Case Presentation 43 year old gentleman with Crytogenic

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Case Presentation 43 year old gentleman with Crytogenic Cirrhosis is admitted to the ICU

Case Presentation 43 year old gentleman with Crytogenic Cirrhosis is admitted to the ICU after massive GI bleed secondary to bleeding esophageal varices. His varices have been successfully banded and he is admitted post-procedure. He received multiple units of blood, as well as platelets to correct his thrombocytopenia and FFP to correct his coaglulopathy (INR 4. 3). He also received 6 L of crystalloid. He is now hemodynamically stable, however, his respiratory requirements have increased, in keeping with his CXR findings of acute pulmonary edema.

 PSV, 12/5, Fi. O 2. 45 He is kept intubated over night and

PSV, 12/5, Fi. O 2. 45 He is kept intubated over night and given multiple boluses of Lasix (total of 200 mg) to help encourage diuresis. When assessed in the morning, it is noted that he has been anuric over night. His admission BUN/Cr were 11/87, and are now 23/192. He is now on PSV 16/8 and Fi. O 2 is. 65. His electrolytes reveal: Na – 128, K – 5. 3, Cl- 97, t. CO 2 – 18. ABG: 7. 31/39/84/19/-2

Question 1 Briefly describe Hepatorenal syndrome and it’s pathophysiology. What are some predisposing factors?

Question 1 Briefly describe Hepatorenal syndrome and it’s pathophysiology. What are some predisposing factors? (Federico)

DEFINITION Hepatorenal syndrome is a clinical condition that usually occurs in patients with advanced

DEFINITION Hepatorenal syndrome is a clinical condition that usually occurs in patients with advanced liver disease and portal hypertension that is characterized by : -Renal failure, with creatinine level more than 1. 5 mg/dl -Marked decrease in GFR and renal plasma flow (RPF) in the absence of other identifiable cause of renal failure. -Marked abnormality in systemic hemodynamics -Activation of endogenous vasoactive systems. HRS occurs predominantly in the setting of cirrhosis, but it may also develop in other types of severe chronic liver diseases, such as alcoholic hepatitis, or in acute liver failure.

 The theory that best fits with the observed alterations in the renal and

The theory that best fits with the observed alterations in the renal and circulatory function in HRS is the vasodilation theory, which proposes that HRS is the result of the effect of vasoconstrictor systems acting on the renal circulation and activated as a homeostatic mechanisms to improve the extreme underfilling of the arterial circulation. That leads to decreased renal perfusion and glomerular filtration rate )GFR (but tubular function is preserved.

 There are two well-differentiated clinical patterns of HRS Type 1 HRS • Characterized

There are two well-differentiated clinical patterns of HRS Type 1 HRS • Characterized by rapid and progressive impairment of renal function defined as a doubling of the initial serum creatinine to a level greater than 2. 5 mg/dl or a 50% reduction of the initial 24 -hour creatinine clearance to a level lower than 20 ml/min in less than 2 weeks. • Usually occur in severe liver failure (Jaundice, encephalopathy, and coagulopathy) • Occur frequently after precipitating factor (e. g. GI bleeding) • Median survival time is only 2 weeks

 Type 2 HRS • Characterized by a less severe and non-progressive reduction of

Type 2 HRS • Characterized by a less severe and non-progressive reduction of GFR. • Associated with relatively preserved liver function. • The main clinical consequence of this type of HRS is refractory ascites, due to a lack of response to diuretics. • Median survival time is about 6 months.

The International Ascites Club has defined criteria for the diagnosis of HRS. Major criteria,

The International Ascites Club has defined criteria for the diagnosis of HRS. Major criteria, necessary only for the diagnosis, are as follows: 1. Low GFR, defined by a serum creatinine greater than 1. 5 mg/d. L or 24 hour clearance lower than 40 m. L/min 2. Absence of shock, ongoing bacterial infection, fluid losses and current treatment with nephrotoxic drugs 3. No sustained improvement in renal function (decrease in serum creatinine to <1. 5 mg/d. L or increase in clearance to >40 m. L/min) following diuretic withdrawal and plasma volume expansion with albumin (or 1. 5 L of isotonic saline). 4. Proteinuria less than 500 mg/d 5. Absence of any evidence of obstructive uropathy or parenchymal disease as shown by ultrasonography

Precipitating factors 1. Bacterial infections 2. Bleeding 3. Large volume paracentesis without plasma expansion

Precipitating factors 1. Bacterial infections 2. Bleeding 3. Large volume paracentesis without plasma expansion

 Patient remains anuric and is given a further bolus of 100 mg of

Patient remains anuric and is given a further bolus of 100 mg of Lasix. Patient remains anuric despite most recent dose of Lasix.

Question 2 Any role for increasing doses of Lasix in an anuric patient? Any

Question 2 Any role for increasing doses of Lasix in an anuric patient? Any harm? Any benefit? (Federico)

Diuretics in AKI Regarding an increased appreciation for the potential detrimental downstream effects of

Diuretics in AKI Regarding an increased appreciation for the potential detrimental downstream effects of volume overload, it may be reasonable to try diuretics for control of volume overload. The clinician should, however, be careful not to delay initiation of RRT for volume overload in the critically ill patient with AKI (Crit. Care 2010, vol 38, n 1)

Question 3 Define Acute Kidney Injury (Federico)

Question 3 Define Acute Kidney Injury (Federico)

RIFLE Criteria The Acute Dialysis Quality Initiative Group proposed the RIFLE system classifying ARF

RIFLE Criteria The Acute Dialysis Quality Initiative Group proposed the RIFLE system classifying ARF into 3 severity groups and 2 clinical outcome categories

Incidence of AKI in the ICU AKI occurs in ~ 7% of all hospitalized

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.

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

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

Traditional methods for detecting AKI Currently available measures do not detect actual kidney injury

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

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

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.

Delay in SCr rise Waikar SS, Bonventre JV. Creatinine kinetics and the definition of

Delay in SCr rise Waikar SS, Bonventre JV. Creatinine kinetics and the definition of acute kidney injury. J Am Soc Nephrol. 2009 Mar; 20(3): 672 -9

Urea Rate of production is not constant Increases with protein intake Increases in critical

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

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.

Novel methods for detecting AKI Serum Cystatin C Kidney injury molecule-1 Neutrophil gelatinase-associated lipocalin

Novel methods for detecting AKI Serum Cystatin C Kidney injury molecule-1 Neutrophil gelatinase-associated lipocalin (NGAL) Urinary IL-18

Serum cystatin c An endogenous cysteine proteinase inhibitor Synthesized at a relatively constant rate

Serum cystatin c An endogenous cysteine proteinase inhibitor Synthesized at a relatively constant rate Released into plasma by all nucleated cells in the body Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measure- ment. Kidney Int 2004; 65: 1416– 1421

Serum cystatin c Reportedly not affected by patient age, sex, muscle mass or diet

Serum cystatin c Reportedly not affected by patient age, sex, muscle mass or diet However, one large study showed that age, sex, height, weight, smoking status, and CRP levels were all associated with cystatin c levels. Also found to be affected by abnormal thyroid function, immunosuppression (steroids), and systemic inflammation Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measure- ment. Kidney Int 2004; 65: 1416– 1421

Serum cystatin c Almost 99% is filtered by the glomerulus Not secreted or reabsorbed

Serum cystatin c Almost 99% is filtered by the glomerulus Not secreted or reabsorbed by the tubules Therefore a rise in cystatin c is a good indication of a decrease in GFR Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13: 638– 644.

Serum cystatin c Cystatin C-based estimates of GFR may perform better in those with

Serum cystatin c Cystatin C-based estimates of GFR may perform better in those with lower SCr concentrations such as: Elderly patients Children Renal transplant recipients Cirrhotics Those that are malnourished May be more sensitive to early and mild changes of kidney function compared with creatinine Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13: 638– 644.

Kidney injury molecule-1 A transmembrane glycoprotein that is normally minimally expressed in kidney tissue.

Kidney injury molecule-1 A transmembrane glycoprotein that is normally minimally expressed in kidney tissue. Shows marked upregulation in proximal renal tubular cells in response to ischemic or nephrotoxic AKI Shed from proximal cells and detected in the urine by immunoassay Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13: 638– 644.

Kidney injury molecule-1 Urinary levels of KIM-1 are significantly higher in established AKI compared

Kidney injury molecule-1 Urinary levels of KIM-1 are significantly higher in established AKI compared with other causes of AKI (i. e. PRA, contrast-induced nephropathy) or CKD. Thus, KIM-1 may represent an early, noninvasive biomarker for proximal tubular AKI. More studies needed to define its role Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13: 638– 644.

Neutrophil gelatinase-associated lipocalin (NGAL) Belongs to the lipocalin superfamily Markedly upregulated in response to

Neutrophil gelatinase-associated lipocalin (NGAL) Belongs to the lipocalin superfamily Markedly upregulated in response to kidney ischemic or nephrotoxic injury May be an early and sensitive urinary biomarker of ischemic and nephrotoxic AKI. Early elevations in urinary NGAL after kidney transplan- tation have been shown to be predictive of: delayed graft failure Need for RRT during the first week following transplantation Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13: 638– 644.

Interleukin-18 IL-18 can be induced in the proximal tubule and detected in the urine

Interleukin-18 IL-18 can be induced in the proximal tubule and detected in the urine in ischemic AKI Is increased in the urine of patients with established AKI when compared to those with prerenal failure, urinary tract infection, CKD or healthy controls. Elevated urinary IL-18 values have been shown to preceded clinical evidence of overt AKI (50% increase in SCr) by 24 – 48 h in critically ill patients with ARDS. Urinary IL-18 values of at least 100 pg/ml were associated with an estimated 6. 5 increased odds of developing AKI within 24 h. Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13: 638– 644.

Summary of novel markers Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury.

Summary of novel markers Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13: 638– 644.

Question 5 What are some traditional and novel methods for early detection of kidney

Question 5 What are some traditional and novel methods for early detection of kidney injury? (Marios)

 Patient continues to have increasing ventilation support requirments and is now on. 85

Patient continues to have increasing ventilation support requirments and is now on. 85 Fi. O 2. His K+ is now 5. 6. He is given routine hyper. K+ therapy. He has been started on vasopressors because of declining MAP

Question 6, 7 What are the indications for CRRT vs IHD. Is one better?

Question 6, 7 What are the indications for CRRT vs IHD. Is one better? What are their associated advantages and disadvantages? (Neil) When should RRT be initiated?

A, E, I, O, U CRRT review Chest 2007

A, E, I, O, U CRRT review Chest 2007

Acute Renal Failure Lancet review. pdf

Acute Renal Failure Lancet review. pdf

Bouman et al. Timingof. CRRT-Curr. Op. Crit. Care 2007. pdf

Bouman et al. Timingof. CRRT-Curr. Op. Crit. Care 2007. pdf

CRRT review Chest 2007

CRRT review Chest 2007

Lameire et al. Lancet 2005

Lameire et al. Lancet 2005

CRRTvs. IHDCochrane 2007. pdf

CRRTvs. IHDCochrane 2007. pdf

Question 8 Define the different modes of CRRT. Use a diagram to highlight the

Question 8 Define the different modes of CRRT. Use a diagram to highlight the differences? (Noemie)

 It is decided to start the patient on CRRT therapy. What kind of

It is decided to start the patient on CRRT therapy. What kind of anticoagulation should he receive?

Question 9 Compare the different modes of anticoagulation. Explain the use of citrate and

Question 9 Compare the different modes of anticoagulation. Explain the use of citrate and how to dose it. Please explain the calcium gap. (Noemie)

Anticoagulation Heparin Can be given systemically or through circuit Aim for PTT 35 -45

Anticoagulation Heparin Can be given systemically or through circuit Aim for PTT 35 -45 sec Regional citrate

Intensive Care Med 2004; 30: 260 -265

Intensive Care Med 2004; 30: 260 -265

Kidney International 2005; 67: 2361 -2367

Kidney International 2005; 67: 2361 -2367

Intensive Care Med 2004; 30: 260 -265 Kidney International 2005; 67: 2361 -2367

Intensive Care Med 2004; 30: 260 -265 Kidney International 2005; 67: 2361 -2367

Anticoagulation Citrate infusion pre-filter Leads to calcium chelation and clotting time Aiming for post

Anticoagulation Citrate infusion pre-filter Leads to calcium chelation and clotting time Aiming for post filter i. Ca btw 0. 25 -0. 35 Post-filter calcium infusion to restore systemic Ca and clotting function

Citrate Concerns: Pricy Operator training + time consuming Repeat labs q 6 h: Post

Citrate Concerns: Pricy Operator training + time consuming Repeat labs q 6 h: Post filter i. Ca, Systemic i. Ca and total Ca Risk of hypocalcemia

Calcium Total plasma Calcium: 40% bound to albumin 45% circulates as ionized calcium 15%

Calcium Total plasma Calcium: 40% bound to albumin 45% circulates as ionized calcium 15% bound to organic/inorganic anions

Citrate and Calcium Gap 50% of citrate cleared through dialyser Remaining citrate metabolized in

Citrate and Calcium Gap 50% of citrate cleared through dialyser Remaining citrate metabolized in the liver to Bicarbonate If citrate systemic delivery >> pt’s ability to metabolize citrate Systemic accumulation of Calcium Citrate hypocalcemia

Calcium gap Calcium gap: Total calcium - ionized Ca Citrate accumulation causes Total calcium

Calcium gap Calcium gap: Total calcium - ionized Ca Citrate accumulation causes Total calcium and i. Ca Pt with acute renal failure and liver failure at increased risk of citrate accumulation

Tidbits from Dodek Citrate toxicity, only clinically relevant if: Leads to hypernatremia Leads to

Tidbits from Dodek Citrate toxicity, only clinically relevant if: Leads to hypernatremia Leads to metabolic acidosis (when citrate is not metabolized, b/c it is an acid) +/- Metabolic acidosis (because it is converted to HCO 3) Hypocalcemia (but just turn up your Ca infusion) In relation to above, calcium gap not all that relevant

Question 10 What is an ideal dialysis dose? (Todd)

Question 10 What is an ideal dialysis dose? (Todd)

What is the ideal dialysis dose? I don’t know. And I’m not the only

What is the ideal dialysis dose? I don’t know. And I’m not the only one.

Speaking of flashbacks… 2 recent studies addressing the issue of “dose” of renal replacement

Speaking of flashbacks… 2 recent studies addressing the issue of “dose” of renal replacement therapy The first included multiple RRT modalities…

 IHD, SLED, CVVHDF Patients enrolled had ATN requiring dialysis and either sepsis or

IHD, SLED, CVVHDF Patients enrolled had ATN requiring dialysis and either sepsis or one additional nonrenal organ failure Excluded patients with chronic kidney disease

 CVVHDF dose was 20 cc/kg/hr in the less intensive group and 35 cc/kg/hr

CVVHDF dose was 20 cc/kg/hr in the less intensive group and 35 cc/kg/hr in the intensive group In the IHD/SLED patients, dosing was 3 times per week or 6 times per week, respectively

Essentially no difference Mortality, recovery of renal function, ICU-free days, organ failure scores, or

Essentially no difference Mortality, recovery of renal function, ICU-free days, organ failure scores, or discharge home without dialysis.

The second rule of (city wide) Journal Club… Critically ill patients with AKI requiring

The second rule of (city wide) Journal Club… Critically ill patients with AKI requiring dialysis Excluded if on dialysis pre-admission CVVHDF, with post-filter replacement fluid 25 cc/kg/hr vs 40 cc/kg/hr Dialysate: replacement fluid (Hmosol B 0) 1: 1

 What does this mean…? That the dose is unimportant? That the dose beyond

What does this mean…? That the dose is unimportant? That the dose beyond a (not quite determined) value is not important? Are we looking for the wrong outcomes?

What box should I check? At RCH: 35 cc/kg hr (as opposed to 45)

What box should I check? At RCH: 35 cc/kg hr (as opposed to 45) Saves a few bucks on dialysis/replacement fluid.

Question 11 It turns out the patient has been feeling very suicidal lately What

Question 11 It turns out the patient has been feeling very suicidal lately What are the indications for RRT in acute intoxications (Todd)

What are the indications for RRT in acute intoxications? If there is indication of

What are the indications for RRT in acute intoxications? If there is indication of severe toxicity If elimination can be improved by an extracorporeal technique. HD, HF, hemoperfusion, MARS Current Opinion in Critical Care 2007, 13: 668– 673

 Dialysis techniques: Discussed already. Hemoperfusion: adsorption of toxins MARS: hemoperfusion technique using albumin

Dialysis techniques: Discussed already. Hemoperfusion: adsorption of toxins MARS: hemoperfusion technique using albumin exchanger. Or hemofiltration And possibly: Carbamazapine, diltiazem, phenytoin and mushrooms

 Patient stabilized on CRRT therapy and slowly his renal function has shown some

Patient stabilized on CRRT therapy and slowly his renal function has shown some improvements with production of small amounts of urine. His hemoglobin has remained stable and HD he is off pressors. However, you are called to his bed side stat as his BP has suddenly dropped. His repeat Hg. B shows a drop of 35. You are entertaining a retroperitoneal bleed and want to do a CT contrast of his abdo/pelvis.

Question 12 Does RRT decrease the incidence of Contrast induced nephropathy? (Todd)

Question 12 Does RRT decrease the incidence of Contrast induced nephropathy? (Todd)

decrease the incidence of contastinduced nephropathy? It should. But there’s no evidence that it

decrease the incidence of contastinduced nephropathy? It should. But there’s no evidence that it does. One trial randomized patients to low-dose hemofiltration in ICU vs ward care with NS at 1 cc/kg/hr, prior to PCI and found no difference in CIN or mortality. Duration was approx. 6 hours pre- and 20 hours post- contrast load. 58 pts per group, average Cr 270. Other strategies, i. e. iso-osmolar contrast, NAC, were included

PRISMA geeks rejoice… Femoral HD line Pump speed 100 cc/min Replacement fluid at 1000

PRISMA geeks rejoice… Femoral HD line Pump speed 100 cc/min Replacement fluid at 1000 cc/hr No net fluid off Heparin anticoagulation

The fine print Control group needed more renal replacement therapy (25% vs 3% in

The fine print Control group needed more renal replacement therapy (25% vs 3% in intervention group)

The end! You now know all about the kidneys!!!

The end! You now know all about the kidneys!!!