CBP: Nephrology

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CBP Nephrology Diseases of the kidneys!
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CBP Nephrology

• A 48-year-old man, otherwise healthy, presents
  with severe unspecific abdominal pain and
  vomiting of 2 days duration.
• He is a stable bipolar personality disorder on
  lithium.
• an X smoker, has history of alcohol use,

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CBP Nephrology

• On physical examination, restless, dehydrated HR
  130 and BP 90/60 (Supine), RR 28, T 37.4. Chest
  and heart exams are unremarkable. Abd. exam
  revealed mild-moderate epigastric abdominal
  tenderness without peritoneal signs. Rest of the
  exam is unremarkable.
• Lab WBC is 16,500, and the HCT is 49. Cr 188 (67
  base line), BUN 12.3 , K 5.5 and the rest of
  electrolyte values are normal.

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CBP Nephrology

• Intubated on admission due to altered LOC and
  inability to protect his airway as well as
  impending hypoxemic respiratory failure, remains
  on multiple vasoactive agents, and is in
  oliguric-to-anuric renal failure
• Admitted to ICU and adequately resuscitated
• Patient remains anuric despite the adequate fluid
  resuscitation

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Question 1

• Any role for increasing doses of Lasix in an
  anuric patient? Any harm? Any benefit? (Eric)

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Diuretics in AKI
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Diuretics in AKI

• Three part question
• Electrolyte management
• Fluid management
• Conversion of oliguric to non-oliguric RF

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Electrolytes Fluid

• Paucity of data answering these specific
  questions
• Remains clinical decision and therapeutic option
• Differentiate fluid management from urine
  output

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Conversion of oliguric to non-oliguric RF

• Ravindra LM et al., Diuretics, Mortality, and
  Nonrecovery of Renal Function in Acute Renal
  Failure, JAMA. 2002288(20)2547-2553

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Confounders

• Diuretic use at the time of consultation was
  significantly associated with older age, presumed
  nephrotoxic (rather than ischemic or
  multifactorial) ARF origin, a lower BUN level,
  acute respiratory failure, and a history of
  congestive heart failure.

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Cause vs Correlate

• After adjusting for covariates associated with
  the risk of death, diuretic use was significantly
  associated with in-hospital mortality an
  non-recovery of renal function, even after
  adjustment for nonrandom treatment assignment
  using propensity scores.

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Diuretics in AKI

• Three part question
• Electrolyte management ?/ ?
• Fluid management ?/ ?
• Conversion of oliguric to non-oliguric RF ?

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Question 2

• Define Acute Kidney Injury (Eric)

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Definitions of AKI
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The dilemma

• More than 35 definitions
• of AKI currently exist in the literature

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AKI vs Acute/Chronic RF
Crit Care Med 2010 38261275
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RIFLE vs AKIN
Bagshaw et al., A comparison of the RIFLE and
AKIN criteria for acute kidney injury in
critically ill patients, Nephrol Dial Transplant
(2008) 23 15691574
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Bottom Line

• Both the RIFLE and AKIN criteria were developed
  to facilitate clinical investigation and
  comparison across study populations.
• To date, most interventional studies (e.g. NAC,
  NaHCO3, etc.) to prevent or mitigate AKI have not
  used these definitions.

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Question 3

1. What is the incidence of AKI in the ICU and how
   does it affect patient outcomes?( yahya)

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Incidence of AKI in the ICU

• AKI occurs in 7 of all hospitalized patients,
  whereas it occurs in 36 67 of critically ill
  patients.
• On average, 5 of ICU patients with AKI require
  renal replacement therapy.

Dennen P, Douglas IS, Anderson R. Acute kidney
injury in the intensive care unit an update and
primer for the intensivist. Crit Care Med. 2010
Jan38(1)261-75
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AKI and mortality

• In most studies, mortality rates rise
  proportionally with severity of AKI.
• Even small increases in serum creatinine have
  been associated with increasing mortality in
  various ICU populations despite adjusting for
  severity of illness and comorbidities.
• In patients with AKI requiring RRT, mortality
  rates reach 50 to 70.

Dennen P, Douglas IS, Anderson R. Acute kidney
injury in the intensive care unit an update and
primer for the intensivist. Crit Care Med. 2010
Jan38(1)261-75
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AKI and other outcomes

• AKI is also associated with
• Increased length of stay
• Increased incidence of CKD and end-stage kidney
  disease
• Increased cost
• For example, an increase in SCr of 0.5 mg/dl (38
  mmol/L)was associated with a
• 6.5-fold increase in the odds of death
• 3.5 day increase in LOS
• nearly 7500 in excess hospital costs

Dennen P, Douglas IS, Anderson R. Acute kidney
injury in the intensive care unit an update and
primer for the intensivist. Crit Care Med. 2010
Jan38(1)261-75
Chertow GM, Burdick E, Honour M, Bonventre JV,
Bates DW. Acute kidney injury, mortality, length
of stay, and costs in hospitalized patients. J Am
Soc Nephrol. 2005 Nov16(11)3365-70
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Question 4

• What are the methods for detecting acute kidney
  injury?( yahya)

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Traditional methods for detecting AKI

• Currently available measures do not detect actual
  kidney injury the way troponin detects myocardial
  injury
• Creatinine
• Urea
• Urine output
• Rather they are markers of abnormal renal
  function, that can be used to presume kidney
  inury has occurred.

Bagshaw SM, Bellomo R. Early diagnosis of acute
kidney injury. Curr Opin Crit Care. 2007
Dec13(6)638-44.
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Serum creatinine

• Used to estimate GFR
• Pros
• Produced at a relatively constant rate
• Freely filtered by glomerulus
• Not reabsorbed or metabolized by the kidney.

Bagshaw SM, Bellomo R. Early diagnosis of acute
kidney injury. Curr Opin Crit Care. 2007
Dec13(6)638-44.
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Serum creatinine

• Used to estimate GFR
• Cons
• 10-40 is secreted by the tubules
• Relatively insensitive (may need a 50 reduction
  in function before a detectable rise in SCr is
  seen)
• Creatinine production varies based on
  age/sex/muscle mass/diet
• Certain disease states can increase production
  (rhabdo)
• Certain drugs can decrease secretion (cimetidine,
  trimethoprim)
• Certain factorsmay affect assay (ketoacidosis,
  cefoxitin, flucytosine)
• Does not reflect real-time changes in GFR

Bagshaw SM, Bellomo R. Early diagnosis of acute
kidney injury. Curr Opin Crit Care. 2007
Dec13(6)638-44.
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Urea

• Rate of production is not constant
• Increases with protein intake
• Increases in critical illness (burns/sepsis/trauma
  )
• GI Bleed
• Steroids
• 40 - 50 of urea is reabsorbed by the kidney
  (even more when dry)

Bagshaw SM, Bellomo R. Early diagnosis of acute
kidney injury. Curr Opin Crit Care. 2007
Dec13(6)638-44.
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Urine output

• Pros
• A dynamic gauge of kidney function.
• May be a barometer for change in kidney perfusion
• Cons
• Poor sensitivity and specificity
• Can have severe AKI with normal or increased
  urine output

Bagshaw SM, Bellomo R. Early diagnosis of acute
kidney injury. Curr Opin Crit Care. 2007
Dec13(6)638-44.
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Summary of novel markers
Bagshaw SM, Bellomo R. Early diagnosis of acute
kidney injury. Curr Opin Crit Care 13638644.
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CBP Nephrology

• Patient continues to have increasing ventilation
  support requirments and is now on .85 FiO2. His
  K is now 5.6. He is given routine hyperK
  therapy. He has been started on vasopressors
  because of declining MAP

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Question 6

• When should RRT be started? (Indication and
  timing) (Brian)

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Historical aspects

• Use of HD in ARF started in the years immediately
  following WWII (1947-1950)
• Initial indications advanced symptoms of renal
  failure clinical uremia, severe hyperkalemia,
  pulmonary edema
• Reduction in mortality could not be demonstrated,
  with high complication rates
• Teschan et al reported improved survival with
  prophylactic dialysis in 1960

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Indisputable indications

• Volume overload
• Hyperkalemia
• Metabolic acidosis
• Uremic signs or symptoms
• Refractory to medical management
• No specific objective criteria

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Other Indications

1. Progressive azotemia in the absence of uremia (no
   consensus)
2. Other electrolyte disturbances (Na, Mg,PO4, Uric
   acid)

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Timing of initiation of RRT

• Competing risks
• Risk of delay in therapy
• Potential harm of therapy, including
  complications of therapy and the potential that
  dialysis may prolong the course of ARF

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Teschan et al. Prophylactic hemodialysis in the
treatment of acute renal failure. Ann Int Med
1960.

• Paul Teschan of US Army Medical Corps after the
  Korean War introduced the concept of
  prophylactic dialysis, applied before overt
  uremic symptoms appeared
• N15, uncontrolled trial, initiation of dialysis
  before serum Urea Nitrogen reached 100 mg/dl
• Twin coil cellulosic dialyzers at BF 75-250ml/min
  to maintain BUN less than 75mg/dl
• All cause mortality 33, mortality due to
  hemorrhage or sepsis 20
• No control group. However, investigators reported
  that the result represented dramatic increase
  in survival cf their past experience in pt in
  whom dialysis was not initiated until
  conventional indications were present

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Early studies
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Bouman et al (CCM 2002)

• 2 center RCT (n106). ICU pts on MV with
  vasopressor dependent circulation and oliguric
  ARF
• ARF CrCllt20, UOlt180ml/6h
• Early CVVH within 12h after onset of liguria
• Late ureagt40mmol/l, pulmonary edema with
  PaO2/FiO2lt150 despite PEEP 10
• Many issues

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Jiang, et al (2005)

• RCT (n37) in severe pancreatitis WITHOUT
  documented evidence of ARF
• Early CVVH within 48 hours onset of abdo pain
• Late within 96 hours
• Improved hemodynamics and 14d survival

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Gettings et al (ICM 1999)

• Retrospective nonrandomized cohort study (n100)
• Trauma patients
• Timing defined by BUN level
• Early RRT started at a mean BUN 15mmol/l
• Late at BUN 34 mmol/L
• Survival 39 Early, 20 Late

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Piccini et al. (ICM 2006)

• Retrospective study (n80)
• Patients with septic shock and oliguric AKI
• Historical control
• Early lt12h after ICU admission
• Late Ureagt35 mmol/l or Crgt600
• Improved hemodynamics, gas exchange, 28d survival

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Elahi et al. (2004)

• Retrospective cohort study (n80)
• Cardiac surgery patients
• Early CVVH when UOlt100ml/8h despite lasix
• Late Ureagt30 mmol/l, Crgt250, or Kgt6 regardless
  of UO
• Survival 44 early, 22 late, plt0.05

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Demirkilic et al. (2004)

• Retrospective study (n61)
• ARF following cardiac surgery
• Historical control
• Early CVVHDF if UOlt100ml/8h
• Late Crgt444
• Hospital mortality 23.5 Early 55 late p0.02

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Summary

• Trend towards better outcome with earlier timing
  of RRT
• Methodology poor
• Nonuniform definition of timing
• Heterogeneity of population
• Heterogeneity of RRT

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Summary

• Nonuniform and arbitrary definition of ARF
  prevents direct comparison of trials
• But how about using RIFLE criteria and AKIN
  definition?

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Shiao et al. (2009)

• Multicenter prospective observational study
• N98 who underwent RRT according to local
  indications for post-major abdo surgery AKI
• Early sRIFLE 0 or Risk
• Late sRIFLE I or F

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RIFLE/AKIN
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Results

• N98
• Early 51 (022, R29)
• Late 47 (I27, F20)
• ICU mortality Early 41.2, Late 68.1
• Hospital mortality Early 43.1, Late 74.5
  (p0.002)
• RRT wean-off rate 21 vs 41 p0.050

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Conclusions/Limitations

• Late dialysis defined by sRIFLE-I or sRIFLE-F is
  an independent predictor for inhospital mortality
• Support earlier initiation of RRT
• Small N
• Only GFR criterion of RIFLE used (sRIFLE)

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Question 7

• Define different modes of RRT (Brian)

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RRT modalities
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Diffusion
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Convection
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SCUF
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CVVH
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CVVHD
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CVVHDF
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IHD

• Blood flow 200-300 ml/min
• Dialysate flow 500-800 ml/min
• Solute removal by diffusion, fluid removal by
  ultrafiltration
• Solute clearance dependent on blood flow
• Advantages rapid solute and fluid removal (rapid
  electrolyte correction, certain toxin removal),
  no need for anticoagulation
• Disadvantages systemic hypotension,

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Renal Replacement Therapy

• All forms of RRT rely on the principle of
  allowing water and solute transport through a
  semipermeable membrane and discarding waste
  products
• Fluid removal ultrafiltration
• Solute transport diffusion, convection, or both

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Question 8

• IHD vs CRRT (Brian)

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Dialysis modality

• 1999 NKF survey revealed IHD as preferred form of
  RRT (75), while CRRT PD was less than 10
• More recent survey revealed IHD as preferred by
  nephrologists/intensivists in 57, while CRRT was
  preferred in 37 in US
• Internationally BEST Kidney study (JAMA 2005)
  revealed CRRT as the initial modality of choice
  for RRT in ICU used in 80, followed by IHD (17)

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So is CRRT better?
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Preference of CRRT Putative advantages

• Improved hemodynamic stability
• More effective control of acid/base and
  electrolyte status
• Improved removal of uremic toxins
• Removal of inflammatory mediators

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Disadvantages

• Need for anticoagulation
• 2-3x more expensive than IHD

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Evidence

• Two 2002 metaanalyses of earlier trials comparing
  survival in ICU AKI assigned to IHD or CRRT and
  adjusted for severity of illness did not support
  CRRT
• Several observational and prospective RCTs
  comparing IHD vs CRRT failed to confirm expected
  survival advantage of CRRT
• Limitations dose difference, high crossover
  rate, randomization failure, nonstandardization
  of protocol

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Cochrane Review 2008

• Intermittent vs. continuous RRT for ARF in adults

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Objectives

• To compare CRRT with IRRT to establish if any of
  these techniques is superior to each other in
  patients with AF

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Methods

• Types of studies RCTs
• Interventions
• IRRT defined as any form of RRT (HD, HF, HDF, UF)
  prescribed for period of lt24h within any 24h
  period
• CRRT defined as any RRT intended to run on a
  continuous basis until recovery of renal function
  occurred

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Methods

• Outcome measures
• Mortality (prior to ICU/hospital DC, time to
  ICU/hospital death/DC
• Recovery of renal function
• Cardiovascular stability
• Complications of therapy (bleeding, sepsis)

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Results Mortality

• In-hospital mortality no difference (7 studies,
  N1245) RR 1.01 (0.92-1.12), no evidence of
  significant heterogeneity
• ICU mortality no difference (5 studies, N515)
  RR 1.03 (0.90-1.26)
• Time to hospital death or discharge no
  difference (1 study, N25)
• Time to ICU discharge or death not assessed

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Results Recovery of RF

• Surviving pt not requiring dialysis No
  difference (3, N161) RR 0.99 (0.92-1.07), no
  evidence of sig. heterogeneity
• sCr or eGFR at hospital discharge no difference
  (1, N129) RR 1.13 (0.94-1.36)

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Results Cardiovascular stability

• Hemodynamic instability no difference (2,
  N205) RR 0.48 (0.2-2.28). One study did not
  specify definition, while the other defined it as
  avaerage variability b/w max ad min daily MAP. No
  heterogeneity
• Hypotension No difference (3, N514) RR 0.92
  (0.72-1.16). Variable definition of hypotension
• MAP at end of study CRRT significantly higher
  (2, N112) mean dif 5.35 (1.41-9.29)
• Systolic BP No difference (1, N30)
• Escalation of pressor rx No difference when
  analysed by random effects model
• Dose of inotropic drugs no difference

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Results Complications of RRT

• Bleeding no difference (5, N638)
• Clotting of dialysis filter CRRT significantly
  more likely to clot filter (3, N149) RR 8.5
  (1.14-63.33)
• Arrhythmia no difference (2, N439)
• RRT modality switch due to complications no
  difference (4, N920)

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Conclusions

• CRRT offers no survival advantage cf IRRT in ARF
• Pt surviving ARF who are managed with CRRT has
  similar recovery of RF as those treated with IRRT
• CRRT is associated with sig higher MAP
• CRRT is associated with sig increased filter
  clotting

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Limitations

• Each RCTs are not large enough to provide an
  accurate evaluation of the difference in outcome
• Considerable variations in definition of ARF and
  hypotension, heterogeneity in dialysis x (dose,
  membrane) and pt characteristics

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What kind of anticoagulation should be used with
CRRT?

• UBC AHD Nephrology CBP
• Samuel Kohen
• November 18, 2010

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Introduction

• CRRT is used in hemodynamically unstable patients
  with renal failure.
• The most common problem with CRRT is circuit
  clotting.
• Anticoagulation decreases this.
• Heparin and Citrate are the two most common CRRT
  anticoagulants.
• Until recently, it was not clear which was
  better.

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Heparin

• IV infusion administered into the inflow limb of
  the extracorporeal circuit.
• IV Bolus of 500-2000 U then infusion of 300-500
  U/h titrated to a goal PTT 1.5-2x normal.
• Stop heparin for bleeding or thrombocytopenia.

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Citrate

• Citrate inhibits clotting by chelating calcium.
• IV calcium is infused post-circuit to maintain
  normal serum Ca levels.
• Citrate is basic so the other dialysate buffers
  (bicarbonate or lactate) must be reduced
• It is hepatically metabolized by the patient.

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Citrate versus heparin for anticoagulation in
continuous venovenous hemofiltration a
prospective randomized study

• Mehran et al.
• Intensive Care Med (2004)
• 30260265

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Mehran et al.

• Prospective trial randomizing 20 patients
  receiving CVVHF to heparin or citrate by
  hemofilter.
• 49 hemofilters used 23 heparin and 26 citrate.
• Patients requiring more than one hemofilter were
  crossed over.
• Patients with liver dysfunction or deemed at high
  risk of bleeding were excluded.

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Mehran et al.

• There is no difference in CRRT function (urea and
  creatinine clearance).
• The median circuit lifetime was longer with
  citrate than heparin (70 vs 40 hours) mostly due
  to clotting (74 vs 46).
• Citrate anticoagulation is associated less
  bleeding
• Fewer significant bleeding episodes (1 UGIB vs 0)
• Fewer PRBC transfusions (1 U/d vs 0.2 U/d)
• Citrate is more often associated with metabolic
  derangements
• Metabolic alkalosis and hypocalcemia.

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Regional citrate versus systemic heparinization
for continuous renal replacement in critically
ill patients.

• Demetrios et al.
• Kidney international. Vol 67 (2005). P 2361
  2367.

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Demetrios et al.

• 30 critically ill adult patients with acute renal
  failure on CRRT were randomized to either heparin
  (16) or citrate (14). 2 patients crossed over
  treatment groups. 79 hemofilters were used
  Heparin (43), Citrate (36).

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Demetrios et al.

• No significant difference in survival to hospital
  discharge.
• (Citrate 14 Heparin 29 p 0.69)
• Filters using citrate functioned much longer than
  those with heparin
• (124.5 vs 38.3 hours).

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Conclusions Citrate is better

• No difference in creatinine clearance or 60 day
  mortality.
• Citrate treated circuits clot less frequently and
  last longer.
• Citrate anticoagulation is associated with fewer
  bleeding episodes.
• Metabolic alkalosis and hypocalcemia are the most
  common complications of citrate-treated circuits
  but are easily detected and usually harmless.

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What are we doing at VGH?

• Prime the circuit with 5000 U heparin and 2 L of
  saline
• Infuse pre-circuit dialysate (1.2 L/h)
• Run high blood flow rates (300 mL/min)
• No continuous anticoagulation

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What is the ideal dialysis dose?

• UBC AHD Nephrology CBP
• Samuel Kohen
• November 18, 2010

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Dialysis dosing
Dialysis Dose Kt / V
K Clearance constant per time t dialysis
time V Patient Fluid volume

• The ideal IHD DD is 1.2
• CVVHF effluent flow rate correlates with solute
  clearance rates.
• Effluent rate of 20 ml/h/kg DD 0.8
• Effluent rate of 35 ml/h/kg DD 1.4
• Initial trials showed that higher dialysis
  intensity improved patient outcomes.
• Two recent trials investigated this further
  VA/NIH and RENAL.

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VA/NIH

• Palevsky et al. Intensity of renal support in
  critically ill patients with acute kidney injury.
  NEJM july 3,2008. 3591 p. 7 20.

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VA/NIH

• 1124 critically ill patients with ARF were
  randomized to low (563) or high (561)
  intensity RRT.
• Low intensity group
• IHD 3x/wk when HD stable (SOFA 0-2)
• CVVHDF at 20 mL/kg/hr or SLED when unstable (SOFA
  3-4).
• High intensity group
• IHD 6d/wk when stable
• CVVHDF at a goal effluent rate of 35 mL/kg/h) or
  SLED when unstable.
• Results
• No significant difference in 60 day mortality
  (low 51.5, high 53.6), duration of RRT, rate of
  renal function recovery or evolution of non-renal
  organ failure.
• Higher rates of hypotension, hypophosphatemia and
  hypokalemia in the high-intensity RRT group.

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RENAL

• Bellomo et al. Intensity of continuous renal
  replacement therapy in critically ill patients.
  NEJM 2009. 36117. 1627 1638.

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RENAL

• 1508 Critically ill patients with ARF on CVVHF
  were randomized to low (25 mL/kg/hr 747
  patients) or high intensity (40 mL/kg/hr 761
  patients) effluent rates.
• There was no difference in 90 day mortality rate
  (44.7) or the need for RRT at 90d between the
  two treatment groups.

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Conclusion Equal

• Higher intensity CVVHF is associated with higher
  rates of electrolyte abnormalities without any
  clinical benefit.
• A goal effluent flow rate of 20 ml/h/kg is
  adequate for patients on CVVHF.