12th Global Nephrologists Annual Meeting Hypotension and the evolution of bacteremia-induced Acute Kidney Injury in the Intensive Care Unit 12th Global Nephrologists Annual Meeting London, 26-28/6/2017 Karin Janssen van Doorn MD, PhD

Introduction - AKI common complication of critical illness  high morbidity and mortality a ‘syndrome’ / ‘kidney attack’ characterized by  rapid decline in renal function and urine output  retention of waste products improved ICU management  diminished morbidity and mortality

Early recognizing of AKI in the critically ill Federaal agentschap voor geneesmiddelen en gezondheidsproducten Afdeling Communicatie Summary of definitions of AKI (adapted from ESC/ESA GUIDELINES. European Heart Journal 2014)

AKI-Type AKI intrinsic post pre

AKI-Type AKI intrinsic post pre

Sepsis/Systemic Inflammatory Response Syndrome (SIRS) Sepsis-definition-old Sepsis/Systemic Inflammatory Response Syndrome (SIRS) Parmar A et al. Current Drug Targets 2009:1-10.

Sepsis-definition-new Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction can be identified as an acute change in total SOFA score > 2 points consequent to the infection. Patients with suspected infection who are likely to have a prolonged ICU stay or to die in the hospital can be identified with qSOFA, ie, alteration in mental status, systolic blood pressure <100mmHg, or respiratory rate >22/min.   Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP >65mmHg and having a serum lactate level >2 mmol/L (18mg/dL) despite adequate volume resuscitation. Singer M et al. JAMA 2016:801-810.

Critical Care Nephrology - Recommendations controlled fluid resuscitation in true or suspected volume depletion. a mean arterial pressure (MAP) > 60-65 mmHg, yet target pressure should be individualized whenever possible and particularly when pre-morbid blood pressure values are known. correction of vasoplegic hypotension in sepsis or systemic inflammatory response syndrome (SIRS) requires the use of either norepinephrine or dopamine as vasopressor agents along with fluid resuscitation. Joannidis M et al. Intensive Care Med 2010:392-411.

Surviving Sepsis Campaign Guidelines 2012-During the first 6 hours of resuscitation, the goals of initial resuscitation should include all of the following as a part of a treatment protocol: -CVP 8–12 mm Hg -MAP ≥ 65 mm Hg -Urine Output ≥ 0.5 mL/kg/hr 2016-The diagnostic criteria and overall management of sepsis has changed. 1. Start resuscitation early with source control, intravenous fluids and antibiotics. -administration of IV antimicrobials be initiated as soon as possible after recognition and within 1 h for both sepsis and septic shock. -during the resuscitation from sepsis-induced hypo-perfusion, at least 30ml/kg of IV crystalloid fluid should be given within the first 3 hours. 2. Frequent assessment of the patients’ volume status throughout resuscitation period. 3. Provide initial target MAP of 65 mmHg in patients with septic shock requiring vasopressors (norepinephrine is first choice vasopressor).

Septic-AKI vs Non Septic-AKI More commonly among elderly and female patients. More likely to have a higher burden of pre-existing co-morbidity. Higher prevalence of congestive heart failure, chronic obstructive pulmonary disease, CKD, liver disease, DM, active malignancy and immune system disorders. Higher illness severity and are more likely admitted for medical indications. Greater organ dysfunction and failure, reflected by the SOFA score. More hemodynamic instability and shock and more frequently need mechanical ventilation. Increasing AKI severity in sepsis is associated with stepwise increases in mortality. Recovery of kidney function is increasingly recognized as an important determinant of morbidity. Parmar A et al. Current Drug Targets 2009:1-10. Bagshaw SM et al. Clin J Am Soc Nephrol 2007:431-9.

Septic-AKI in septic-AKI, the glomerular filtration rate decreases rapidly, despite preserved or increased cardiac output and hyper-dynamic circulation. a delay in the administration of appropriate antimicrobials is an important independent factor associated with a higher risk of AKI. Bagshaw SM et al. Can J Anaesth 2010:999-1013. Intensive Care Med 2009:871-81.

Janssen van Doorn K et al. PLoS One 2014 How does severe hypotension influence the evolution of AKI during sepsis? Purpose: to examine the impact of hypotension on the evolution of AKI in septic patients. 1) the influence of hypotension during sepsis, 2) the influence of proven sepsis to Failure and 3) the influence of hypotension on the evolution to Failure. Janssen van Doorn K et al. PLoS One 2014

RIFLE classification on the day of a positive BSI test Patient characteristics according to the RIFLE criteria   RIFLE classification on the day of a positive BSI test Variables All patients (n=137) Risk (n=40) Injury (N=44) Failure (N=53) p-value Age (y) 62.23 (14.20) 59.73 (16.05) 63.57 (12.86) 63.02 (13.80) 0.6099 Gender (male) 47/137 (34.31%) 14/40 (35.00%) 16/44 (36.36%) 17/53 (32.08%) 0.9011 DM 23/137 (16.79%) 7/40 (17.50%) 9/44 (20.45%) 7/53 (13.21%) 0.6299 SAPS-3 61.52 (14.37) 55.33 (13.67) 58.86 (12.98) 68.40 (13.3) <0.0001 SOFA.total 10.57 (4.22) 8.95 (3.69) 9.09 (3.78) 13.02 (3.84) LOS.ICU (d) 15 (5 – 33) 16 (5 – 24) 13 (6 – 29) 21 (3 – 44) 0.8312 Days prior ICU (d) 4 (1 – 13) 4 (1 – 9) 3 (1 – 6) 7 (1 – 23) 0.0491 Mortality ICU 63/137 (45.99%) 16/40 (40.00%) 38/53 (71.70%) Diuresis.cum (ml) 1005 (250 – 1965) 1985 (1223 – 2654) 1275 (504 – 1930) 136 (10 – 564) Diuretics 35/137 (25.55%) 15/40 (37.5%) 13/44 (29.55%) 0.0222 Hemoglobin (g/dl) 9.68 (1.85) 9.44 (1.74) 10.12 (2.16) 9.48 (1.60) 0.2657 Albumin (g/dl) 2.44 (0.60) 2.39 (0.61) 2.47 (0.59) 2.46 (0.60) 0.8014 CRP (mg/dl) 11.9 (6.0 – 17.0) 10.9 (17.0 – 7.9) 8.1 (4.3 – 15.3) 12.9 (8.2 – 18.1) 0.1869 Lactate (mg/dl) 1.7 (1.2 – 3.3) 1.4 (1.1 – 2.0) 2.0 (1.2 – 3.3) 1.9 (1.4 – 4.1) 0.0170 MII 0.24 (0.00 – 1.29) 0.00 (0.00 – 0.52) 0.04 (0.00 – 0.65) 0.72 (0.00 – 2.87) 0.0012 VPload 0.00 (0.00 – 0.01) 0.01 (0.00 – 0.02) 0.0005 Daily Fluid Balance (ml) 680 (67 – 1557) 296 (-928 – 676) 668 (155 – 1684) 1044 (392 – 2343) 0.0001 Bacteria 0.9380 Gram + 59/137 (43.07%) 18/40 (45.00%) 17/44 (38.64%) 24/53 (45.28%) Gram – 61/137 (44.53%) 17/40 (42.50%) 22/44 (50.00%) 22/53 (41.51%) Other 17/137 (12.41%) 5/40 (12.50%) 5/44 (11.36%) y = years, d = days, DM = diabetes mellitus, SAPS-3 = Simplified Acute Physiology Score III, SOFA = Sequential Organ Assessment Score, LOS = length of stay, Days prior ICU = length of hospital stay prior to ICU admission, CRP = C-reactive protein, MII = mean inotropic index, VPload = vasopressor load. All laboratory values were collected on day of positive BSI. Data are presented as mean (SD between brackets) or number/total (% between brackets)

What is the influence of hypotension during sepsis? On the day on which sepsis was proven, hypotension occurred in 75% of the patients. The daily fluid balance is positively correlated with the duration of hypotension: the higher the fluid net positive balance, the longer the duration of hypotension and the higher the number of periods of hypotension. When only the amount of administered fluid was taken into account, there was a significant influence on the evolution to Failure: the higher the administration of daily fluid, the lower the evolution to Failure.

2. The influence of sepsis on the evolution of the RIFLE category After BSI, the probability for a patient to be in Failure is significantly higher than before BSI. This probability is also significantly higher for patients who were in Failure on the day of admission compared to patients in R/N. Patients who were in Injury on the day of admission have a slightly lower chance of evolving to Failure, compared to patients in R/N. Between all groups, there was no difference in the delay of antibiotic treatment, episodes of septic shock or the total number of days in septic shock. No significant difference between patients with Gram-positive or -negative infection in the occurrence of hypotension, the duration of hypotension or the number of periods of hypotension.

3. How does severe hypotension influence evolution to failure? Patients have a significantly higher risk of evolving to Failure if the duration of severe hypotension is longer. In our population of septic patients, a cut-off of at least 51 minutes of severe hypotension (<65 mmHg) or at least 5.5 periods of severe hypotension within 1 day was determined to identify patients with increased risk of evolving to Failure. ROC curve for the detection of RIFLE = F based on the duration of the number of periods of severe hypotension.

4. Conclusion Patients who were in Injury on the day of admission do not have a significant risk of evolving to Failure, compared to patients in R/No-AKI. Positive fluid balance has a significant positive effect on the evolution to Failure. Significant influence of duration and number of periods of severe hypotension (<65 mmHg) on the evolution to Failure. Minimal duration (51 min) of a MAP <65 mmHg in which a septic patient evolves to AKI or passes from R or I to F. In fact, the 3-hour period proposed in the new SSC guidelines for achieving a MAP >65 mmHg is too long to protect the renal function of a critically ill patient.

Reflection: blood pressure level No randomized controlled studies on the effects of different blood pressure levels on outcome. Limited data suggest a sort of consensus on the use of arterial blood pressure targets in sepsis, and the preferred target range is 65-75 mmHg. We preferred a MAP target of 65 mmHg because the most recent SSC guidelines recommend that vasopressor therapy initially target a MAP of 65 mmHg (grade 1C). Association between the arterial blood pressure during the first 24 h and mortality in sepsis and concluded that a MAP level ≥ 60 mmHg may be as safe as higher MAP levels during the first 24h in septic patients. A MAP of 60 mmHg does not influence mortality, a higher MAP may be required to maintain kidney function. Takala J. Crit Care Med 2010: S613-9. Dünser MW et al. Intensive Care Med 2009:1225-33.

Reflection: duration hypotension The duration of hypotension before initiation of effective microbial therapy is a critical determinant of survival in human septic shock. We observed that the duration of hypotension seemed more important than the number of hypotensive periods in critically ill patients with proven BSI. FINNAKI study: investigated the progression of AKI within the first 5 days of ICU admission defined as new onset or worsening of AKI.  patients with progression of AKI had significantly lower MAP, 74.4 mmHg [68.3-80.8], than those without progression, 78.6 mmHg [72.9-85.4], p < 0.001. A cut-off value of 73 mmHg MAP best predicted the progression of AKI. Moreover, only the duration of a MAP<60 mmHg had a highly significant bad influence on the progression of AKI. Kumar A et al. Crit Care Med 2006: 1589-96. Poukkanen M et al. Crit Care 2013: R295.

Consideration Patients with and at increased risk for AKI require careful attention for their hemodynamic status. hypotension  decreased renal perfusion  kidney injury. the injured kidney loses autoregulation of blood flow. management of blood pressure and cardiac output require careful titration of fluids and vasoactive medication. Increased risk for fluid overload.

Final Conclusion In the recent SSC guidelines the maximal fluid load or recommendations regarding the evolution of the renal function are not included. The 3-hour period proposed in the new SSC guidelines for achieving a MAP >65 mmHg is too long to protect the renal function of a critically ill patient.

Duration of hypotension Recommendations AKI Antibiotics Duration of hypotension Optimal MAP Sepsis

Questions?