachycardia than dopamine
• More rapid and effective BP control
• May increase splanchnic perfusion
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Best Pressor: Norepinephrine?• Effect of norepinephrine compared with high dose
dopamine and/or epinephrine on the outcome ofseptic shock– Prospective, observational cohort– N=97– Norepinephrine ↓ mortality
• 62% vs 82%• P<0.001• RR=0.68• 95% CI, 0.54-0.87
Martin et al, CCM 2000
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Best Pressor: Epinephrine?• 30 adult patients with septic shock• MAP ≤60 mm Hg• Norepinephrine and dobutamine vs
epinephrine to MAP >80 mm Hg• Results
– Similar effect on hemodynamics– Epinephrine
• ↑ Lactate• ↑ Lactate/pyruvate ratio• ↓ Gastric pHi
Levy et al, Intens Care Med, 1997
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Best Pressor: Phenylephrine?• 13 patients with septic shock• Treated with fluids and either low-dose dopamine
or dobutamine, but remained hypotensive• Phenylephrine added
– 0.5 to 9 µg/kg/min– MAP >70 mm Hg
• Results– Increased MAP, SVR, CI, stroke index, DO2, VO2
and urine output– No change in HR– Dose 3.7 (0.4-9.1) µg/kg/min– Mean duration 65 hours
Gregory et al, CCM, 1991
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What about vasopressin?
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Vasopressin mechanism ofaction
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• Vasopressin plus NE versus NE alone• Randomized trial of 48 patients• Hemodynamic outcomes measured
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Vasopressin administration resulted in:reduced heart rateincreased MAPincreased CIincreased SVIincreased LVSWIdecreased NE requirements
But:no difference in mortalityno difference in organ
dysfunctionIncreased bilirubin in AVP
group
Dunser et al, Circulation 2003.
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What are the therapeuticgoals?
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What is the BP Target?
• BP targets are arbitrary• Autoregulation is lost below MAP 55-
60 mmHg• What is the data that we should target
a MAP of 65 mmHg?
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Crit Care Med 2005; 33:780 –786
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How Much BP is Enough?Blood Lactate (meq/l) Oxygen Consumption (ml/min/m2)
Oxygen Delivery (ml/min/m2) Oxygen Extraction Ratio (%)
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How Much BP is Enough?Urine Output (ml/h) Creatinine Clearance (ml/min)
Crit Care Med 2005; 33:780-786
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Optimizing oxygen delivery:Early goal-directed therapy
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• Randomized, prospective trial of early, goal-directed resuscitation of patients with severesepsis
• Patients randomized to 6 hours of goal-directed therapy vs standard therapy
• 260 patients randomized• In-hospital mortality was 30.5% with goal-
directed therapy vs 46.5% with standardtherapy
Rivers et al, NEJM, 2001;345:1368-77
Central Venous Oximetry
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Central Venous Oximetry
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Inotropic agents
Supplemental oxygen +endotracheal intubation and
mechanical ventilation
Transfusion of red cellsUntil hematocrit > 30%ScvO2
<70%
>70%
<70%
>70%
Vasoactive agentsMAP< 65 mmHg>90 mmHg
>65 and <90 mmHg
< 8 mmHgCrystalloid
Colloid
CVP
8-12 mmHg
YesHospital admission GoalsAchieved
No
Central venous andarterial catheterization
Sedation, paralysis(if intubated), or both
Rivers et al, NEJM, 2001;345:1368-77
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Evidence: The Importance ofEarly Goal Directed Therapy
• Early goal-directedtherapy in patients withsevere sepsisproduced:– 42% ↓ in relative risk
of in-hospital and 28-day mortality(P=0.009, =0.01)
– 33% in relative risk ofdeath at 60 days(P=0.03)
• NNT to prevent 1 event(death) = 6 to 8
Rivers E, et al. N Engl J Med 2001;345:1368-77.
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Management of Renal Failure
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Impact of ARF on Mortality in Critically IllPatients
Metnitz et al, Critical Care Medicine, 2002
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Decreasedeffective
Blood volume
Obstruction ofcollectingsystem
Prerenal Failure Intrinsic Renal Postrenal Failure
Acute Renal Failure
Vascular AcuteGlomerulo-nephritis
AcuteTubular Necrosis
Ischemic Nephrotoxic
AcuteInterstitialnephritis
EndogenousExogenous
HRS
HR
S
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Acute Tubular Necrosis
Lamiere et al, Lancet: 2005
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Hepatorenal Syndrome:Consensus Definition, International Ascites Club
Major Criteria• Acute/chronic liver disease with hepatic failure and portal hypertension• Low GFR: serum Cr > 1.5 mg/dl or 24 hour creatinine clearance < 40
cc/min• Absence of shock, ongoing infection, fluid loss, treatment with
nephrotoxins• No improvement in renal function following withdrawal of diuretics,
expansion of plasma volume with 1.5 L isotonic saline• Proteinuria < 500 mg/d and no ultrasonographic evidence of
obstructive uropathy or parenchymal disease
Minor Criteria• Urine volume < 500 cc/d• Urine Na < 10 meQ/d• Urine osm > Plasma osm• Urine RBC < 50/hpf• Serum Na < 130 meQ/L
Arroyo et al, Hepatology 23(1996): 164-176
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Hepatorenal Syndrome
Type I:Doubling of serum Cr to > 2.5 mg/dL or a 50%reduction of initial GFR to less than 20 cc/minwithin 2 weeks
Type II:Moderate and stable reduction in GFR withouta rapidly progressive course
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When To Initiate CRRT?
Drug overdose with dialysable toxinHyperthermiaPlasma sodium >155 mmol/L or <120mmol/LUremic pericarditisUremic neuropathy/myopathyUremic encephalopathyAzotemia: urea concentration >30mmol/LSevere acidemia: pH<7.0Hyperkalemia: potassium >6.5 mmol/LAnuria: urine output <50mL in 12hOliguria with <200 mL in 12h
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Hemodialysis
Forni. NEJM, 1997Movement of small moleculesacross a selective membrane
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Hemofiltration
Forni. NEJM, 1997
Movement of water and small moleculesacross a selective membrane, with selective fluidreplacment
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IHD vs CRRT
Lamiere et al, Lancet: 2005
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Continuous RenalReplacement Therapy
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Slow removal of excess intra/extravascular volume
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Convective solute clearance without dialysis
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Dialysis with solute and nitrogen removal
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Solute and nitrogen clearance, with fluid replacement
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Does dialysis dose matter? Ronco et al, Lancet: 2000
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Dialysis Dose and MortalityRonco et al, Lancet: 2000
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Management of RespiratoryFailure
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Respiratory Abnormalities in ALF
• Hepatopulmonary syndrome (HPS)
• Portopulmonary hypertension (PPH)
• Acute lung injury and the acuterespiratory distress syndrome (ALI/ARDS)
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Hepatopulmonary vs Pulmonary Hypertension
Herve et al, Eur Resp J, 1998
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Hepatopulmonary Syndrome
• Defined as:–Presence of liver disease–Hypoxemia on room air–Intrapulmonary vascular dilation
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Portopulmonary Hypertension
• Defined as:– Histologic changes in the pulmonary
circulation leading to increased vascularresistance.
– Mean PAP > 25 mmHg, with PCWP > 15mmHg
– Evidence of portal hypertension
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Definition of ARDS• Clinical syndrome characterized by:
– oxygenation defect (PaO2/FiO2<200mmHg)– bilateral infiltrates on CXR– No evidence of CHF
• PCWP < 18 mmHg
• Acute Lung Injury (ALI)– above, except (PaO2/FiO2<300mmHg)
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Pressure-volume relationship
Paw
V
appropriateVt
excessiveVt
Pflex
protectiveVt
Normal lung
Consolidatedlung
PleuralEffusion
CT in Early ARDS
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PaOPaO22 / FiO / FiO22
120
140
160
180
200
0 1 2 3 4Study Day
P/F
6 ml/kg
12 ml/kg
* *
ARDSnet, NEJM 2000
Median Organ Failure Free DaysMedian Organ Failure Free Days
*
*
*
*
= 6 ml/kg= 12 ml/kg
ARDSnet, NEJM 2000
UCSF Department of Anesthesia and Perioperative Care
Ventilator-Free DaysVentilator-Free Days
0
2
4
6
8
10
12
14
6 ml/kg 12 ml/kg
6 ml/kg
12 ml/kg
ARDSnet, NEJM 2000
UCSF Department of Anesthesia and Perioperative Care
Mortality Prior to HospitalMortality Prior to HospitalDischargeDischarge
0
10
20
30
40
50
Mortality (Percent)
6 ml/kg 12 ml/kg
P=0.0054
ARDSnet, NEJM 2000
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Conclusions• Shock resuscitation is time-sensitive• Consider central venous oxygen saturation
as a resuscitation target• Continuous renal replacement therapy is a
powerful tool for achieving homeostasis inacute renal failure
• Use a protective ventilation strategy inpatients with acute lung injury