Evaluate the change of some parameters in patients with multiple organ failure supported by continuous renal replacement therapy – Huynh Thi Ngoc Thuy

Journal of military pharmaco-medicine n o 7-2018 130 EVALUATE THE CHANGE OF SOME PARAMETERS IN PATIENTS WITH MULTIPLE ORGAN FAILURE SUPPORTED BY CONTINUOUS RENAL REPLACEMENT THERAPY Huynh Thi Ngoc Thuy*; Hoang Trung Vinh**; Do Quoc Huy* SUMMARY Objectives: Evaluating the changes of some clinical and subclinical parameters in patients with multiple organ failure supported by continuous renal replacement therapy and comparing some factors related to continuous renal replacement therapy and the outcome of the patients supported by pre- and post-dilution to those by post-dilution only. Subjects and methods: Prospective trial, compare before and after intervention in 77 patients diagnosed as multiple organ failure according to SOFA score. The patients were divided into 2 groups: 41 patients in group 1 - study group (supported by pre- and post-dilution), 36 patients in group 2 - control group (supported by post-dilution). Data were received from clinical examination, diagnostic tests during treatment. Results: Comparing with post-dilution, patients in group of pre- and post- dilution had significant TNF-α clearance (p < 0.01), filter lifetime was longer (33.8 ± 11.8 h vs. 28.2 ± 11.7 h, p < 0.05), lower serum creatinine (1.6 ± 1.3 mg/dL vs. 2.4 ± 1.6 mg/dL, p < 0.05) at the time of 72 h after intervention. Mechanical ventilation time, days in intensive care unit and mortality rates of the two groups were similar (70.7% and 72.2%). Conclusion: Pre- and post- dilution has many advantages in improving kidney function, purifying cytokines and prolonging the filter lifetime. * Keywords: Multiple organ failure; Continuous renal replacement therapy; Post-dilution; Pre-dilution. INTRODUCTION Multiple organ failure (MOF) is the disease with severe progression and make many patients stay at intensive care unit (ICU) for a long time. In spite of therapeutic progresses, the mortality rates remained the highest in ICU. So that, besides the intensive treatment methods, the supportive assistance is always focused to improve organ function and reduce mortality rates. Continuous renal replacement therapy (CRRT) can replace the decreased kidney function and release inflammatory cytokines. This technique was supported for patients with MOF in many researches, but there have not been any trial comparing pre- and post- dilution with post-dilution one. Therefore, aims of this study are: - Evaluating the changes of some clinical and subclinical parameters in patients with MOF supported by CRRT. - Comparing some factors related to CRRT and the outcome of the patients supported by pre- and post-dilution to those by post-dilution only. * People’s Hospital 115 ** 103 Military Hospital Corresponding author: Huynh Thi Ngoc Thuy (bshuynhthingocthuy@gmail.com) Date received: 20/05/2018 Date accepted: 22/08/2018 Journal of military pharmaco-medicine n o 7-2018 131 SUBJECTS AND METHODS 1. Subjects. 77 patients with MOF were appointed for CRRT, including 2 groups: 41 patients in group 1 supported by pre- and post- dilution and 36 patients in group 2 supported by post-dilution were treated at ICU of People's Hospital 115 from Feb, 2014 to Feb, 2016. * Inclusion criteria: - Patient age > 18 years diagnosed with MOF according to the SOFA score (table 1). + 6 organs: Cardiovascular, respiratory, kidney, liver, coagulation, central nervous system. + Criteria: SOFA score ≥ 2 or defined by one of three approaches: . As a single variable that reflects a physiologic derangement. . As a single variable that reflects a therapeutic intervention in response to a physiologic derangement. . As a combination of variables that in their own right define a syndrome. + Acute liver failure (ALF) with 1 in 2 following criteria: total bilirubin level > 1.9 mg/dL or having all of 3 criteria of ALF by the AASLD (table 3). + MOF: At least 2 failured organ and lasting more than 24 hours. - Have the acute kidney injury identified by RIFLE criteria (table 2): Serum creatinine increased 2 times compared to baseline, urine output < 0.5 mL/kg/h x at least 12 h. - Causes of MOF were different: Sepsis, shock, acute pancreatitis. - With or without identified chronic diseases. - Receiving continuous veno-venous hemofiltration (CVVH). * Exclusion criteria: - MOF without acute kidney injury. - Died within 24 hours after admission to ICU. - Lack of test of kidney function after intervention. - Indicated for surgery without effective treatment. - The end-stage disease: Decompensated cirrhosis, metastatic cancer. - Pregnant or breast feeding. 2. Methods. * Trial design: Prospective study, compare before and after intervention. * Trial content: - Doing clinical examination and test for evaluating organ injury, consists of urea, creatinine, bilirubine, platelet, IL-6, TNF-α, arterial blood gas. - Critical care and treating basic diseases. - Setting CRRT for two groups with the parameters such as mode: CVVH; input: femoral vein or internal jugularvein; filter: AN69, if being clotted, change the new; heparine dose: 10 - 20 UI/kg BW/h; blood flow: 120 - 150 mL/min; replacement flow: 30 - 40 mL/kg/h; output flow: 0 - 200 mL/h, it was depended on body fluid through by charateristics as edema, weight, CVP, urine output, blood Journal of military pharmaco-medicine n o 7-2018 132 pressure; dilution: group 1 (pre- and post- dilution), group 2 (post-dilution). + Criteria for stopping CRRT: Recovering shock: heart rate < 110 bpm, MAP ≥ 70 mmHg, CVP < 12 cmH2O, blood pressure is still stable after stopping vasopressors ≥ 2 h, UO > 50 mL/h, serum creatinine < 1.6 mg/dL. Patient died or too heavy to cure. + Doing blood test: After 12 h (T12), 24 h (T24), 48 h (T48), end of CRRT (Tn). * Criteria for diagnosis, classification in the study: Table 1: SOFA score [4]. SOFA score 1 2 3 4 Respiratory PaO2/FiO2 (mmHg) ≤ 400 ≤ 300 ≤ 200 with respatory support ≤ 100 with respatory support Cardiovascular Hypotension* MAP < 70 Dopamin ≤ 5 or dobutamin (any dose) Dopamin > 5 or epinephrin ≤ 0.1 or NE ≤ 0.1 Dopamin > 15 or epinephrin > 0.1 or NE > 0.1 Kidney Creatinine (mg/dL) or urine output (mL/day) 1.2 - 1.9 2 - 3.4 3.5 - 4.9 < 500 > 5 < 200 Liver Total bilirubine (mg/dL) 1.2 - 1.9 2 - 5.9 6 - 11.9 > 12 Coagulation Platelets x 103/mm3 ≤ 150 ≤ 100 ≤ 50 ≤ 20 Central nervous system Glasgow Coma Score 13 - 14 10 -12 6 - 9 < 6 (* Adrenergic agents administered for at least one hour (doses given are in µg/kg/min)). Table 2: RIFLE criteria [5]. Creatinine criteria Urine output criteria Risk Increased creatinine x 1.5 UO < 0.5 mL/kg/h x 6 h Injury Increased creatinine x 2 UO < 0.5 mL/kg/h x 12 h Failure Increased creatinine x 3 or creatinine ≥ 4 mg/dL (acute rise of ≥ 0.5 mg/dL) UO < 0.5 mL/kg/h x 24 h or anuria x 12 h Loss Persistent ARF = complete loss of renal function > 4 weeks End stage renal disease Journal of military pharmaco-medicine n o 7-2018 133 Table 3: Definition of acute liver failure by the AASLD (American Association for the Study of Liver Diseases) [6]. Criteria Characteristics Acute liver disease < 26 weeks without preexisting cirrhosis Grade 1: Changes in behavior with minimal change in level of consciousness Grade 2: Gross disorientation, drowsiness, possible asterixis, inappropriate behavior Grade 3: Marked confusion, incoherent speech, sleeping most of the time but arousable to vocal stimuli Encephalopathy Grade 4: Comatose, unresponsive to pain, decorticate or decerebrate posturing Coagulation abnormality INR ≥ 1.5 * Data analysis: Using SPSS 22 to analyze the percentage and the average values. RESULTS 1. The common characteristics of patients. Table 4: Compare some characteristics between 2 groups. Injured organ Group 1 (n = 41) Group 2 (n = 36) p Mean 3.98 ± 0.88 3.94 ± 0.75 > 0.05 Number of injured organ 2 (n, %) 2 (100) 0 > 0.05 3 (n, %) 7 (41.2) 10 (58.8) > 0.05 4 (n, %) 22 (52.4) 20 (47.6) > 0.05 5 (n, %) 9 (64.3) 5 (35.7) > 0.05 6 (n, %) 1 (50) 1 (50) > 0.05 Type of injured organ Kidney (n, %) 41 (53.2) 36 (46.8) Respiratory (n, %) 40 (53.3) 35 (46.7) > 0.05 Cardiovascular (n, %) 38 (55.1) 31 (44.9) > 0.05 Central nervous system (n, %) 26 (53.1) 23 (46.9) > 0.05 Coagulation (n, %) 10 (50) 10 (50) > 0.05 Liver (n, %) 9 (60) 6 (40) > 0.05 The number and type of injured organs had no differences between 2 groups. Journal of military pharmaco-medicine n o 7-2018 134 Table 5: Compare some subclinical characteristics. Parameter Group 1 (n = 41) Group 2 (n = 36) p Glucose (mg/dL) 183.3 ± 107.0 152.2 ± 75.9 > 0.05 Urea (mg/dL) 95.8 ± 54.8 119.1 ± 65.4 > 0.05 Creatinine (mg/dL) 3.4 ± 2.2 3.6 ± 1.7 > 0.05 Total bilirubine (mg/dL) 1.9 ± 2.5 4.2 ± 5.8 > 0.05 Sodium (mmol/L) 135.8 ± 9.4 137.8 ± 8.5 > 0.05 Potassium (mmol/L) 4.2 ± 1.0 4.2 ± 1.1 > 0.05 Platelet count (K/µL) 200.3 ± 131.2 156.5 ± 81.6 > 0.05 CRP (mg/dL) 144.3 ± 100.6 160.2 ± 113.5 > 0.05 Lactate (mmol/L) 6.6 ± 5.9 5.1 ± 4.6 > 0.05 IL-6 (pg/mL)* 951.2 616.3 > 0.05 TNF-α (pg/mL)* 38.3 30.6 > 0.05 pH 7.26 ± 0.11 7.29 ± 0.13 > 0.05 PaCO2 (mmHg) 34.9 ± 15.0 32.7 ± 10.8 > 0.05 HCO3- (mmol/L) 16.1 ± 5.1 16.3 ± 5.9 > 0.05 PaO2 (mmHg) 106.3 ± 57.2 107.7 ± 94.7 > 0.05 PaO2/FiO2 188.3 ± 132.8 174.2 ± 161.5 > 0.05 (* IL-6 and TNF-α are not the normal distribution, using median and Mann-Whitney test) The average values of subclinical parameters between 2 groups were similar. 2. Compare some results between two groups. Table 5: Compare serum urea and creatinine at the evaluated times between 2 groups. Group 1 (n = 41) Group 2 (n = 36) Parameters Number X ± SD Number X ± SD p Urea (mg/dL) T0 41 95.8 ± 54.8 36 119.1 ± 65.4 > 0.05 T24 41 66.9 ± 38.9 36 99.3 ± 76.2 < 0.05 T48 37 62.0 ± 37.1 31 77.8 ± 72.7 > 0.05 T72 31 51.6 ± 27.8 27 78.0 ± 44.2 < 0.05 Creatinine (mg/dL) T0 41 3.4 ± 2.2 36 3.6 ± 1.7 > 0.05 T24 41 2.1 ± 1.6 36 2.5 ± 1.8 > 0.05 T48 37 1.9 ± 1.2 31 2.0 ± 1.6 > 0.05 T72 31 1.3 ± 0.6 27 1.9 ± 1.2 < 0.05 - The average values of serum urea and creatinine in group 1 were lower statistically than that in group 2 at 72 h after intervention. - There were no differences between 2 groups at the other time. Journal of military pharmaco-medicine n o 7-2018 135 Table 6: Compare serum IL-6 và TNF-α between 2 groups. Group 1 (n = 41) Group 2 (n = 36) p Number Median Number Median IL-6 (pg/mL) Before CRRT 41 951.2 36 616.3 > 0.05 After CRRT 41 247.9 36 135.5 > 0.05 TNF-α (pg/mL) Before CRRT 24 38.3 24 30.6 > 0.05 After CRRT 24 31.7 24 37.9 > 0.05 (* Some blood samples were failed while transport, no full enough of TNF-α) There were no differences between 2 groups about serum IL-6 and TNF-α before and after CRRT. Table 7: Compare the change of serum IL-6 and TNF-α before and after CRRT. Group 1 (n = 41) Group 2 (n = 36) Parameters Number Median Number Median IL6 (pg/mL) ∆ Before - after 41 703.3 36 480.8 p ∆ 41 < 0.001 36 < 0.001 TNFα (pg/mL) ∆ Before-After 24 6.6 24 (-) 7.3 p ∆ 24 0.05 (* Using Wilcoxin test for evaluating the difference between before and after CRRT) - IL-6 concentrations were significantly reduced in both groups. - TNF-α level was only statistically significant reduced in group 1. Table 8: Mechanical ventilation time, days in ICU and mortality of 2 groups. Parameters Group 1 (n = 41) Group 2 (n = 36) p Mechanical ventilation (days) 5.9 ± 5.3 9.1 ± 10.7 > 0.05 Days in ICU 8.2 ± 6.0 10.9 ± 10.9 > 0.05 Mortality (n, %) 29 (70.7) 26 (72.2) > 0.05 There were no differences between 2 groups about above parameters. Journal of military pharmaco-medicine n o 7-2018 136 Table 9: Some factors related to CRRT. Parameters Group 1 (n = 41) Group 2 (n = 36) p Time of starting CRRT (hour) 7.7 ± 6.8 11.7 ± 13.8 > 0.05 Numbers of CRRT 1.9 ± 1.3 1.5 ± 0.7 > 0.05 Average filter lifetime (hour) 33.8 ± 11.8 28.2 ± 11.7 < 0.05 Replacement volume (mL/kg/h) 36.7 ± 4.1 37.9 ± 5.1 > 0.05 - Average filter lifetime in group 1 was longer than that in group 2. - The other parameters were similar in the 2 groups. DISCUSSION 77 patients in this trial were treated MOF with guidelines and recommendations. They were also supported by CRRT with two dilution modes. Patients in the research were injured from 2 to 6 organs and the ones with 4 organ failure had the highest ratio. The study also showed that the ratio of organ failure changed from high to low as followed: kidney, respiratory, cardiovascular, central nervous system, coagulation and liver. The common characteristics about injured organs and subclinical parameters were similar in the two groups. This similarity was the basis for evaluating and comparing the effect of pre- and post-dilution CRRT with post- dilution CRRT in MOF patients. Continuous renal replacement therapy is one of mainly kidney replacement methods in treating acute kidney injury with oliguria/anuria. In this study, serum urea and creatinine decreased gradually after CRRT and there was no difference between the two groups before intervention; as well as at 24 h and 48 h. However, at the time of 72 h after intervention, the average value of serum urea and creatinine in group used pre- and post-dilution was lower statistically than those in group used post-dilution. The ability to filter creatinine effectively under unstable hemodynamic conditions demonstrates the important role of continuous dialysis in critical illness. Olivier Joannes-Boyau et al in the IVOIRE study showed the improvement of serum creatinine level from 2.37 mg/dL (1.80 - 3.12) at baseline versus 0.99 mg/dL (0.7 - 1.4) at the 4th day after dialysis [4]. The results from studies by T.N Hai and N.G Binh also showed improvement in creatinine concentration after filtration [1, 2]. About the inflammatory cytokine clearance, the study showed that concentrations of serum IL-6 and TNF-α decreased after CRRT and there was no difference between two groups. Especially, analyzing by Wilcoxin test, result showed that CRRT could purify the inflammatory cytokines clearly. IL-6 concentrations were significantly reduced in both groups, while TNF-α levels were only statistically significantly reduced in group 1. The trial results of H.V Quang also recorded that CRRT reduced the concentrations of cytokines [7]. However, Cole and Klouche proved that although prognosis improved, CRRT did not change blood Journal of military pharmaco-medicine n o 7-2018 137 cytokine level, this was explained to be related to "immune threshold hypothesis", in which the removing cytokines from the blood leads to removing cytokines in the tissue due to the balance of concentration [8]. This study also recorded the parameters such as mechanical ventilation, days in ICU and mortality were no differences between 2 groups. The mortality in our study was higher than the others; such as Elizabeth 56%, H.V Quang 55% and N.G Bình 67.7% [2, 3, 7]. The mortality was related to the number of injured organs, this study showed that the mean of organ failure was 3.98 ± 0.88 in group supported with pre- and post-dilution CRRT. About the parameters of CRRT, this research showed that the replacement volume in 2 groups also had no differences, with 36.7 ± 4.1 mL/kg/h in group 1 and 37.9 ± 5.1 mL/kg/h in group 2. This result was similar to Joannes-Boyau's trial (35 mL/kg/h) and Piccini's trial (45 mL/kg/h) [4, 9]. The number and the time of starting CRRT were not different between 2 groups, but the average filter lifetime with pre- and post-dilution was significantly longer than that with post-dilution (33.8 ± 11.8 hours versus 28.2 ± 11.7 hours). Van der Voort and Uchino showed that post-dilution shortened the filter lifetime compared with pre-dilution [10, 11]. Thus, a combination of general tendency in improving the kidney function during treatment together with the higher inflammatory cytokine clearance and the longer filter lifetime when patients were supported with pre- and post-dilution CRRT compared to the basal method (post-dilution CRRT) proved that this method can apply in clinical practice. 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