A. Jörres 10-2015

Prof. Achim Jörres, M.D.

Dept. of Nephrology and

Medical Intensive Care

Charité University Hospital

Campus Virchow Klinikum

Berlin, Germany

achim.joerres@charite.de

Septic AKI in ICU patients

A. Jörres 10-2015

Agenda

• Epidemiology

• Pathophysiology

• Initial treatment

A. Jörres 10-2015

• Retrospective analysis of prospectively collected data from the ANZICS

Adult Patient Database, 57 ICUs across Australia, in total 120,123 patients

admitted to ICU for more than 24 hours (1 Jan 2000 to 31 Dec 2005)

• Of 33,375 patients with sepsis-related diagnosis, 14,039 (42.1%) had

concomitant AKI (septic AKI)

• Sepsis accounted for 32.4% of all patients with AKI.

• Septic AKI was associated with greater severity of AKI (RIFLE category

injury or failure) compared with nonseptic AKI.

• Septic AKI was associated with a significantly higher crude and co-variate

adjusted mortality in the ICU (19.8% vs 13.4%; OR 1.60, 95% CI1.5 to 1.7;

P<0.001) and in hospital (29.7% vs 21.6%; OR1.53, 95% CI 1.46 to 1.60;

P<0.001) compared with nonseptic AKI.

Bagshaw SM et al., Crit. Care 2008; 12: R47

A. Jörres 10-2015 Schrier RW & Wang W, NEJM 2004;351:159-69

A. Jörres 10-2015 Bonventre & Yang, J. Clin. Invest. 2011; 121: 4210-21

The pars recta of the proximal

tubule and the thick ascending

limb are already normally

hypoxic.

Regional ischemia (especially in

the outer medulla) during AKI is

enhanced by:

• enhanced vasoconstriction

• small vessel occlusion due

to endothelial-leukocyte

interactions

• activation of the coagulation

system

• local edema

Nephron Anatomy and Corticomedullary

Oxygen Gradient

Countercurrent

exchange of oxygen

results in gradient of

decreasing O2

tension in vasa recta

A. Jörres 10-2015

• 423 patients with severe sepsis and electronically recorded continuous hemodynamic

data in the prospective observational FINNAKI study.

• 153 patients (36.2%) had progression of AKI (KDIGO criteria).

• Patients with progression of AKI had significantly lower time-adjusted MAP (74.4

mmHg [68.3-80.8] vs 78.6 mmHg [72.9-85.4], P < 0.001) than those without

progression (cut-off value for prediction 73 mmHg)

Poukkanen M et al, Crit. Care 2013; 17: R295

A. Jörres 10-2015

• 790 patients with AKI I, admitted to the ICU of Guy’s and St. Thomas’ Hospital (July

2007 – June 2009).

• Of 210 patients with haemodynamic monitoring, 85 patients (41.5%) progressed to

AKI III (AKIN criteria) and 91 (43%) died in the hospital.

• AKI progressors had higher SOFA scores, lower indexed systemic oxygen delivery

(DO2I; 325 vs 405 ml/min per m2; P,0.001), higher CVP (16 vs 13; P=0.02), and lower

MAP (71 vs 74 mmHg, P=0.01) in the first 12 h of AKI I

Raimundo M et al, Clin. J. Am. Soc. Nephrol. 2015; 10: 1340-9

A. Jörres 10-2015

• Prospective multicenter, open-label RCT

randomizing 776 patients with septic shock

to undergo resuscitation with a MAP target

of either 80-85 mm Hg (high-target group)

or 65-70 mm Hg (low-target group)

[SEPSIPAM trial].

• No difference in mortality at 28 days (36.6% vs 34.0%) or 90 days

• No overall difference in serious adverse events including renal endpoints or

requirement of acute renal replacement therapy.

• However, among patients with chronic hypertension, those in the high-target group

required less renal replacement therapy than did those in the low-target group.

Asfar P et al, NEJM 2014; 370:1583-93

A. Jörres 10-2015

• Mechanically ventilated pigs with faecal peritonitis and sepsis and Noradrenaline

infusion to maintain mean MAP 65 mmHg

• All pigs developed hyperdynamic shock and AKI but renal blood flow and renal

vascular resistance remained unchanged.

• Renal perfusion pressure and renal

cortex microvascular perfusion

significantly decreased as a result of

increased renal venous pressure.

• Renal histology with only subtle changes

without signs of ATN.

Chvojka J et al, Crit. Care 2008; 12: R164

• Data challenge the concept of renal vasoconstriction and tubular necrosis as substrate

of early septic AKI and point at renal venous congestion as a hidden and clinically

unrecognised mechanism.

Tubular epithelial

cell vacuolisation

with damage of

brush border

A. Jörres 10-2015

• 137 patients diagnosed with severe sepsis or septic shock in surgical ICU of

Lariboisière Hospital, Paris (2006 – 2010).

• 69 patients had new or persistent AKI.

• AKI patients higher SOFA scores, and higher mortality, but no difference in MAP,

ScvO2 and CO than patients without AKI.

• AKI patients had lower diastolic artery

pressure and higher CVP (P=0.0003).

• CVP level was associated with the risk of

developing new or persistent AKI even

after adjustment for fluid balance and

PEEP (OR = 1.22 [1.08-1.39], P = 0.002)

• There was a linear relationship between

CVP and the risk of new or persistent AKI

Legrand M et al, Crit. Care 2013; 17: R278

A. Jörres 10-2015

• Animal models and human studies have shown that the occurrence of

sepsis-induced AKI is not exclusive of decreased renal blood flow states,

and that, on the contrary, can develop in the setting of increased RBF

• A consistent observation in septic humans and animals, regardless of

disease stage, severity, or organ examined, appears to be the presence of

three main alterations:

– diffuse microcirculatory flow abnormalities

– inflammation

– cell bioenergetic adaptive responses to injury

Gomez H et al, Shock 2014; 41: 3-11

A. Jörres 10-2015 Prowle JR & Bellomo R, Semin. Nephrol. 2015; 35: 64-74

Normal Sustained AKI

A. Jörres 10-2015 Prowle JR & Bellomo R, Semin. Nephrol. 2015; 35: 64-74

A. Jörres 10-2015

Ischemia/reperfusion AKI with disruptions of the

glycocalyx and endothelial monolayer

Bonventre & Yang, J. Clin. Invest. 2011; 121: 4210-21

• Ischemia/reperfusion causes

– swelling of endothelial cells

– disruptions of glycocalyx and

endothelial monolayer

– upregulation of adhesion molecules

(ICAMs; VCAMs; selectins) resulting

in enhanced leukocyte-endothelium

interactions.

• There is formation of microthrombi, and

some leukocytes migrate through the

endothelial cells into the interstitial

compartment.

• The interstitial compartment is expanded

with enhanced numbers of inflammatory

cells and interstitial edema forms.

Immune response in ischemic AKI

A. Jörres 10-2015 Bonventre & Yang, J. Clin. Invest. 2011; 121: 4210-21

Immune response in ischemic AKI

• The injured tubular epithelium

releases proinflammatory

cytokines and chemokines,

which aid in recruiting immune

cells, and express adhesion

molecules, TLRs, and T cell

costimulatory molecules.

• Neutrophils, macrophages, and

natural killer T cells cause direct

injury to tubular epithelial cells.

• Dendritic cells are involved in

both the innate and adaptive

immune responses through

secretion of inflammatory

cytokines and presentation of

antigens to T lymphocytes.

A. Jörres 10-2015 Bonventre & Yang, J. Clin. Invest. 2011; 121: 4210-21

Damage and Repair Cycle of Tubular

Epithelial Cells

A. Jörres 10-2015

Agenda

• Epidemiology

• Pathophysiology

• Initial treatment

A. Jörres 10-2015

• Prospective RCT in 263 patients

with severe sepsis / septic shock

upon hospital admission, six

hours of early goal-directed

therapy vs. standard therapy

before admission to ICU

• In-hospital mortality was 30.5%

in the group with early goal-

directed therapy, vs. 46.5% with

standard therapy (P=0.009).

Rivers E et al, NEJM 2001; 345:1368-77

A. Jörres 10-2015

• Total fluid administered over 72

h was not different between the

groups, however:

• During the first 6 hours patients

with early goal-directed therapy

received significantly more fluid

infusion

“Early golden hours”

Rivers E et al, NEJM 2001; 345:1368-77

A. Jörres 10-2015

Protocol-based hemodynamice management

New studies after Rivers et al. (2001)

N=1.600

NEJM 2014; 370: 1683-1693

N=1.341

NEJM 2014; 371: 1496-506

NEJM 2014; 371: 1496-506

N=1.260

A. Jörres 10-2015

Updated Bundles in Response

to New Evidence (April 2015)

With publication of 3 trials that do not demonstrate superiority of required use of a central

venous catheter to monitor central venous pressure (CVP) and central venous oxygen

saturation (ScvO2) in all patients with septic shock who have received timely antibiotics

and fluid resuscitation compared with controls or in all patients with lactate >4 mmol/L, the

SSC Executive Committee has revised the improvement bundles as follows:

TO BE COMPLETED WITHIN 3 HOURS OF TIME OF PRESENTATION:

1. Measure lactate level

2. Obtain blood cultures prior to administration of antibiotics

3. Administer broad spectrum antibiotics

4. Administer 30 ml/kg crystalloid for hypotension or lactate ≥4mmol/L

http://www.survivingsepsis.org/

A. Jörres 10-2015

Updated Bundles in Response

to New Evidence (April 2015)

TO BE COMPLETED WITHIN 6 HOURS OF TIME OF PRESENTATION:

5. Apply vasopressors (for hypotension that does not respond to initial fluid

resuscitation) to maintain a mean arterial pressure (MAP) ≥65mmHg

6. In the event of persistent hypotension after initial fluid administration

(MAP < 65 mm Hg) or if initial lactate was ≥4 mmol/L, re-assess volume

status and tissue perfusion and document findings.

7. Re-measure lactate if initial lactate elevated.

http://www.survivingsepsis.org/

A. Jörres 10-2015

Updated Bundles in Response

to New Evidence (April 2015)

DOCUMENT REASSESSMENT OF VOLUME STATUS AND TISSUE

PERFUSION WITH EITHER

• Repeat focused exam (after initial fluid resuscitation) by licensed

independent practitioner including vital signs, cardiopulmonary, capillary

refill, pulse, and skin findings.

OR TWO OF THE FOLLOWING:

• Measure CVP

• Measure ScvO2

• Bedside cardiovascular ultrasound

• Dynamic assessment of fluid responsiveness with passive leg raise or fluid

challenge

http://www.survivingsepsis.org/

A. Jörres 10-2015

Excessive Fluid Resuscitation Clinical consequences

• Impaired pulmonary function

• Impaired mental status

• Bowel dysfunction

• Intra-abdominal compartment syndrome

• Myocardial dysfunction

• Increased risk of decubital ulcers

• Delayed wound healing

• Muscle weakness / impaired mobilisation

A. Jörres 10-2015

• Prospective observational

study; 618 critically ill

patients with AKI (5 US-

centres)

• Fluid overload (>10% over

baseline) independently

associated with mortality…

• …but kidney function and

renal recovery not improved

Bouchard et al., Kidney Int. 2009; 76: 422-7

With RRT

Without RRT

A. Jörres 10-2015

Fluid Resuscitation

• Early interventions to achieve

hemodynamic stability in

patients with septic shock may

reduce mortality

• Rapid fluid resuscitation of

central importance

• Excessive fluid resuscitation

and overhydration may lead to

increased mortality and worse

renal recovery

A. Jörres 10-2015

• Prospective, randomised study; 6,997 ICU patients in Australia and New Zealand

• Comparison of fluid resuscitation with 4% albumin vs. saline (28 days)

• 726 deaths in the albumin group, 729 deaths in the saline group

(RR 0.99; 95 % CI, 0.91-1.09; P=0.87).

• No difference regarding:

– ICU days (6.5 ± 6.6 with albumin vs. 6.2 ± 6.2 with saline, P=0.44)

– Hospital days (15.3 ± 9.6 vs. 15.6+/-9.6, P=0.30)

– Days on mechanical ventilation (4.5 ± 6.1 and 4.3 ± 5.7, P=0.74)

– Days on RRT (0.5 ± 2.3 and 0.4 ± 2.0, P=0.41).

Finfer et al, NEJM 2004; 350: 2247-56

A. Jörres 10-2015

• Meta-analysis of 38 randomized controlled trials

• Hydroxyethyl starch was found to be associated with

– increased mortality among 10,290 patients (RR 1.09; 95% CI 1.02 -1.17)

– increased renal failure among 8,725 patients (RR, 1.27; 95% CI 1.09-1.47) and

– increased use of renal replacement therapy among 9,258 patients (RR, 1.32;

95% CI, 1.15 to 1.50)

Zarychanski R et al, JAMA 2013; 309 (7):678-688

FDA & EMEA:

Do not use HES solutions in critically ill adult patients,

including those with sepsis!

A. Jörres 10-2015

Hemodynamic monitoring and support

for prevention and management of AKI

1. In the absence of hemorrhagic shock, we recommend using isotonic

crystalloids rather than colloids (albumin or starches) as initial management

for expansion of intravascular volume in patients at risk for AKI or with AKI.

(1B)

2. We recommend the use of vasopressors to maintain perfusion pressure in

volume-resuscitated patients with vasomotor shock with, or at risk for, AKI.

(1C)

3. We suggest using protocol-based management of hemodynamic and

oxygenation parameters to prevent development or worsening of AKI in

high-risk patients. (2C)

The ad-hoc working group of ERBP, NDT 2012; 27: 4263-4272

A. Jörres 10-2015

Vasoctive Agents

• If hypotension is severe or if it persists despite adequate fluid resuscitation,

use of vasopressors is indicated:

– Vasopressor of first choice: Norepinephrin (0.1-2.0 µg/kg/min)

– Dopamin not better than Norepinephrin but may induce more arrhythmias,

increased mortality in cardiogenic shock*

– Epinephrin not better than Norepinephrin**

• Inotropic agent of first choice: Dobutamine

• PDE-III inhibitors (Milrinone, Enoximone) combine inotropic and vasodilatory effects

and may reinforce the effects of dobutamine

*De Backer D et al., NEJM 2010; 362: 779-89

**Annane D et al., Lancet 2007; 370: 676-84

A. Jörres 10-2015

Summary for the Clinician

• Sepsis can initiate a deleterious cascade of:

– impaired microcirculation,

– activation of inflammatory pathways,

– tubular cell injury or death,

resulting in impaired kidney function and the initiation of a repair response.

• The assumption that renal perfusion pressure essentially equals MAP is

probably not valid in the clinical scenario of sepsis with severe capillary

leak and aggressive fluid resuscitation.

• Both venous congestion due to elevated right atrial/central venous pressure

and sepsis-induced capillary leak with consecutive tissue oedema may lead

to increased renal venous pressure and associated reduction in the

glomerular filtration gradient.

A. Jörres 10-2015

Summary for the Clinician

• Initial treatment must aim at rapid restoration of (systemic and renal)

circulation

– fluid resuscitation (cristalloids)

– vasopressor therapy (+ inotropes if required)

• Conservative treatment must then aim at

– optimising fluid status; avoid fluid overload (monitor fluid intake and

output; assess daily body weight if feasible)

– correcting metabolic/electrolyte abnormalities

– avoiding nephrotoxins

• There is currently no established specific pharmacotherapy for

prevention/treatment of septic AKI