Septic AKI in ICU patients

Transcription

1 Septic AKI in ICU patients Prof. Achim Jörres, M.D. Dept. of Nephrology and Medical Intensive Care Charité University Hospital Campus Virchow Klinikum Berlin, Germany

2 Agenda Epidemiology Pathophysiology Initial treatment

3 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

4 Schrier RW & Wang W, NEJM 2004;351:159-69

5 Nephron Anatomy and Corticomedullary Oxygen Gradient The pars recta of the proximal tubule and the thick ascending limb are already normally hypoxic. Countercurrent exchange of oxygen results in gradient of decreasing O 2 tension in vasa recta 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 Bonventre & Yang, J. Clin. Invest. 2011; 121:

6 423 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 [ ] vs 78.6 mmhg [ ], P < 0.001) than those without progression (cut-off value for prediction 73 mmhg) Poukkanen M et al, Crit. Care 2013; 17: R295

7 790 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 (DO 2 I; 325 vs 405 ml/min per m 2 ; 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:

8 Prospective multicenter, open-label RCT randomizing 776 patients with septic shock to undergo resuscitation with a MAP target of either mm Hg (high-target group) or 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:

9 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. Tubular epithelial cell vacuolisation with damage of brush border 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. Chvojka J et al, Crit. Care 2008; 12: R164

10 137 patients diagnosed with severe sepsis or septic shock in surgical ICU of Lariboisière Hospital, Paris ( ). 69 patients had new or persistent AKI. AKI patients higher SOFA scores, and higher mortality, but no difference in MAP, ScvO 2 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 [ ], 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

11 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

12 Normal Sustained AKI Prowle JR & Bellomo R, Semin. Nephrol. 2015; 35: 64-74

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

14 Immune response in ischemic AKI 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. Ischemia/reperfusion AKI with disruptions of the glycocalyx and endothelial monolayer 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. Bonventre & Yang, J. Clin. Invest. 2011; 121:

15 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. Bonventre & Yang, J. Clin. Invest. 2011; 121:

16 Damage and Repair Cycle of Tubular Epithelial Cells Bonventre & Yang, J. Clin. Invest. 2011; 121:

17 Agenda Epidemiology Pathophysiology Initial treatment

18 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 goaldirected therapy, vs. 46.5% with standard therapy (P=0.009). Rivers E et al, NEJM 2001; 345:

19 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:

20 Protocol-based hemodynamice management New studies after Rivers et al. (2001) N=1.600 NEJM 2014; 371: N=1.341 NEJM 2014; 370: NEJM 2014; 371: N=1.260

21 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 (ScvO 2 ) 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

22 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.

23 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 ScvO 2 Bedside cardiovascular ultrasound Dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge

24 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

25 Prospective observational study; 618 critically ill patients with AKI (5 UScentres) With RRT Fluid overload (>10% over baseline) independently associated with mortality but kidney function and renal recovery not improved Without RRT Bouchard et al., Kidney Int. 2009; 76: 422-7

26 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

27 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, ; 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 /-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:

28 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 ) increased renal failure among 8,725 patients (RR, 1.27; 95% CI ) and increased use of renal replacement therapy among 9,258 patients (RR, 1.32; 95% CI, 1.15 to 1.50) FDA & EMEA: Do not use HES solutions in critically ill adult patients, including those with sepsis! Zarychanski R et al, JAMA 2013; 309 (7):

29 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:

30 Vasoctive Agents If hypotension is severe or if it persists despite adequate fluid resuscitation, use of vasopressors is indicated: Vasopressor of first choice: Norepinephrin ( 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: **Annane D et al., Lancet 2007; 370:

31 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.

32 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