It’s April…Your Patient has Acute Renal Failure…Now What? Critical Care Grand Rounds Jennifer Hancock, MD, FRCPC, CCM Jan 15, 2009

Objectives Discuss the epidemiology of renal failure in the ICU according to the RIFLE criteria Review the pathophysiology ATN Discuss the practical aspects of CRRT including the different modes, timing, dosing and anticoagulation Discuss future applications of RRT in the ICU setting

Discuss the epidemiology of renal failure in the ICU according to the RIFLE criteria

Review the pathophysiology ATN

Discuss the practical aspects of CRRT including the different modes, timing, dosing and anticoagulation

Discuss future applications of RRT in the ICU setting

Case 1 70 kg 80yr  post-op emergency AAA Supra-renal x-clamp 60mins, massive transfusion Post-op: FiO 2 100%, Sats 88%, CXR volume O/L BP 100/60 on levo 0.2 ug/kg/min, CVP 18 Aneuric despite a lasix trial pH 7.12/28/55/10 K 5.3 Decision is made to start dialysis

70 kg 80yr  post-op emergency AAA

Supra-renal x-clamp 60mins, massive transfusion

Post-op:

FiO 2 100%, Sats 88%, CXR volume O/L

BP 100/60 on levo 0.2 ug/kg/min, CVP 18

Aneuric despite a lasix trial

pH 7.12/28/55/10 K 5.3

Decision is made to start dialysis

Case 2 45 year old male admitted with septic shock and MOF secondary to pneumonia. Treated with antibiotics, resuscitation, steroids, pressors and APC By ICU Day 3: Intubated FiO2 60% sats 90% CVP 14, levo 0.15ug/kg/min pH 7.34, HCO3 18, K 4.3, Cr 325 No uremic complications Urine O/P ~10cc/hr, Running balance +13L

45 year old male admitted with septic shock and MOF secondary to pneumonia. Treated with antibiotics, resuscitation, steroids, pressors and APC

By ICU Day 3:

Intubated FiO2 60% sats 90%

CVP 14, levo 0.15ug/kg/min

pH 7.34, HCO3 18, K 4.3, Cr 325

No uremic complications

Urine O/P ~10cc/hr,

Running balance +13L

Both patients have ARF presumed secondary to ATN… Now what????

Why Worry About Acute Renal Failure? Common problem Reported incidence of 5-25% Serious problem Mortality ranges from 30-90% Approaches 100% if 3 organ systems fail simultaneously Crit Care Med 2006;34:1913-1917

Common problem

Reported incidence of 5-25%

Serious problem

Mortality ranges from 30-90%

Approaches 100% if 3 organ systems fail simultaneously

Crit Care Med 2006;34:1913-1917

Acute Dialysis Quality Initiative: RIFLE Criteria GFR Criteria U/O Criteria Cr  1.5X N GFR  >25% Cr  2X N GFR  >50% Cr  3XN or >354 GFR  >75% <0.5 cc/kg/hr X 6hr <0.5 cc/kg/hr X 12hr <0.3cc/kg/hr X 24hr Persistent loss > 4wks ESRD >3/12 R isk I njury F ailure L oss E SKD Crit Care Med 2004;8:204-212

Validation of the RIFLE Criteria Incidence of ARF: Risk: 9-10% Injury: 4.5-5% Failure: 3.7-3.4% Mortality Rates: Risk: 15-22% Injury: 29-41% Failure: 41-51% Australian study of 21,000 patients Crit Care Med 2006;34:1913-1917

Incidence of ARF:

Risk: 9-10%

Injury: 4.5-5%

Failure: 3.7-3.4%

Mortality Rates:

Risk: 15-22%

Injury: 29-41%

Failure: 41-51%

Acute Renal Failure in the ICU International multi-centered prospective study of 29269 patients 5.7% developed ARF 52% ICU mortality, 60% Hospital mortality 13.8% of survivors needed RRT at discharge

International multi-centered prospective study of 29269 patients

5.7% developed ARF

52% ICU mortality, 60% Hospital mortality

13.8% of survivors needed RRT at discharge

What Has Happened to the Kidneys?  MAP sensed by receptors  sympathetic tone, Renin/ATII, ADH Renal vasoconstriction =  renal flow & GFR =  pO2 of the medulla ?differences in sepsis RBF may  and tone  in sepsis Inflammatory mediators Microthrombi NEJM 1995:332;647 Crit Care Med 2008:36;S198

 MAP sensed by receptors

 sympathetic tone, Renin/ATII, ADH

Renal vasoconstriction =  renal flow & GFR =  pO2 of the medulla

?differences in sepsis

RBF may  and tone  in sepsis

Inflammatory mediators

Microthrombi

So What…How Do We Help? Diuretics  pO 2 in medulla from 16 to 35 mmHg  urine O/P “flush out tubules” Multiple studies show no benefit and potentially harm Fenoldapam/Dopamine No Benefit Dialysis IHD CRRT SLEDD

Diuretics

 pO 2 in medulla from 16 to 35 mmHg

 urine O/P “flush out tubules”

Multiple studies show no benefit and potentially harm

Fenoldapam/Dopamine

No Benefit

Dialysis

IHD

CRRT

SLEDD

Acute Dialysis Options: What do we know? No difference in mortality outcomes regardless of mode of dialysis Some patients do not tolerate IHD Symptomatic  BP occurs in 15-50% of IHD Am J Nephrol 1990;10(3):177-80 CRRT Enhanced hemodynamic stability Increased net salt and water removal Potentially improved renal recovery Better preservation of cerebral perfusion

No difference in mortality outcomes regardless of mode of dialysis

Some patients do not tolerate IHD

Symptomatic  BP occurs in 15-50% of IHD Am J Nephrol 1990;10(3):177-80

CRRT

Enhanced hemodynamic stability

Increased net salt and water removal

Potentially improved renal recovery

Better preservation of cerebral perfusion

Timing of RRT Conventional indications Observational studies suggest that “earlier initiation” may improve outcomes Volume overload i Surgical patients: Restricting fluids  anastomotic leaks, sepsis, bleeding, return to OR, dehiscence J Card Surg 2004:17 Clin J Am Soc Nephrol 2006;915  lung function  vent free days  ICU stay NEJM 2006:354;2564 Ann Surg 2003:238;641

Conventional indications

Observational studies suggest that “earlier initiation” may improve outcomes

Volume overload

i

Surgical patients:

Restricting fluids  anastomotic leaks, sepsis, bleeding, return to OR, dehiscence

QEII CRRT Orders Filters Mode of dialysis Calculating dose Anticoagulation Replacement Solutions

Filters

Mode of dialysis

Calculating dose

Anticoagulation

Replacement Solutions

CRRT Filters ST100 is an AN69 membrane Increased risk of anaphylactoid reactions in patients taking an ACE inhibitor HF1000 is a PAES membrane

ST100 is an AN69 membrane

Increased risk of anaphylactoid reactions in patients taking an ACE inhibitor

HF1000 is a PAES membrane

CRRT Mode CVVHD Continuous Venovenous Hemodialysis CVVH Continuous Venovenous Hemofiltration CVVHDF Continuous Venovenous Hemodiafiltration SCUF Slow Continuous Ultrafiltration

CVVHD

Continuous Venovenous Hemodialysis

CVVH

Continuous Venovenous Hemofiltration

CVVHDF

Continuous Venovenous Hemodiafiltration

SCUF

Slow Continuous Ultrafiltration

CVVHD - Hemodialysis Diffusion of solutes passively down a concentration gradient Na, Urea, Creatinine move from blood to dialysate HCO 3 , Ca move from dialysate to blood Blood from patient Blood to patient Dialysate flow

Diffusion of solutes passively down a concentration gradient

Na, Urea, Creatinine move from blood to dialysate

HCO 3 , Ca move from dialysate to blood

CVVH - Hemofiltration The hydrostatic pressure gradient induces convection of water across the membrane. The frictional forces between the solutes and water results in transport of small and middle weight molecules. Blood from patient Blood to patient High Pressure Low Pressure Replacement Fluid

The hydrostatic pressure gradient induces convection of water across the membrane. The frictional forces between the solutes and water results in transport of small and middle weight molecules.

CVVHDF - HemoDiafiltration A combination of both CVVH and CVVHD Blood from patient Blood to patient Dialysate flow High Pressure Low Pressure Replacement Fluid High Concentration Low Concentration

A combination of both CVVH and CVVHD

CRRT Practice Patterns Crit Care Resus 2008: 10; 225

Dosing in All Causes of ARF ATN Study Intensive therapy (CVVHDF 35 ml/kg/hr) vs. less intensive therapy (CVVHDF 20 ml/kg/hr) >50 % of patients ARF related to sepsis Average APACHE II 26 NEJM 2008:359;E1

ATN Study

Intensive therapy (CVVHDF 35 ml/kg/hr) vs. less intensive therapy (CVVHDF 20 ml/kg/hr)

>50 % of patients ARF related to sepsis

Average APACHE II 26

Determining Dose in CVVHDF Dialysis Dosing = Effluent Rate Effluent Rate = Dialysate flow + Replacement Rate For a 70 kg person at 20ml/kg/hr = 1400 ml/hr = 700 ml/hr dialysate flow & 700 ml/hr replacement rate

Dialysis Dosing = Effluent Rate

Effluent Rate = Dialysate flow + Replacement Rate

For a 70 kg person at 20ml/kg/hr

= 1400 ml/hr

= 700 ml/hr dialysate flow & 700 ml/hr replacement rate

Dialysis Dosing at the QEII

Sepsis, Dosing & Hemofiltration High volume hemofiltration is aimed at non-selectively removing both pro and anti-inflammatory mediators Prospective study of 15 septic patients receiving HVHF (85 ml/kg/hr X 6 hr) then 35 ml/kg/hr Mortality 48% vs. predicted mortality of 72% APACHEII and 69% SAPS Semin Dial 2006:19;69

High volume hemofiltration is aimed at non-selectively removing both pro and anti-inflammatory mediators

Prospective study of 15 septic patients receiving HVHF (85 ml/kg/hr X 6 hr) then 35 ml/kg/hr

Mortality 48% vs. predicted mortality of 72% APACHEII and 69% SAPS

Sepsis, Dosing & Hemofiltration Pilot study of 20 septic patients Randomized to HVHF (65 ml/kg/hr) or LVHF (35ml/kg/hr) HVHF  norepi dose and  urine O/P No mortality difference IVOIRE study Randomized multi-centered European study Septic patients to HVHF (70 ml/kg/hr) vs. LVHF (35 ml/kg/hr) Recruitment due to end Dec 2008 Intensive Care Med 2008: 34; 1646

Pilot study of 20 septic patients

Randomized to HVHF (65 ml/kg/hr) or LVHF (35ml/kg/hr)

HVHF  norepi dose and  urine O/P

No mortality difference

IVOIRE study

Randomized multi-centered European study

Septic patients to HVHF (70 ml/kg/hr) vs. LVHF (35 ml/kg/hr)

Recruitment due to end Dec 2008

Anticoagulation Clotting and the CRRT circuit Multifactorial: Patients with hypercoaguable states Procoagulation effect of the circuit Low blood flow rates High convective transfer with CVVH or CVVHDF Time responding to machine alarms Effects: Less effective dialysis Loss of blood in the circuit Increased costs

Clotting and the CRRT circuit

Multifactorial:

Patients with hypercoaguable states

Procoagulation effect of the circuit

Low blood flow rates

High convective transfer with CVVH or CVVHDF

Time responding to machine alarms

Effects:

Less effective dialysis

Loss of blood in the circuit

Increased costs

Types of Anticoagulation Systemic Heparin  Antithrombin III activity  s Xa and IIa activity Problem if high bleeding risk Risk of HITT Reports of use of APC and argactaban Regional Citrate Prostacyclin

Systemic

Heparin

 Antithrombin III activity  s Xa and IIa activity

Problem if high bleeding risk

Risk of HITT

Reports of use of APC and argactaban

Regional

Citrate

Prostacyclin

Prostacyclin Prostacyclin and prostaglandin E1 inhibits platelet activation Short acting Systemic hypotension, H/A, flushing Filter life without any additional heparin only ~15 hours Very expensive! Crit Care 2007:11;218

Prostacyclin and prostaglandin E1 inhibits platelet activation

Short acting

Systemic hypotension, H/A, flushing

Filter life without any additional heparin only ~15 hours

Very expensive!

Regional Citrate Citrate chelates Ca iCa < 0.35 inhibits coagulation Citrate clearance Partially diffusion and convection Partially enters circulation 1 citrate metabolized by the liver and skeletal muscle to 3 HCO 3

Citrate chelates Ca

iCa < 0.35 inhibits coagulation

Citrate clearance

Partially diffusion and convection

Partially enters circulation

1 citrate metabolized by the liver and skeletal muscle to 3 HCO 3

Citrate Anticoagulation Filter Effluent Waste Citrate Ca Replacement Fluid

Citrate Anticoagulation Pros No systemic anticoagulation Can be used with suspected HITT patients Possibly longer filter life Heparin ~48hr Citrate ~72 hr Cons More complicated system Citrate and calcium infusions Needs close monitoring Especially in liver patients! Hypo/hyper calcemia Metabolic Alkalosis Metabolic Acidosis Crit Care 2007:11;218

Pros

No systemic anticoagulation

Can be used with suspected HITT patients

Possibly longer filter life

Heparin ~48hr

Citrate ~72 hr

Cons

More complicated system

Citrate and calcium infusions

Needs close monitoring

Especially in liver patients!

Hypo/hyper calcemia

Metabolic Alkalosis

Metabolic Acidosis

Citrate Toxicity & the Citrate Ratio Citrate accumulation may occur if: Unintentional citrate over infusion Decreasing liver function Decreasing function of the filter Results in: Hypocalcemia Metabolic Acidosis Citrate Ratio: [Total Ca2+]/[ iCa2+] Measured q12h Ratio > 2.5 stop citrate anticoagulation!

Citrate accumulation may occur if:

Unintentional citrate over infusion

Decreasing liver function

Decreasing function of the filter

Results in:

Hypocalcemia

Metabolic Acidosis

Citrate Ratio: [Total Ca2+]/[ iCa2+]

Measured q12h

Ratio > 2.5 stop citrate anticoagulation!

Anticoagulation at the QEII Two options: Citrate anticoagulation Citrate infusion pre-printed orders Post filter iCa 0.25-0.35 mmol/L Calcium infusion pre-printed orders Systemic iCa 1.0-1.35 mmol/L No anticoagulation Use if patient on systemic anticoagulation for other reasons Severe liver disease

Two options:

Citrate anticoagulation

Citrate infusion pre-printed orders

Post filter iCa 0.25-0.35 mmol/L

Calcium infusion pre-printed orders

Systemic iCa 1.0-1.35 mmol/L

No anticoagulation

Use if patient on systemic anticoagulation for other reasons

Severe liver disease

Replacement Solutions Prismocal Calcium 0 mmol/L Mg 0.5 mmol/L Cl 106 mmol/L Na 140 mmol/L Lactate 3 mmol/L Bicarb 32 mmol/L

Prismocal

Calcium 0 mmol/L

Mg 0.5 mmol/L

Cl 106 mmol/L

Na 140 mmol/L

Lactate 3 mmol/L

Bicarb 32 mmol/L

QEII Citrate Orders

No Anticoagulation Orders

Starting someone on CRRT at the QEII Joint process between both the Division of Critical Care and the Division of Nephrology ICU must contact nephrology before starting any patient on CRRT This may be in the form of a phone consultation Lines to be inserted by ICU Orders can be written by either ICU or Nephrology

Joint process between both the Division of Critical Care and the Division of Nephrology

ICU must contact nephrology before starting any patient on CRRT

This may be in the form of a phone consultation

Lines to be inserted by ICU

Orders can be written by either ICU or Nephrology

Starting someone on CRRT at the QEII Indications Hemodynamically unstable (defined as already requiring vasopressors or inotropes to maintain blood pressure) The patient became hemodynamically unstable (requiring vasopressors of inotropes to maintain blood pressure) during a previous IHD or SLEDD run In the initial implementation stages of CRRT at the QEII only 1 patient per unit will be on CRRT at a time, even if there is another patient hemodynamically unstable who requires dialysis.

Indications

Hemodynamically unstable (defined as already requiring vasopressors or inotropes to maintain blood pressure)

The patient became hemodynamically unstable (requiring vasopressors of inotropes to maintain blood pressure) during a previous IHD or SLEDD run

In the initial implementation stages of CRRT at the QEII only 1 patient per unit will be on CRRT at a time, even if there is another patient hemodynamically unstable who requires dialysis.

Starting someone on CRRT at the the QEII Also during the implementation stages, CRRT will be the preferred mode of dialysis provided to unstable patients (over SLEDD) Patients would not be a candidate for CRRT regardless of their hemodynamic status if: The patient has taken an overdose that requires dialysis The patient is presenting with acute hyperkalemia refractory to medical management

Also during the implementation stages, CRRT will be the preferred mode of dialysis provided to unstable patients (over SLEDD)

Patients would not be a candidate for CRRT regardless of their hemodynamic status if:

The patient has taken an overdose that requires dialysis

The patient is presenting with acute hyperkalemia refractory to medical management

Putting it Together Case 1 70 kg 80 yr female Volume overload Poor oxygenation MA - HCO3 10 K - 5.5 No reason to avoid citrate

Case 1

70 kg 80 yr female

Volume overload

Poor oxygenation

MA - HCO3 10

K - 5.5

No reason to avoid citrate

Remember: Dose = Replacement + Dialysate Dose = 70kg x 20ml/kg/hr =1.4 L/hr 1/2 given as replacement and dialysate

Putting it together…. Case 2 85 kg 45 year old male with sepsis induced acute renal failure on APC No conventional indications for dialysis Sats ok on 60% Metabolically stable No uremic changes However 12.5L +ve cumulative balance, no renal recovery and acute lung injury Temp: 39.2

Case 2

85 kg 45 year old male with sepsis induced acute renal failure on APC

No conventional indications for dialysis

Sats ok on 60%

Metabolically stable

No uremic changes

However 12.5L +ve cumulative balance, no renal recovery and acute lung injury

Temp: 39.2

Remember: Dose = Replacement + Dialysate Dose = 85kg x 20ml/kg/hr =1.7 L/hr 1/2 given as replacement and dialysate

Drugs and Dialysis Not Straight Forward! CVVH clearance CVVHD clearance Will need much input from pharmacy Loading doses shouldn’t be altered…it’s the maintenance that will need adjustment Sieving Coefficient Protein Binding Membrane Type Ultrafiltration Rate Molecular Size

Not Straight Forward!

CVVH clearance

CVVHD clearance

Will need much input from pharmacy

Loading doses shouldn’t be altered…it’s the maintenance that will need adjustment

Future Directions Plasma Exchange High Volume CVVH in septic patients?? Waiting results of the IVOIRE study Liver dialysis? Molecular Adsorbents Recirculating System (MARS) Albumen dialysis Small studies suggest improved encephalopathy

Plasma Exchange

High Volume CVVH in septic patients??

Waiting results of the IVOIRE study

Liver dialysis?

Molecular Adsorbents Recirculating System (MARS)

Albumen dialysis

Small studies suggest improved encephalopathy