Transcript CBP: Nephrology – Diseases of the kidneys!

CBP: Nephrology – Diseases of
the kidneys!
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,
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.
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
Question 1
• Any role for increasing doses of Lasix in an
anuric patient? Any harm? Any benefit? (Eric)
Diuretics in AKI
Diuretics in AKI
• Three part question:
1. Electrolyte management
2. Fluid management
3. Conversion of oliguric to non-oliguric RF
Electrolytes & Fluid*
• Paucity of data answering these specific
questions
• Remains clinical decision and therapeutic
option
* Differentiate fluid management from urine
output
Conversion of oliguric to non-oliguric RF
Ravindra LM et al., Diuretics, Mortality, and Nonrecovery of Renal Function in Acute Renal Failure, JAMA. 2002;288(20):2547-2553
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.
Cause vs Correlate
• After adjusting for covariates associated with
the risk of death, diuretic use was significantly
associated with in-hospital mortality an nonrecovery of renal function, even after
adjustment for nonrandom treatment
assignment using propensity scores.
Diuretics in AKI
• Three part question:
1. Electrolyte management ✓/ ✗
2. Fluid management ✓/ ✗
3. Conversion of oliguric to non-oliguric RF
✗
Question 2
• Define Acute Kidney Injury (Eric)
Definitions of AKI
The dilemma
“More than 35 definitions
of AKI currently exist in the literature”
AKI vs Acute/Chronic RF
Crit Care Med 2010; 38:261–275
RIFLE vs AKIN
Bagshaw et al., A comparison of the RIFLE and AKIN
criteria for acute kidney injury in critically ill patient
Nephrol Dial Transplant (2008) 23: 1569–1574
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.
Question 3
1. What is the incidence of AKI in the ICU and
how does it affect patient outcomes?( yahya)
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 Jan;38(1):261-75
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 Jan;38(1):261-75
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 Jan;38(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 Nov;16(11):3365-70
Question 4
• What are the methods for detecting acute
kidney injury?( yahya)
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 Dec;13(6):638-44.
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 Dec;13(6):638-44.
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 Dec;13(6):638-44.
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 Dec;13(6):638-44.
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 Dec;13(6):638-44.
Summary of novel markers
Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13:638–644.
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
Question 6
• When should RRT be started? (Indication and
timing) (Brian)
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
“Indisputable” indications
1.
2.
3.
4.
Volume overload
Hyperkalemia
Metabolic acidosis
Uremic signs or symptoms
• Refractory to medical management
• No specific objective criteria
Other Indications
1. Progressive azotemia in the absence of
uremia (no consensus)
2. Other electrolyte disturbances (Na, Mg,PO4,
Uric acid)
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
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
• N=15, 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
Early studies
Bouman et al (CCM 2002)
• 2 center RCT (n=106). ICU pts on MV with
vasopressor dependent circulation and
oliguric ARF
• ARF: CrCl<20, UO<180ml/6h
• Early: CVVH within 12h after onset of liguria
• Late: urea>40mmol/l, pulmonary edema with
PaO2/FiO2<150 despite PEEP 10
• Many issues
Jiang, et al (2005)
• RCT (n=37) 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
Gettings et al (ICM 1999)
• Retrospective nonrandomized cohort study
(n=100)
• 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
Piccini et al. (ICM 2006)
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Retrospective study (n=80)
Patients with septic shock and oliguric AKI
Historical control
Early: <12h after ICU admission
Late: Urea>35 mmol/l or Cr>600
Improved hemodynamics, gas exchange, 28d
survival
Elahi et al. (2004)
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Retrospective cohort study (n=80)
Cardiac surgery patients
Early: CVVH when UO<100ml/8h despite lasix
Late: Urea>30 mmol/l, Cr>250, or K>6
regardless of UO
• Survival 44% early, 22% late, p<0.05
Demirkilic et al. (2004)
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Retrospective study (n=61)
ARF following cardiac surgery
Historical control
Early: CVVHDF if UO<100ml/8h
Late: Cr>444
Hospital mortality 23.5% Early 55% late
p=0.02
Summary
• Trend towards better outcome with earlier
timing of RRT
• Methodology poor
• Nonuniform definition of timing
• Heterogeneity of population
• Heterogeneity of RRT
Summary
• Nonuniform and arbitrary definition of ARF
prevents direct comparison of trials
• But how about using RIFLE criteria and AKIN
definition?
Shiao et al. (2009)
• Multicenter prospective observational study
• N=98 who underwent RRT according to local
indications for post-major abdo surgery AKI
• Early: sRIFLE – 0 or Risk
• Late: sRIFLE – I or F
RIFLE/AKIN
Results
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•
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•
N=98
Early = 51 (0=22, R=29)
Late = 47 (I=27, F=20)
ICU mortality = Early 41.2%, Late 68.1%
Hospital mortality = Early 43.1%, Late 74.5%
(p=0.002)
• RRT wean-off rate = 21% vs 41% p=0.050
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)
Question 7
• Define different modes of RRT (Brian)
RRT modalities
Diffusion
Convection
SCUF
CVVH
CVVHD
CVVHDF
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,
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
Question 8
• IHD vs CRRT (Brian)
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%)
So: is CRRT better?
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
Disadvantages
• Need for anticoagulation
• 2-3x more expensive than IHD
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
Cochrane Review 2008
Intermittent vs. continuous RRT for
ARF in adults
Objectives
• To compare CRRT with IRRT to establish if any
of these techniques is superior to each other
in patients with AF
Methods
• Types of studies: RCTs
• Interventions
– IRRT defined as any form of RRT (HD, HF, HDF, UF)
prescribed for period of <24h within any 24h
period
– CRRT defined as any RRT intended to run on a
continuous basis until recovery of renal function
occurred
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)
Results – Mortality
• In-hospital mortality – no difference (7
studies, N=1245): RR 1.01 (0.92-1.12), no
evidence of significant heterogeneity
• ICU mortality – no difference (5 studies,
N=515): RR 1.03 (0.90-1.26)
• Time to hospital death or discharge – no
difference (1 study, N=25)
• Time to ICU discharge or death – not assessed
Results – Recovery of RF
• Surviving pt not requiring dialysis – No
difference (3, N=161) RR 0.99 (0.92-1.07), no
evidence of sig. heterogeneity
• sCr or eGFR at hospital discharge – no
difference (1, N=129) RR 1.13 (0.94-1.36)
Results – Cardiovascular stability
• Hemodynamic instability – no difference (2, N=205) 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, N=514) RR 0.92 (0.721.16). Variable definition of hypotension
• MAP at end of study – CRRT significantly higher (2,
N=112) mean dif 5.35 (1.41-9.29)
• Systolic BP – No difference (1, N=30)
• Escalation of pressor rx – No difference when analysed
by random effects model
• Dose of inotropic drugs – no difference
Results – Complications of RRT
• Bleeding – no difference (5, N=638)
• Clotting of dialysis filter – CRRT significantly
more likely to clot filter (3, N=149) RR 8.5
(1.14-63.33)
• Arrhythmia – no difference (2, N=439)
• RRT modality switch due to complications – no
difference (4, N=920)
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
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
What kind of anticoagulation
should be used with CRRT?
UBC AHD Nephrology CBP
Samuel Kohen
November 18, 2010
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.
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.
Citrate
• Citrate inhibits clotting by
chelating calcium.
• IV calcium is infused postcircuit 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.
Citrate versus heparin for
anticoagulation in continuous
venovenous hemofiltration: a
prospective randomized study
Mehran et al.
Intensive Care Med (2004)
30:260–265
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.
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.
Regional citrate versus systemic
heparinization for continuous renal
replacement in critically ill patients.
Demetrios et al.
Kidney international. Vol 67 (2005). P
2361 – 2367.
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).
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).
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.
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
What is the ideal dialysis dose?
UBC AHD Nephrology CBP
Samuel Kohen
November 18, 2010
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.
VA/NIH
Palevsky et al. Intensity of renal
support in critically ill patients with
acute kidney injury. NEJM july 3,2008.
359:1 p. 7 – 20.
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 nonrenal organ failure.
– Higher rates of hypotension, hypophosphatemia and hypokalemia in
the high-intensity RRT group.
RENAL
Bellomo et al. Intensity of continuous
renal replacement therapy in critically ill
patients. NEJM 2009. 361:17. 1627 –
1638.
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.
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.