Case Report Received: September 12, 2014 Accepted: October 27, 2014 Published online: December 19, 2014
Blood Purif 2014;38:234–238 DOI: 10.1159/000369379
High Cutoff Membrane to Reduce Systemic Inflammation Due to Differentiation Syndrome: A Case Report Gianluca Villa a, b Jose J. Zaragoza a, c Aashish Sharma a, d Cosimo Chelazzi b Claudio Ronco a A. Raffaele De Gaudio b
International Renal Research Institute of Vicenza, b Department of Health Science, Section of Anesthesiology and Intensive Care, University of Florence, Italy; c Intensive Care Unit, Hospital Español, Mexico City, Mexico; d Department of Nephrology, Indraprastha Apollo Hospitals, New Delhi, India
Key Words Blood purification · Systemic inflammatory syndrome · High cutoff membrane · Retinoic acid · Differentiation syndrome · Acute promyelocytic leukemia
Abstract Background: Differentiation syndrome is a life-threatening complication of therapy that is carried out with agents used for acute promyelocytic leukemia. Its physiopathology comprehends the production of inflammatory mediators by differentiating granulocytes, endothelial and alveolar cells due to stimulation by all-trans retinoic acid and leading to sustained systemic inflammation. Methods: Treatment with high cut-off continuous veno-venous hemodialysis (HCO-CVVHD) was performed to reduce the circulating mediators of systemic inflammation. Results: After 52 h of treatment, an important reduction was observed in inflammatory mediators (IL-1β: from 10 to 2 pg/ml; IL-8: from 57 to 40 pg/ml; TNF-α: from 200 to 105 pg/ml; IL-6: from 263 to 91 pg/ml), as well as in anti-inflammatory mediators (IL-10: from 349 to 216 pg/ml). Conclusions: HCO-CVVHD should be explored as a part of treatment in systemic inflammation states other than sepsis (e.g., differentiation syndrome). Furthermore, its immunomodulatory effects could be particularly useful in immunocompromised © 2014 S. Karger AG, Basel patient treated with corticosteroids.
© 2014 S. Karger AG, Basel 0253–5068/14/0384–0234$39.50/0 E-Mail [email protected] www.karger.com/bpu
Case Report A 43-year-old man with an unremarkable past medical history presented to the emergency department (ED) with complaints of massive melena, dyspnea, and uneasiness. On examination, his vital signs were: a pulse rate of 125 per minute, respiratory rate of 32, and mean arterial pressure of 42 mm Hg. The rest of his physical examination revealed disseminated bruising and purpura. Severe respiratory distress and hypovolemic shock were aggressively treated with mechanical ventilation, blood transfusions, fluid challenge, and vasoactive drugs. Laboratory analysis revealed hemoglobin 3.1 g/dl, white blood cell count (WBC) 90 × 109/l, platelet count 31 × 109/l, serum creatinine 1.2 mg/dl, antithrombin III (AT III) 21%, and D-dimer 16,540 ng/ml. The patient was immediately shifted to the Intensive Care Unit (ICU). Acute kidney injury (AKI) (urinary output of 0.3 ml/kg/h for 13 h, KDIGO stage 2) [1] was managed with continuous veno-venous hemofiltration (CVVH) using a high-flux membrane. A mean net fluid removal of 100 ml/h and a convective dose of 35 ml/kg/h were prescribed and continued for the next 11 days. Calcium-citrate as regional anticoagulation was used in view of disseminated intravascular coagulopathy [1]. Peripheral blood smear showed Auer bodies, highly suggestive of Acute Promyelocytic Leukemia (APL). Definitive diagnosis was made by testing for the PML/RARα fusion gene in peripheral blood. Treatment for APL with retinoic acid, idarubicin, and prednisolone was commenced. Following the next 5 days in the ICU, the patient’s clinical condition progressively improved. On the fifth ICU day, the patient achieved hemodynamical stability and supportive measures were gradually discontinued. WBC count was 1.5 × 109/l. The protocol for mechanical ventilation weaning was started.
Gianluca Villa, MD Department of Nephrology, Dialysis and Transplantation International Renal Research Institute, San Bortolo Hospital Viale Rodolfi 37, IT–36100 Vicencza (Italy) E-Mail gianlucavilla1 @ gmail.com
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a
Table 1. Biochemical and physiologic variables observed in the patient at the emergency department and during ICU stay
ED
CRRT MAP, mm Hg PaO2/FiO2 Norepinephrine, μg/kg/min Epinephrine, μg/kg/min WBC (×109/l) Platelet (×109/l) AT III, % D-dimer, ng/ml Fibrinogen, mg/l Creatinine, mg/dl Diuresis, ml/kg/h Albumin, g/dl PCT, ng/ml
High-flux CVVH
HCO-CVVHD (52 h)
ICU-day ICU-day ICU-day ICU-day ICU-day 2 4 6 9 11
ICU-day ICU-day 12 13
42 165
60 200 0.12
70 220 0.07
65 85 0.20
90 31 21 16,540 1,410 1.2 0.3 2.5 1.6
11 21 60 18,530 1,740 0.9 0 2.2 1.7
1.5 25 71 13,450 1,643 1.3 0.4 2.3 1.4
51 28 68 17,895 1,656 1.6 0.2 2.5 1.5
65 75 0.10 0.05 1.5 31 71 15,650 1,598 1.6 0 2.2 0.6
Sierologic evaluation microbial components Cultural samples Negative
63 75 0.25 0.05 13 22 60 15,455 1,590 1.3 0 2.2 1.1
67 70 0.25 0.1 2 25 72 16,240 1,655 1.5 0 2.3 1.6
61 57 0.10 0.05 1.1 25 73 12,465 1,680 1.2 0 2.1 0.8
Negative Negative Galactomannan Negative Negative Aspergillum Sp
MAP is expressed as the average of daily values. Norepinephrine and epinephrine are expressed as daily mean dosage. Serologic evaluation had included antibodies toward main viral and bacterial infection in immunocompromised patient. Microbial components comprehended endotoxin activity assay and Galactomannan. ED = Emergency department; CRRT = continuous renal replacement therapy; MAP = mean arterial pressure; WBC = white blood cells count; AT III = antithrombin III; PCT = procalcitonin.
IL-10 IL-6 71)į IL-8 ,/DŽ
350 300 250 200 150 100 50 0 Before HCO
After HCO
Fig. 1. Serum concentration of cytokines before and after the 52 h
of treatment with HCO-CVVHD.
Blood Purif 2014;38:234–238 DOI: 10.1159/000369379
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Hemopurification in Differentiation Syndrome
400
pg/ml
However, on the sixth day, WBC increased to 51 × 109/l. Fever, severe impairment of pulmonary oxygenation (PaO2/FiO2 0.01 μm, cut-off 60 kDa), the extent of molecules cleared is significantly broadened [14]. This is more important for middle molecular weight (MW) molecules, such as inflammatory mediators. Morgera et al. [15] in a 236
Blood Purif 2014;38:234–238 DOI: 10.1159/000369379
prospective single-center pilot trial, treated sixteen patients with multiple organ failure induced by septic shock using HCO-hemofiltration for 12 h per day for 5 days. They reported that the sieving coefficient (SC) for IL-6 resulted at 0.87 (0.76–1.00) 30 min after initiation of hemofiltration and remained stable throughout the treatment. IL-6 clearance was 12–17 ml/min during the entire treatment. In this study, a significant reduction in the total amount of circulating IL-6 was observed [15]. The same group in a prospective controlled trial, [12] randomized 24 septic patients with AKI to receive diffusive versus convective HCO renal replacement therapy. Convective technique was demonstrated to be more efficient than diffusive to reduce circulating IL-6 and IL-1ra, but was associated with a higher albumin loss in the effluent (100–830 vs. 40–410 mg/h with 1 l/h in effluent for CVVH and CVVHD, respectively). Considering that MW of albumin (69 kDa) is very close to the membrane cutoff, an unwanted albumin loss has been demonstrated during HCO use, particularly during convection [12]. Increasing the treatment flows has shown to improve the extracorporeal clearance of inflammatory mediators. If higher flows are prescribed with a pure diffusive technique, this effect on inflammatory mediators is maintained with a negligible removal of albumin. In particular, in a double-bind, cross-over, controlled trial, Haase et al. [16] randomized 10 septic patients with AKI to HCO or high-flux intermittent hemodialysis. They found a significant and stable decrease in serum IL-6 concentration after 4 h in patients treated using HCO, without a concomitant loss of albumin. Moreover, for IL-8 and IL-10 a greater decrease in post-filter relative to pre-filter cytokines level were observed during HCO relative to highflux hemodialysis [16]. The same efficacy in reducing circulating cytokines and improving clinical conditions observed in septic patients should also be expected in other syndromes where the systemic inflammation is the main physiopathological mechanism involved in organ damage. For example, Chelazzi et al. reported the use of HCO-CVVHD for severe acute pancreatitis (SAP) in absence of sepsis. They reported a net reduction of serum cytokine concentrations during the treatment, in particular of IL-6, recognized as one of the most important molecules in the physiopathology of SAP [11]. We decided to switch our patient from CVVH with high-flux membrane to HCO-CVVHD in order to improve cytokine removal. A dose higher than what was prescribed by the more recent guidelines for the renal replacement therapy in the ICU [1] was set in our patient Villa/Zaragoza/Sharma/Chelazzi/Ronco/ De Gaudio
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CVVHD was performed in our patient. No membrane or circuit clotting complication was observed. The worsening of alveolar hemorrhage resulted in severe hypoxemia leading to the patient’s death despite all medical efforts.
prehensive approach, just than a pharmacological one, in patients with DS can lead to the reduction of corticosteroid doses and can also decrease the risk of opportunistic infections. Moreover, according to ‘peak concentration hypothesis’ [21], the contemporary reduction of inflammatory and anti-inflammatory mediators may attenuate the immunological impairment in these patients. This might reduce bacterial, virus, and/or fungal superinfections and achieve the immunomodulation. Theoretically, considering the MW of Protein C (62 kDa), Protein S (69 kDa) and AT III (60 kDa), a reduction in these molecules should be suspected during HCO. However, in a prospective trial of 16 septic patients treated by intermittent HCO hemofiltration, coagulation factors were not affected. Stable values were found for AT III, Factor II (69 kDa), Protein C, Protein S, and Factor VIII (265 kDa) at baseline, at 12 h and at 72 h after initiation of the treatment [15]. The clearance of these molecules when only the diffuse technique is used should be minimal. During the 52 h treatment with HCO-CVVHD, a strict monitoring in indices of disseminated intravascular coagulopathy (DIC) was performed. No differences were observed in AT III during the whole HCO-CVVHD treatment (table 1). In this case, taking into account the DIC and the consequent high risk of bleeding, CVVH with high-flux membrane was performed with isotonic citrate regional anticoagulation [1]. Contrary, if isotonic citrate anticoagulation is applied to HCO, the convective dose delivered as predilution could increase the albumin and coagulation factors clearance [12]. The use of hypertonic citrate solutions reduces this predilution but may increase the risk of citrate systemic accumulation in patients with potentially reduced citrate metabolism. Regional anticoagulation with heparin-protamine is controversial in patients with thrombocytopenia. For all these reasons, HCO-CVVHD was performed without anticoagulation, enhancing the non-pharmacological strategies to reduce membrane fouling. However, the lack of anticoagulation may reduce the transmembrane clearance during the treatment, mainly for molecules with higher molecular weight (as TNF-α). Despite HCO-CVVHD being able to reduce the referred inflammatory mediators, as observed in our case report, the patient’s alveolar hemorrhage and subsequent severe hypoxemia affected the prognosis. An early onset of HCO-CVVHD could be more efficient rather than when endothelial and alveolar damages have already occurred. A thorough review on the adequate uses of HCO is required.
Hemopurification in Differentiation Syndrome
Blood Purif 2014;38:234–238 DOI: 10.1159/000369379
237
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to increase cytokine clearance. A pure dialytic technique was then applied to reduce albumin loss. Serum albumin and cytokine concentrations were monitored strictly and, in line with data of literature previously reported [12, 15, 16], unchanged serum albumin concentrations and reduction in circulating inflammatory mediators (fig. 1) were observed during the entire treatment (see table 1). Unfortunately, no cytokine or albumin clearances were calculated in our patient and only the value before and after the HCO-CVVHD treatment have been measured. In particular, levels of inflammatory mediators such as TNF-α (54 kDa) and IL-6 (30 kDa) [17] were significantly reduced during the 52 h-treatment with HCO-CVVHD (fig. 1). On the other hand, a less reduction was observed for IL-1β (17 kDa) and IL-8 (10 kDa) [17], distinguished by their lower molecular weight. This fact could be related to the low initial concentrations of IL-1β and IL-8. The feasible explanation could be the removal by highflux CVVH performed during the previous 5 days. Indeed, high-flux membranes have an SC of 0.66–0.83 for IL-1β and 0.35–0.66 for IL-8 [18] ergo removal should be expected. HCO presents a higher clearance for IL-1β and IL-8 than high-flux membrane according to the higher SC observed (0.71–1 and 0.44–0.80, respectively [18]). Furthermore, considering the development of ‘protein cake’ and subsequent reduction in the SC, the larger pores of HCO may prolong the removal of these molecules in respect to the high-flux membranes. Although high-flux CVVH could remove the molecules related to the initiation of DS pathogenesis (IL-1β and IL-8), but can’t modulate the final inflammatory pathway, characterized by the overexpression of TNF-α and IL-6 (SC 0.22 and 0.04, respectively) [17], which is common in any systemic inflammatory syndrome. As suggested in ‘threshold hypothesis’ [19], the reduction in humoral pathway of inflammation through the removal of one single mediator is very unlikely because of their pleiotropic and redundant effects. In other words, it is less likely to reduce the clinical expression of DS pathogenesis only by the removal of IL-1β and IL-8. HCO is also able to reduce the circulating levels of TNF-α and IL-6 (SC of 0.73–0.84 and 0.94–1, respectively [20]), actually modulating the final pathway of systemic inflammation. A reduction in anti-inflammatory mediators, such as IL-10 (40 kDa), may be a further advantage of HCOCVVHD. We present findings in a hematologic immunedepressed patient treated with high-dose corticosteroids, who developed an opportunistic infection. A more com-
Conclusion
We present a case report of a patient with APL complicated by DS. As per our best knowledge, this is the first report showing the use of high cutoff membranes also
with the objective of reducing circulating inflammation factors and achieving immunomodulation. In future research, HCO-CVVHD should be explored as a part of treatment pattern in systemic inflammatory syndromes other than sepsis.
References
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8 Bi KH, Jiang GS: Relationship between cytokines and leukocytosis in patients with APL induced by all-trans retinoic acid or arsenic trioxide. Cell Mol Immunol 2006;3:421–427. 9 Luesink M, Pennings JL, Wissink WM, Linssen PC, Muus P, Pfundt R, et al: Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome. Blood 2009;114:5512–5521. 10 Rimmelé T, Kellum JA: Clinical review: blood purification for sepsis. Crit Care 2011;15:205. 11 Chelazzi C, Giugni D, Giannoni C, Villa G, De Gaudio A: Use of Continuous Venovenous Hemodiafiltration with a High Cutoff Membrane in a Patient with Severe Acute Pancreatitis. Open J Nephrol 2012;2:78–81. 12 Morgera S, Slowinski T, Melzer C, Sobottke V, Vargas-Hein O, Volk T, et al: Renal replacement therapy with high-cutoff hemofilters: impact of convection and diffusion on cytokine clearances and protein status. Am J Kidney Dis 2004;43:444–453. 13 Morgera S, Haase M, Kuss T, Vargas-Hein O, Zuckermann-Becker H, Melzer C, et al: Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure. Crit Care Med 2006;34:2099–2104. 14 Haase M, Bellomo R, Morgera S, Baldwin I, Boyce N: High cut-off point membranes in septic acute renal failure: a systematic review. Int J Artif Organs 2007;30:1031–1041. 15 Morgera S, Rocktäschel J, Haase M, Lehmann C, von Heymann C, Ziemer S, et al: Intermittent high permeability hemofiltration in septic patients with acute renal failure. Intensive Care Med 2003;29:1989–1995.
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16 Haase M, Bellomo R, Baldwin I, Haase-Fielitz A, Fealy N, Davenport P, et al: Hemodialysis membrane with a high-molecular-weight cutoff and cytokine levels in sepsis complicated by acute renal failure: a phase 1 randomized trial. Am J Kidney Dis 2007;50:296– 304. 17 Heering P, Morgera S, Schmitz FJ, Schmitz G, Willers R, Schultheiss HP, et al: Cytokine removal and cardiovascular hemodynamics in septic patients with continuous venovenous hemofiltration. Intensive Care Med 1997; 23: 288–296. 18 Mariano F, Fonsato V, Lanfranco G, Pohlmeier R, Ronco C, Triolo G, et al: Tailoring highcut-off membranes and feasible application in sepsis-associated acute renal failure: in vitro studies. Nephrol Dial Transplant 2005; 20: 1116–1126. 19 Honore PM, Joannes-Boyau O: High volume hemofiltration (HVHF) in sepsis: a comprehensive review of rationale, clinical applicability, potential indications and recommendations for future research. Int J Artif Organs 2004;27:1077–1082. 20 Morgera S, Klonower D, Rocktaschel J, Haase M, Priem F, Ziemer S, et al: TNF-alpha elimination with high cut-off haemofilters: a feasible clinical modality for septic patients? Nephrol Dial Transplant 2003;18:1361–1369. 21 Ronco C, Tetta C, Mariano F, Wratten ML, Bonello M, Bordoni V, et al: Interpreting the mechanisms of continuous renal replacement therapy in sepsis: the peak concentration hypothesis. Artif Organs 2003;27:792–801.
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1 Khwaja A: KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012;120:c179–c184. 2 Montesinos P, Sanz MA: The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the pethema group and review of the literature. Mediterr J Hematol Infect Dis 2011; 3:e2011059. DOI: 10.4084/mjhid.2011.059. 3 Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al: Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111–121. 4 Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, et al: Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol 2010;28:3866–3871. 5 Ghavamzadeh A, Alimoghaddam K, Rostami S, Ghaffari SH: Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol 2011;29:2753–2757. 6 Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP: The ‘retinoic acid syndrome’ in acute promyelocytic leukemia. Ann Intern Med 1992;117:292–296. 7 Gao Y, Camacho LH, Mehta K: Retinoic acidinduced CD38 antigen promotes leukemia cells attachment and interferon-gamma/interleukin-1beta-dependent apoptosis of endothelial cells: Implications in the etiology of retinoic acid syndrome. Leuk Res 2007; 31: 455–463.
Blood Purif 2014;38:234–238 DOI: 10.1159/000369379
High Cutoff Membrane to Reduce Systemic Inflammation Due to Differentiation Syndrome: A Case Report Gianluca Villa a, b Jose J. Zaragoza a, c Aashish Sharma a, d Cosimo Chelazzi b Claudio Ronco a A. Raffaele De Gaudio b
International Renal Research Institute of Vicenza, b Department of Health Science, Section of Anesthesiology and Intensive Care, University of Florence, Italy; c Intensive Care Unit, Hospital Español, Mexico City, Mexico; d Department of Nephrology, Indraprastha Apollo Hospitals, New Delhi, India
Key Words Blood purification · Systemic inflammatory syndrome · High cutoff membrane · Retinoic acid · Differentiation syndrome · Acute promyelocytic leukemia
Abstract Background: Differentiation syndrome is a life-threatening complication of therapy that is carried out with agents used for acute promyelocytic leukemia. Its physiopathology comprehends the production of inflammatory mediators by differentiating granulocytes, endothelial and alveolar cells due to stimulation by all-trans retinoic acid and leading to sustained systemic inflammation. Methods: Treatment with high cut-off continuous veno-venous hemodialysis (HCO-CVVHD) was performed to reduce the circulating mediators of systemic inflammation. Results: After 52 h of treatment, an important reduction was observed in inflammatory mediators (IL-1β: from 10 to 2 pg/ml; IL-8: from 57 to 40 pg/ml; TNF-α: from 200 to 105 pg/ml; IL-6: from 263 to 91 pg/ml), as well as in anti-inflammatory mediators (IL-10: from 349 to 216 pg/ml). Conclusions: HCO-CVVHD should be explored as a part of treatment in systemic inflammation states other than sepsis (e.g., differentiation syndrome). Furthermore, its immunomodulatory effects could be particularly useful in immunocompromised © 2014 S. Karger AG, Basel patient treated with corticosteroids.
© 2014 S. Karger AG, Basel 0253–5068/14/0384–0234$39.50/0 E-Mail [email protected] www.karger.com/bpu
Case Report A 43-year-old man with an unremarkable past medical history presented to the emergency department (ED) with complaints of massive melena, dyspnea, and uneasiness. On examination, his vital signs were: a pulse rate of 125 per minute, respiratory rate of 32, and mean arterial pressure of 42 mm Hg. The rest of his physical examination revealed disseminated bruising and purpura. Severe respiratory distress and hypovolemic shock were aggressively treated with mechanical ventilation, blood transfusions, fluid challenge, and vasoactive drugs. Laboratory analysis revealed hemoglobin 3.1 g/dl, white blood cell count (WBC) 90 × 109/l, platelet count 31 × 109/l, serum creatinine 1.2 mg/dl, antithrombin III (AT III) 21%, and D-dimer 16,540 ng/ml. The patient was immediately shifted to the Intensive Care Unit (ICU). Acute kidney injury (AKI) (urinary output of 0.3 ml/kg/h for 13 h, KDIGO stage 2) [1] was managed with continuous veno-venous hemofiltration (CVVH) using a high-flux membrane. A mean net fluid removal of 100 ml/h and a convective dose of 35 ml/kg/h were prescribed and continued for the next 11 days. Calcium-citrate as regional anticoagulation was used in view of disseminated intravascular coagulopathy [1]. Peripheral blood smear showed Auer bodies, highly suggestive of Acute Promyelocytic Leukemia (APL). Definitive diagnosis was made by testing for the PML/RARα fusion gene in peripheral blood. Treatment for APL with retinoic acid, idarubicin, and prednisolone was commenced. Following the next 5 days in the ICU, the patient’s clinical condition progressively improved. On the fifth ICU day, the patient achieved hemodynamical stability and supportive measures were gradually discontinued. WBC count was 1.5 × 109/l. The protocol for mechanical ventilation weaning was started.
Gianluca Villa, MD Department of Nephrology, Dialysis and Transplantation International Renal Research Institute, San Bortolo Hospital Viale Rodolfi 37, IT–36100 Vicencza (Italy) E-Mail gianlucavilla1 @ gmail.com
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a
Table 1. Biochemical and physiologic variables observed in the patient at the emergency department and during ICU stay
ED
CRRT MAP, mm Hg PaO2/FiO2 Norepinephrine, μg/kg/min Epinephrine, μg/kg/min WBC (×109/l) Platelet (×109/l) AT III, % D-dimer, ng/ml Fibrinogen, mg/l Creatinine, mg/dl Diuresis, ml/kg/h Albumin, g/dl PCT, ng/ml
High-flux CVVH
HCO-CVVHD (52 h)
ICU-day ICU-day ICU-day ICU-day ICU-day 2 4 6 9 11
ICU-day ICU-day 12 13
42 165
60 200 0.12
70 220 0.07
65 85 0.20
90 31 21 16,540 1,410 1.2 0.3 2.5 1.6
11 21 60 18,530 1,740 0.9 0 2.2 1.7
1.5 25 71 13,450 1,643 1.3 0.4 2.3 1.4
51 28 68 17,895 1,656 1.6 0.2 2.5 1.5
65 75 0.10 0.05 1.5 31 71 15,650 1,598 1.6 0 2.2 0.6
Sierologic evaluation microbial components Cultural samples Negative
63 75 0.25 0.05 13 22 60 15,455 1,590 1.3 0 2.2 1.1
67 70 0.25 0.1 2 25 72 16,240 1,655 1.5 0 2.3 1.6
61 57 0.10 0.05 1.1 25 73 12,465 1,680 1.2 0 2.1 0.8
Negative Negative Galactomannan Negative Negative Aspergillum Sp
MAP is expressed as the average of daily values. Norepinephrine and epinephrine are expressed as daily mean dosage. Serologic evaluation had included antibodies toward main viral and bacterial infection in immunocompromised patient. Microbial components comprehended endotoxin activity assay and Galactomannan. ED = Emergency department; CRRT = continuous renal replacement therapy; MAP = mean arterial pressure; WBC = white blood cells count; AT III = antithrombin III; PCT = procalcitonin.
IL-10 IL-6 71)į IL-8 ,/DŽ
350 300 250 200 150 100 50 0 Before HCO
After HCO
Fig. 1. Serum concentration of cytokines before and after the 52 h
of treatment with HCO-CVVHD.
Blood Purif 2014;38:234–238 DOI: 10.1159/000369379
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Hemopurification in Differentiation Syndrome
400
pg/ml
However, on the sixth day, WBC increased to 51 × 109/l. Fever, severe impairment of pulmonary oxygenation (PaO2/FiO2 0.01 μm, cut-off 60 kDa), the extent of molecules cleared is significantly broadened [14]. This is more important for middle molecular weight (MW) molecules, such as inflammatory mediators. Morgera et al. [15] in a 236
Blood Purif 2014;38:234–238 DOI: 10.1159/000369379
prospective single-center pilot trial, treated sixteen patients with multiple organ failure induced by septic shock using HCO-hemofiltration for 12 h per day for 5 days. They reported that the sieving coefficient (SC) for IL-6 resulted at 0.87 (0.76–1.00) 30 min after initiation of hemofiltration and remained stable throughout the treatment. IL-6 clearance was 12–17 ml/min during the entire treatment. In this study, a significant reduction in the total amount of circulating IL-6 was observed [15]. The same group in a prospective controlled trial, [12] randomized 24 septic patients with AKI to receive diffusive versus convective HCO renal replacement therapy. Convective technique was demonstrated to be more efficient than diffusive to reduce circulating IL-6 and IL-1ra, but was associated with a higher albumin loss in the effluent (100–830 vs. 40–410 mg/h with 1 l/h in effluent for CVVH and CVVHD, respectively). Considering that MW of albumin (69 kDa) is very close to the membrane cutoff, an unwanted albumin loss has been demonstrated during HCO use, particularly during convection [12]. Increasing the treatment flows has shown to improve the extracorporeal clearance of inflammatory mediators. If higher flows are prescribed with a pure diffusive technique, this effect on inflammatory mediators is maintained with a negligible removal of albumin. In particular, in a double-bind, cross-over, controlled trial, Haase et al. [16] randomized 10 septic patients with AKI to HCO or high-flux intermittent hemodialysis. They found a significant and stable decrease in serum IL-6 concentration after 4 h in patients treated using HCO, without a concomitant loss of albumin. Moreover, for IL-8 and IL-10 a greater decrease in post-filter relative to pre-filter cytokines level were observed during HCO relative to highflux hemodialysis [16]. The same efficacy in reducing circulating cytokines and improving clinical conditions observed in septic patients should also be expected in other syndromes where the systemic inflammation is the main physiopathological mechanism involved in organ damage. For example, Chelazzi et al. reported the use of HCO-CVVHD for severe acute pancreatitis (SAP) in absence of sepsis. They reported a net reduction of serum cytokine concentrations during the treatment, in particular of IL-6, recognized as one of the most important molecules in the physiopathology of SAP [11]. We decided to switch our patient from CVVH with high-flux membrane to HCO-CVVHD in order to improve cytokine removal. A dose higher than what was prescribed by the more recent guidelines for the renal replacement therapy in the ICU [1] was set in our patient Villa/Zaragoza/Sharma/Chelazzi/Ronco/ De Gaudio
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CVVHD was performed in our patient. No membrane or circuit clotting complication was observed. The worsening of alveolar hemorrhage resulted in severe hypoxemia leading to the patient’s death despite all medical efforts.
prehensive approach, just than a pharmacological one, in patients with DS can lead to the reduction of corticosteroid doses and can also decrease the risk of opportunistic infections. Moreover, according to ‘peak concentration hypothesis’ [21], the contemporary reduction of inflammatory and anti-inflammatory mediators may attenuate the immunological impairment in these patients. This might reduce bacterial, virus, and/or fungal superinfections and achieve the immunomodulation. Theoretically, considering the MW of Protein C (62 kDa), Protein S (69 kDa) and AT III (60 kDa), a reduction in these molecules should be suspected during HCO. However, in a prospective trial of 16 septic patients treated by intermittent HCO hemofiltration, coagulation factors were not affected. Stable values were found for AT III, Factor II (69 kDa), Protein C, Protein S, and Factor VIII (265 kDa) at baseline, at 12 h and at 72 h after initiation of the treatment [15]. The clearance of these molecules when only the diffuse technique is used should be minimal. During the 52 h treatment with HCO-CVVHD, a strict monitoring in indices of disseminated intravascular coagulopathy (DIC) was performed. No differences were observed in AT III during the whole HCO-CVVHD treatment (table 1). In this case, taking into account the DIC and the consequent high risk of bleeding, CVVH with high-flux membrane was performed with isotonic citrate regional anticoagulation [1]. Contrary, if isotonic citrate anticoagulation is applied to HCO, the convective dose delivered as predilution could increase the albumin and coagulation factors clearance [12]. The use of hypertonic citrate solutions reduces this predilution but may increase the risk of citrate systemic accumulation in patients with potentially reduced citrate metabolism. Regional anticoagulation with heparin-protamine is controversial in patients with thrombocytopenia. For all these reasons, HCO-CVVHD was performed without anticoagulation, enhancing the non-pharmacological strategies to reduce membrane fouling. However, the lack of anticoagulation may reduce the transmembrane clearance during the treatment, mainly for molecules with higher molecular weight (as TNF-α). Despite HCO-CVVHD being able to reduce the referred inflammatory mediators, as observed in our case report, the patient’s alveolar hemorrhage and subsequent severe hypoxemia affected the prognosis. An early onset of HCO-CVVHD could be more efficient rather than when endothelial and alveolar damages have already occurred. A thorough review on the adequate uses of HCO is required.
Hemopurification in Differentiation Syndrome
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to increase cytokine clearance. A pure dialytic technique was then applied to reduce albumin loss. Serum albumin and cytokine concentrations were monitored strictly and, in line with data of literature previously reported [12, 15, 16], unchanged serum albumin concentrations and reduction in circulating inflammatory mediators (fig. 1) were observed during the entire treatment (see table 1). Unfortunately, no cytokine or albumin clearances were calculated in our patient and only the value before and after the HCO-CVVHD treatment have been measured. In particular, levels of inflammatory mediators such as TNF-α (54 kDa) and IL-6 (30 kDa) [17] were significantly reduced during the 52 h-treatment with HCO-CVVHD (fig. 1). On the other hand, a less reduction was observed for IL-1β (17 kDa) and IL-8 (10 kDa) [17], distinguished by their lower molecular weight. This fact could be related to the low initial concentrations of IL-1β and IL-8. The feasible explanation could be the removal by highflux CVVH performed during the previous 5 days. Indeed, high-flux membranes have an SC of 0.66–0.83 for IL-1β and 0.35–0.66 for IL-8 [18] ergo removal should be expected. HCO presents a higher clearance for IL-1β and IL-8 than high-flux membrane according to the higher SC observed (0.71–1 and 0.44–0.80, respectively [18]). Furthermore, considering the development of ‘protein cake’ and subsequent reduction in the SC, the larger pores of HCO may prolong the removal of these molecules in respect to the high-flux membranes. Although high-flux CVVH could remove the molecules related to the initiation of DS pathogenesis (IL-1β and IL-8), but can’t modulate the final inflammatory pathway, characterized by the overexpression of TNF-α and IL-6 (SC 0.22 and 0.04, respectively) [17], which is common in any systemic inflammatory syndrome. As suggested in ‘threshold hypothesis’ [19], the reduction in humoral pathway of inflammation through the removal of one single mediator is very unlikely because of their pleiotropic and redundant effects. In other words, it is less likely to reduce the clinical expression of DS pathogenesis only by the removal of IL-1β and IL-8. HCO is also able to reduce the circulating levels of TNF-α and IL-6 (SC of 0.73–0.84 and 0.94–1, respectively [20]), actually modulating the final pathway of systemic inflammation. A reduction in anti-inflammatory mediators, such as IL-10 (40 kDa), may be a further advantage of HCOCVVHD. We present findings in a hematologic immunedepressed patient treated with high-dose corticosteroids, who developed an opportunistic infection. A more com-
Conclusion
We present a case report of a patient with APL complicated by DS. As per our best knowledge, this is the first report showing the use of high cutoff membranes also
with the objective of reducing circulating inflammation factors and achieving immunomodulation. In future research, HCO-CVVHD should be explored as a part of treatment pattern in systemic inflammatory syndromes other than sepsis.
References
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