Objectives: To evaluate the outcome of the patients with multiple organ failure (MOF) supported by pre-and-post-dilution continuous renal replacement therapy (CRRT) and compare some factors related to the results, progression and prognosis of the patients supported by preand-post-dilution to those by post-dilution only.
Journal of military pharmaco-medicine no2-2018 RESULTS OF TREATMENT OF PATIENTS WITH MULTIPLE ORGAN FAILURE SUPPORTED BY PRE-AND POST-DILUTION CONTINUOUS RENAL REPLACEMENT THERAPY Huynh Thi Ngoc Thuy*; Hoang Trung Vinh**; Do Quoc Huy* SUMMARY Objectives: To evaluate the outcome of the patients with multiple organ failure (MOF) supported by pre-and-post-dilution continuous renal replacement therapy (CRRT) and compare some factors related to the results, progression and prognosis of the patients supported by preand-post-dilution to those by post-dilution only Subjects and methods: Prospective trial, compared before and after intervention in 77 patients diagnosed of MOF according to SOFA score, including groups: 41 patients in group (study group) (supported by pre-and-postdilution), 36 patients in group (control group) (supported by post-dilution) Data were received from clinical examination, diagnostic tests during treatment Results: Comparing with postdilution, patients in group of pre-and-post-dilution had lower serum creatinine at the end of study (1.6 ± 0.9 mg/dL versus 2.3 ± 1.5 mg/dL), higher TNF-α clearance (16.8 pg/mL versus 4.0 pg/mL), filter lifetime was longer (31.9 ± 10.8 h versus 26.7 ± 10.6 h), the percentage of patients with acute kidney injury (AKI) as well as failure of ≥ were lower at the end of the study (36.6% vs 72.2% and 24.4% vs 50%) The 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; Preand-post-dilution INTRODUCTION Multiple organ failure is the disease with severely progression and makes many patients stayed at intensive care unit (ICU) for a long time Although therapeutic progresses, the mortality rates remained the highest in ICU So that, besides of the intensive treatment methods, the supportive assistance is always focused to improve organ function and reduce mortality rates CRRT can replace the decreased kidney function and release inflammatory cytokines This technique was supported for patients with MOF in many researchers, but there have not had any trials comparing preand-post-dilution CRRT with post-dilution one Therefore, this study is for objectives: Evaluating the outcome of the MOF patients supported by pre-and-post-dilution CRRT and comparing some factors related to the results, progression and prognosis of the patients supported by pre-and-postdilution to those by post-dilution only ** People’s Hospital 115 *** 103 Military Hospital Corresponding author: Huynh Thi Ngoc Thuy (bshuynhngocthuy@gmail.com) Date received: 21/11/2017 Date accepted: 18/01/2018 113 113 Journal of military pharmaco-medicine no2-2018 SUBJECTS AND METHODS Subjects 77 patients with MOF appointed for CRRT, including groups: 41 patients in group (study group) supported by preand-post-dilution and 36 patients in group (control group) supported by post-dilution, were treated at ICU of People's Hospital 115 from Feb 2014 to Feb 2016 * The inclusion criteria: - Patient age > 18 years diagnosed of MOF according to the SOFA score (table 1) + organs: Cardiovascular, respiratory, kidney, liver, coagulation, CNS + Criteria: SOFA score ≥ and total SOFA score increase at least point compared with admission + Acute liver failure (ALF) with in following criteria: Total bilirubin level > 1.9 mg/dL or having all of criteria of ALF by the AASLD (table 3) + MOF: At least failured organs and lasting more than 24 hours - Having the acute kidney injury identified by RIFLE criteria (table 2): Serum creatinine increased times baseline or urine output < 0.5 mL/kg/h x 12h - Causes of MOF were different: sepsis, shock, acute pancreatitis - With or without identified chronic diseases - Receiving continuous veno-venous hemofiltration (CVVH) * The exclusion criteria: - MOF without AKI - Died within 24 hours after admission to ICU 114 - Lack of test of kidney function after intervention - Indicated for surgery without effective treatment - The end-stage disease: decompensated cirrhosis, metastatic cancer… - Pregnant or breastfeeding Methods * Trial design: Prospective, 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- , arterial blood gas (pH, PaCO2, HCO3-, aO2, PaO2/FiO2) - Critical care and treating basic diseases - Setting CRRT for two groups with the parameters such as mode: continuous veno-venous hemofiltration; input: femoral vein or internal jugular vein; filter: AN69, if being clotted, change the new; heparin dose: 500 - 1,000 UI/h; blood flow: 120 150 mL/mn, replacement flow: 30 40 mL/kg/h; output flow: - 200 mL/h, it was depended on body fluid through by charateristics as edema, weight, CVP, urine output, blood pressure; dilution: group (pre-and-post-dilution), group (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 ≥ 2h, UO > 50 mL/h, serum creatinin < 1.6 mg/dL Patient is died or too heavy to cure - Doing blood test: after 12h (T12), 24h (T24), 48h (T48), end of CRRT (Tn) Journal of military pharmaco-medicine no2-2018 * Criteria for diagnosis, classification in the study: Table 1: SOFA score SOFA score ≤ 400 ≤ 300 ≤ 200 with respiratory support ≤ 100 with respiratory support Cardiovascular hypotension* MAP or epinephrine ≤ 0,1 or NE ≤ 0,1 Dopamin > 15 or epinephrine > 0,1 or NE > 0,1 Kidney creatinine (mg/dL) or urine output (mL/day) 1,2 - 1,9 - 3,4 3,5 - 4,9 < 500 >5 < 200 Liver total bilirubine (mg/dL) 1,2 - 1,9 - 5,9 - 11,9 > 12 ≤ 150 ≤ 100 ≤ 50 ≤ 20 13 - 14 10 -12 6-9 weeks ESRD End stage renal disease Table 3: Definition of acute liver failure by the AASLD (American Association for the Study of Liver Diseases) Criteria Acute liver disease Characteristics < 26 weeks without preexisting cirrhosis Grade 1: Changes in behavior with minimal change in level of consciousness Encephalopathy Grade 2: Gross disorientation, drowsiness, possibly asterixis, inappropriate behavior Grade 3: Marked confusion, incoherent speech, sleeping most of the time but arousable to vocal stimuli Grade 4: Comatose, unresponsive to pain, decorticate or decerebrate posturing Coagulation abnormality INR ≥ 1,5 * Data analysis: Using SPSS 22 to analyse the percentage and the average values 115 Journal of military pharmaco-medicine no2-2018 RESULTS The common characteristics of patients Table 4: Compare some common characteristics between the groups Parameters Average age (year) Group (n = 41) Group (n = 36) p 66.00 ± 16.17 68.28 ± 18.54 > 0.05 Female (n, %) 24 (53,3%) 21 (46.7%) Male (n, %) 17 (53.1%) 15 (46.9%) Chronic disease (n, %) 28 (58.3%) 20 (41.7%) > 0.05 3.8 ± 0.9 3.8 ± > 0.05 Kidney (n, %) 41 (100%) 36 (100%) Cardiovascular system (n, %) 38 (92.7%) 32 (88.9%) > 0.05 Lung (n, %) 35 (85.4%) 30 (83.3%) > 0.05 Central neutral system (n, %) 22 (53.7%) 23 (63.9%) > 0.05 Coagulation (n, %) 14 (34.1%) 11 (30.6%) > 0.05 (22%) (22.2%) > 0.05 Number of injured organ > 0.05 Type of injured organ Liver (n, %) Age, sex, chronic disease, number and type of injured organs were not different between the groups Table 5: Compare some clinical and subclinical characteristics Parameters Group (n = 41) Group (n = 36) p 38 (92.7%) 32 (88.9%) > 0.05 34 (54%) 29 (46%) > 0.05 29 (70.7%) 23 (63.9%) > 0.05 Creatinine (mg/dL) 3.3 ± 2.3 3.7 ± 2.1 > 0.05 Total bilirubine (mg/dL) 2.3 ± 2.4 5.7 ± 6.6 > 0.05 192.9 ± 131.9 155.1 ± 78.1 > 0.05 2,310.7 ± 2,178.2 1,429.7 ± 1,626.1 > 0.05 TNF-α (pg/mL) 49.0 ± 41.9 45.3 ± 41.7 > 0.05 pH 7.21 ± 0.10 7.24 ± 0.16 > 0.05 39.9 ± 15.5 40.2 ± 27.7 > 0.05 HCO3 (mmol/L) 16.3 ± 5.6 16.6 ± 6.7 > 0.05 PaO2 (mmHg) 97.6 ± 62.3 102.8 ± 92.3 > 0.05 222.1 ± 142.4 243.7 ± 239.1 > 0.05 MAP < 70 mmHg (n, %) Ventilation (n, %) Oliguria/anuria (n, %) Platelet (K/µL) IL-6 (pg/mL) PaCO2 (mmHg) - PaO2/FiO2 The percentage and average values of clinical and subclinical parameters between the groups were similar 116 Journal of military pharmaco-medicine no2-2018 Compare some results between the two groups Table 6: Compare serum ure and creatinin between the groups Group (n = 41) Parameters Group (n = 36) p Number X ± SD Number X ± SD T0 41 96.7 ± 55.8 36 144.8 ± 90.0 > 0.05 T12 41 78.8 ± 44.5 36 94.0 ± 62.9 > 0.05 T24 41 56.1 ± 29.9 36 75.9 ± 41.9 > 0.05 Tn 41 68.9 ± 39.8 36 98.3 ± 52.3 < 0.01 T0 41 3.4 ± 2.3 36 3.7 ± 2.1 > 0.05 T12 41 2.6 ± 1.7 36 2.5 ± 1.8 > 0.05 T24 41 1.9 ± 1.3 36 2.0 ± 1.2 > 0.05 Tn 41 1.6 ± 0.9 36 2.3 ± 1.5 < 0.05 Urea (mg/dL) Creatinine (mg/dL) The average values of serum urea and creatinine in group was statistically lower than that in group at the end of study Table 7: Compare serum IL-6 TNF-α between the groups Group (n = 41) Group (n = 36) p Number X ± SD Number X ± SD Before CRRT 40 2,310.7 ± 2,178.2 34 1,429.8 ± 1,626.1 > 0.05 After CRRT 40 966.0 ± 1,444.3 34 791.2 ± 1,478.3 > 0.05 ∆ after-before 40 (-) 1,344.7 ± 1,720.1 34 (-) 638.5 ± 1,723.6 > 0.05 IL-6 (pg/mL) < 0.001 p∆ < 0.05 TNF-α (pg/mL) Before CRRT 23 49.0 ± 41.9 22 45.3 ± 41.7 > 0.05 After CRRT 23 32.2 ± 14.4 22 41.3 ± 19.9 > 0.05 ∆ after-before 23 (-) 16.8 ± 31.7 22 (-) 4.0 ± 39.2 > 0.05 p∆ < 0.05 > 0.05 - IL-6 concentrations were significantly reduced in both groups - TNF-α level was only statistically significantly reduced in group - Before and after intervention, the variability of serum IL-6 and TNF-α was not different between the groups 117 Journal of military pharmaco-medicine no2-2018 Table 8: Number of injured organ at the Tn Group (n = 41) Injured organs Group (n = 36) p Number (n) Percentage (%) Number (n) Percentage (%) 14.6 5.6 > 0.05 7.3 16.7 > 0.05 7.3 5.6 > 0.05 9.8 8.3 > 0.05 16 39 13.8 < 0.05 ≥5 22 18 50 < 0.05 - At the end of CRRT, the patients with failure of organs in group were higher whereas those of ≥ organs were significantly less than group - The percentage of - failure organs or without was similar in the groups Table 9: Some factors related to the results and mortality of the groups Parameters Group (n = 41) Group (n = 36) p Average filter lifetime (hour) 31.9 ± 10.8 26.7 ± 10.6 < 0.05 Replacement volume (mL/kg/h) 36.4 ± 4.1 37.9 ± 5.6 > 0.05 Mechanical ventilation (days) 5.4 ± 5.1 8.9 ± 10.2 > 0.05 Days in ICU 7.7 ± 5.9 9.9 ± 10.4 > 0.05 29 (70.7%) 26 (72.2%) > 0.05 Mortality (n, %) - Average filter lifetime in group1 was longer than that in group - The other parameters were similar in the groups Table 10: Estimated mortality of some factors Survey factors n (%) Odd ratio (OR) 95%CI p 7.87 0.97 - 63.79 < 0.05 4.50 1.53 - 13.26 < 0.01 3.75 1.27 - 11.08 < 0.05 Coma at hospitalization Died Survived 15 (93.8%) (6.2%) Mechanical ventilation Died 45 (80.4%) Survived 11 (19.6%) APACHE II score ≥ 25 118 Died 45 (78.9%) Survived 12 (21.1%) Journal of military pharmaco-medicine no2-2018 SOFA score (at day 1) > 10 Died 44 (83%) Survived (17%) 5,78 1.97 - 16.95 < 0.01 3,52 1,26 - 9,86 < 0,05 Failure > organs Died 39 (81.3%) Survived (18.7%) The factors as coma at hospitalization, mechanical ventilation, APACHE II score ≥ 25, SOFA score > 10, failure > organs increased patients' mortality DISCUSSION 77 patients in this trial were treated MOF with guidelines and recommendations They also were supported by CRRT with two dilution modes The common characteristics, clinical 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 postdilution CRRT in MOF patients Continuous renal replacement therapy is one of mainly kidney replacement methods in treating AKI with oliguria/ anuria In this study, serum urea and creatinine decreased gradually after CRRT and there was the difference between the two groups before intervention; as well as at 12h, and 24h after intervention But at the end of CRRT, the average value of serum urea and creatinine in group used pre-and-post-dilution was statistically lower than that in group used post-dilution multicenter randomized studies - RENAL and ATN showed that the effect of CRRT in improving kidney function in severe patients with AKI 4, 5] About the inflammatory cytokine clearance, study showed that concentrations of serum IL-6 and TNF-α decreased after CRRT and there had not difference between the two groups Especially, while analyzing by paired-samples t-test, results 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 Hoang Van Quang and Nguyen Gia Binh also recorded CRRT reduced the concentrations of cytokines [1, 2] However, Cole and Klouche proved that although improved prognosis, CRRT did not change blood 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 [6] At the end of study, the mean number of injured organ in the two groups was not different However, when comparing each group of organ failure, the impairment of ≤ organs did not differ between the two 119 Journal of military pharmaco-medicine no2-2018 groups, the group had more patients with organs failure whereas ≥ organs had significantly less compared with group It means that the tendency of severe progression in study group was less than that of control group Besides, study also recorded the average filter lifetime with pre-and-post-dilution was significantly longer than that with postdilution (31.9 ± 10.8 hours versus 26.7 ± 10.6 hours) Van der Voort and Uchino showed that post-dilution shortened the filter lifetime compared with pre-dilution [7, 8] Multiple organ failure is the disease with severely progression and influences many organs Results of the study showed that, the factors as coma at hospitalization, mechanical ventilation, APACHE II score ≥ 25, SOFA score > 10, failure of > organs increased patients' mortality Study of Nguyen Gia Binh recorded APACHE II score > 25 impairment of > organs was related to mortality [2] Hoang Van Quang also said that APACHE II, SOFA and failure more organs were related to prognosis [1] Truong Ngoc Hai researched and identified the factors related to mortality, and concluded that age ≥ 55, mechanical ventilation, pH < 7.1; APACHE II score ≥ 25, SOFA score ≥ 10 and failure of > organs were the prognosis factors [3] CONCLUSIONS Studying MOF patients supported by pre-and-post-dilution CRRT and comparing with those supported by post-dilution, had the folowing results: 120 * Common results: - At the end of CRRT, serum urea and creatinine as well as percentage of AKI in group used pre-and-post-dilution were lower than that in control group - At the end of CRRT, percentage of injury ≥ organs was lower - The variability of IL-6, TNF-α and parameters of arterial blood gas had not the statistically difference between the groups * Some factors related to the results, progression and prognosis: - Average filter lifetime was longer while using pre-and-post-dilution CRRT - Mechanical ventilation time, days in ICU and mortality were not statistically significant between the groups - The factors ascoma at hospitalization, mechanical ventilation, APACHE II score ≥ 25, SOFA score > 10, failure > organs increased patients' mortality REFERENCES Hoàng Văn Quang Nghiên cứu đặc điểm lâm sàng kết điều trị suy đa tạng bệnh nhân sốc nhiễm khuẩn Luận án Tiến sỹ Y học Trường Đại học Y Hà Nội 2009 Nguyễn Gia Bình, Đặng Quốc Tuấn, Đỗ Tất Cường, Trần Duy Anh, Đỗ Quốc Huy CS Nghiên cứu ứng dụng số kỹ thuật lọc máu đại cấp cứu, điều trị số bệnh Đề tài cấp Nhà nước Bộ Khoa học Công nghệ - Bộ Y tế 2008 Trương Ngọc Hải Nghiên cứu lâm sàng, cận lâm sàng hiệu điều trị liệu pháp lọc máu liên tục bệnh nhân suy đa tạng Luận án Tiến sỹ Y học Học viện Quân y 2009 Journal of military pharmaco-medicine no2-2018 Bellomo R, Cass A, Cole L et al Intensity of continouous renal-replacement therapy in critically ill patients N Engl J Med 2009, 361, pp.1627-1638 Palevsky P.M, Zhang J.H, O'Connor T.Z et al Intensity of renal support in critically ill patients with acute kidney injury N Engl J Med 2008, 359, pp.357-320 Klouche K et al Continuous venovenous hemofiltration improves hemodynamics in septic shock with acute renal failure without modifying TNF-α and IL-6 plasma concentrations J Nephrol 2002, 15, pp.150-157 Van der Voort P.H.J, Gerritsen R.T, Kuiper M.A, Egbers P.H.M, Kingma W.P, Boerma E.C Filter run time in CVVH: Preversus post-dilution and nadroparin versus regional heparin-protamine anticoagulation Blood Purif 2005, 23, pp.175-180 Uchino S1, Fealy N, Baldwin I, Morimatsu H, Bellomo R Pre-dilution vs postdilution during hemofiltration: continuous impact on veno-venous filter life and azotemic control Nephron Clin Pract 2003, 94 (94), pp.94-98 121 ... Studying MOF patients supported by pre- and- post- dilution CRRT and comparing with those supported by post- dilution, had the folowing results: 120 * Common results: - At the end of CRRT, serum urea and. .. effect of pre- and- post- dilution CRRT with postdilution CRRT in MOF patients Continuous renal replacement therapy is one of mainly kidney replacement methods in treating AKI with oliguria/ anuria... Voort and Uchino showed that post- dilution shortened the filter lifetime compared with pre- dilution [7, 8] Multiple organ failure is the disease with severely progression and influences many organs