Background
High volume hemofiltration and very high volume hemofiltration
Terminology
Technical aspects
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Type of dialyzer: high flux dialyzer (Kuf > 25 ml/h/mmHg/m2).
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Blood flow rate (Qb): since HVHF and VHVHF require high ultrafiltration flows, required Qb typically must guarantee no excessive filtration fraction values (not > 25–30%).
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Dose: convective, greater than 35–45 ml/kg/h. The overall dose can be higher (50–70 ml/kg/h) due to a complementary diffusive component (continuous veno-venous hemodiafiltration (CVVHDF)).
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Replacement fluid (Qr): in pre- and/or post-dilution mode. For a given target dose, it is necessary to consider that the pre-dilution Qr must be higher than the post-dilution.
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Duration: tailored to the patient’s condition.
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Anticoagulation: heparin or citrate.
The evidence
Honoré et al. 2000 [18] | Cole et al. 2001 [15] | Joannes-Boyau et al. 2004 [12] | Ratanarat et al. 2005 [19] | Cornejo et al. 2006 [14] | Piccinni et al. 2006 [13] | Boussekey et al. 2008 [16] | Joannes-Boyau et al. 2013 [17] (IVOIRE) | |
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Study design | Cohort, uncontrolled prospective | Randomized crossover | Cohort, uncontrolled prospective | Cohort, uncontrolled prospective | Cohort, uncontrolled prospective | Retrospective | Prospective randomized study | Prospective, randomized, open, multicenter |
Study population (n) | 20 septic shock patients | 11 septic shock patients | 24 septic shock patients | 15 severe sepsis patients | 20 septic shock patients | 80 septic shock patients | 20 septic shock patients and AKI | 140 septic shock patients and AKI |
Prescribed dose | HVHF (4 h, 35 L of UF removed) followed by conventional CVVH for at least 4 days | 8 h of HVHF (6 L/h) or 8 h of standard CVVH (1 L/h) | 40–60 ml/kg/h for 96 h | HVHF 85 ml/kg/h for 6–8 h followed by CVVH 35 ml/kg/h for 16–18 h | 100 ml/kg/h Single session of 12 h | HVHF (40 patients) at 45 ml/kg/h over 6 h followed by conventional CVVH compared to 40 historic patients treated with conventional therapy | HVHF 65 ml/(kg h) vs LVHF 35 ml/(kg h) | HVHF at 70 ml/kg/h vs SVHF at 35 ml/kg/h for 96 h |
Survival/mortality | 28-day observed survival of 45% compared to expected of 21% (p < 0.05) | Hospital mortality 54.5% | 28-day mortality of 46% compared to predicted mortality of 70% (p < 0.075) | 28-day mortality of 47% compared to predicted mortality of 68–72% | Observed hospital survival of 60% compared to expected survival of 37% (p < 0.03) | 28-day survival of 55% compared to 27.5% in the conventional group (p < 0.05) | • ICU mortality of 33.3% in HVHF group vs 60% in LVHF group but not significantly different • 28-day mortality of 33.3% in the HVHF • group vs 50% in the LVHF group | • 28 day mortality of 37.9% in HVHF vs 40.8% in SVHF, (p = 0.94) • No difference in 60 and 90 days mortality |
Length of ICU stay | – | – | – | – | – | Significant improvement (p < 0.002) | No difference | No difference |
Hemodynamics | Improvement in 11/20 patients | Greater reduction in NE, HVHF vs standard CVVH (68% vs 7%; p = 0.02) | Significant improvement (p < 0.05) | Significant improvement (p = 0.001) | Improvement in 11/20 patients | Significant improvement (p < 0.05) | Improvement in VP dose in the treatment group (p = 0.004) | No difference |
Safety | – | No AE | – | – | – | – | No AE | Hypokalemia (30% in HVHF vs 20% in SVHF (p = 0.1) Hypophosphatemia 88% in HVH vs 38 in SVHF (p = 0.01) |
HVHF is feasible and readily available in centers capable of performing conventional CRRT. The evidence to support its effectiveness in improving patient hemodynamics and mortality (although promising in earlier studies) is insufficient. |
High cut-off membranes
Terminology
Technical aspects
The evidence
Morgera et al. 2004 [27] | Morgera et al. 2006 [30] | Haase et al. 2007 [31] | Chelazzi et al. 2016 [32] | Kade et al. 2016 [34] | Villa et al. 2017 [33] | ||
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Study design | Prospective single-center pilot trial | Prospective RCT | Prospective RCT | Double-blind, crossover RCT | Retrospective, observational | Retrospective, single center | Observational prospective multicenter study |
Study population (n) | 16 septic shock patients | 24 patients with sepsis-induced AKI | 30 septic patients with AKI | 10 septic patients with AKI | 16 patients with Gram-negative sepsis | 28 patients with septic shock | 38 patients with septic shock and AKI |
Prescribed dose | Intermittent HP-HF over 5 days for 12 h/day alternating with conventional HF (12 h) | CVVH (UF 1 L/h) vs CVVH (UF 2.5 L/h) vs CVVHD (dialysate flow rate of 1 L/h) vs CVVHD (dialysate flow rate of 2.5 L/h) | HCO vs conventional HF | 4 h of HCO-IHD and 4 h of HF-IHD | HCO 35 ml/kg/h vs CVVHDF 45 ml/kg/h | HCO-CVVHDF | HCO-CVVHD for 72 h |
Results | High IL-6 elimination | Increasing UF volume or dialysate flow led to a significant increase in IL-1ra and IL-6 clearance rates (p < 0.00001) | Significant reduction in VP dose in the HCO group (p = 0.0002) Clearance rates for IL-6 and IL-1ra were significantly higher in the HCO group (p < 0.0001) | Greater decrease in plasma IL-6 levels (p = 0.05), plasma IL-8 (p = 0.02) and plasma IL-10 (p = 0.04) in the HCO group | ICU mortality rates were 37.5 and 87.5% for HCO and HF groups, respectively (p = 0.03) ICU LOS: 16 and 9 days (HCO- and HF-group; p = 0.03). Improvement of hemodynamics in the HCO group (p < 0.03) | Significant reduction in IL-10 and IL-12 levels | Significant reduction in circulating levels of TNFα and IL-6 among survivors |
Safety or S/E | High cumulative 12-h protein loss (7.60 g; IQR 6.2–12.0) | High protein and albumin losses with 2.5-L/h HF mode | None | Albumin loss of 7.7 g in the HCO group vs < 1.0 g (p < 0.01) | – | – | – |
Based on the reviewed literature, there is no evidence to support the use of HCO hemofiltration in sepsis. Lack of standardized definitions of dialysis membranes [36] has contributed to the paucity of high-quality data supporting their use. |
Adsorption
Terminology
Technical aspects
Toraymyxin | Cytosorb | Oxiris | LPS adsorber | HA 330 | |
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Composition | Polymyxin B-immobilized fiber blood-purification column | Porous polymer beads | AN69-based membrane, surface treated with PEI and grafted with heparin | Synthetic polypeptide bound to porous polyethylene discs | Styrene divinylbenzene copolymers |
Indication | Severe sepsis and septic shock | Severe sepsis and septic shock Cardiac surgery with SIRS | Severe sepsis and septic shock | Severe sepsis and septic shock | Severe sepsis and septic shock |
Toxins removed | Endotoxins | Cytokines/chemokines Anaphylatoxins Myoglobin Free hemoglobin Bilirubin/bile acids Toxins/metals Drugs | Endotoxin Cytokines | Endotoxins | Cytokines Complements Free hemoglobin |
Prescription | 2-h session daily for 2 consecutive days | Up to 24-h therapy daily for 2–7 consecutive days | Prescribed dose > 35 ml/kg/h (60% convective). Filter replacement after 24 h or if there is no reduction in VP dose by 50%. Treatment should be stopped if VP are reduced by > 50% or after 3 days of treatment in case of no-response | 2–6 h. One session is usually sufficient to achieve improvement. Repeated procedures can be performed | 2–6 h daily for 2 days |
Blood flow rate (ml/min) | 80–120 | 150–700 | 100–450 | 150 ± 50 | 100–300 |
Anticoagulation | Heparin | Heparin or citrate | Heparin | Heparin | Heparin or citrate |
Additional features | Polymyxin B antimicrobial effect | Largest surface area | Lower risk of thrombogenicity by adsorbing antithrombin-III from the blood |
The evidence
European pilot study (2005) [37] | EUPHAS (2009) [38] | Japan Registry (2014) [41] | ABDO-MIX (2015) [39] | Japan Registry (2016) [40] | EUPHAS 2 (2016) [42] | |
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Study design | Multicenter, open-label, pilot, RCT | Multicenter, open-label, prospective RCT | Propensity-matched analysis | Multicenter, prospective RCT | Propensity-matched analysis | Retrospective study |
Study population (n) | 36 patients with intra-abdominal sepsis | 64 patients with intra-abdominal sepsis or septic shock | PMX = 642 intra-abdominal sepsis patients vs 590 propensity score-matched pairs | 232 patients with intra-abdominal septic shock/peritonitis | Septic shock patients with CRRT-requiring AKI | 357 patients with suspected Gram-negative sepsis |
EAA assessment | Measured | Not measured | Not measured | Not measured | Not measured | Some centers |
Prescribed dose | 1 session (2 h) | 2 sessions (2 h) | 1–2 sessions | 1–2 sessions (2 h) | 1–2 sessions | 1–2 sessions (2 h) |
Timing (h) | 24–48 (from diagnosis) | 24 (from abdominal surgery) | 24 (from surgery) | 12 (from surgery) | 24 (from starting CRRT) | 24–48 (from diagnosis) |
Survival/ mortality | Mortality, 29% in the PMX group vs 28% in the control group (p = 0.749) | • PMX group had a significant reduction in 28-day mortality (adjusted HR 0.36; 95% CI 0.16–0.80; p = 0.01) • PMX group had a significant reduction in hospital mortality rate (adjusted HR 0.43; 95% CI 0.21–0.90; p = 0.026) | 28-day mortality was 17.1% in the treatment group and 16.3% in the control group (p = 0.696) | • 28-day mortality 27.7% in the treatment group vs 19.5% in the control group (p = 0.14) • 90-day mortality was 33.6% in the treatment group vs 24% in the control group (p = 0.10) | • The 28-day mortality was 40.2% in the treatment group and 46.8% in the control group (p = 0.003) • 28-day mortality in patients receiving 2 PMX was 35.7% vs 42.6% in the group treated with one session | • 28-day survival 54.5% • ICU survival 55.2% • Hospital survival 50% • Patients with abdominal sepsis treated within 24 h survival 64.5% |
Length of ICU stay | 13.2 ± 9.4 days in the PMX; vs 17.0 ± 9.4 days | No significant difference | – | No significant difference | – | – |
Hemodynamics | Significant improvement in the PMX group | Significant reduction in VP dose in the treatment group | – | No significant difference | No significant difference | – |
Other results | No significant difference in the change of IL-6 levels compared to baseline | – | – | – | – | – |
Safety | Higher AE (mainly change in vitals in the treatment arm) | No adverse events reported | – | 6 severe adverse events (hemorrhagic episodes in the treatment group) Platelet drop | – | Significant platelet drop with no clinical implications |
Schädler et al. 2013 [51] | Friesecke et al. 2017 [50] | Schädler et al. 2017 [52] | Kogelmann et al. 2017 [49] | |
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Study design | Multicenter, open label, RCT | Prospective interventional single center | Multicenter, open label, RCT | Case series |
Study population (n) | 43 septic patients with ALI | 25 septic shock patients | 97 septic patients with ALI or ARDS | 16 septic shock patients |
IL-6 assessment (pg/ml) | – | > 1000 | Average of 565 | – |
Prescribed dose | ST vs ST + HP (6 h/day for 7 days) | One session in the pre-filter mode. Further treatments at the discretion of the study physicians | HP vs no HP (6 h/day for up to 7 days) RRT as clinically indicated in both groups | HP in the pre-filter mode (1–5 treatments) |
Timing | – | Within 24 h | – | < 24 to > 48 h (outcomes better in the early group) |
Survival | 28-day mortality 28% in the treatment group vs 24% in the controls (p = 0.84) 60-day mortality (39% in the treatment group vs 32% the controls (p = 0.75) | – | 28-day mortality 36.2% in the treatment group vs 18.0% in the controls (p = 0.073) 60-day mortality of 44.7% in the treatment group vs 26.0% in the controls (p = 0.039) | The actual 28-day, ICU, and hospital mortality was 61.54%, 73.08%, and 80.77%, respectively, compared with 89.9% as predicted by APACHE II score |
Hemodynamics | – | Significant reduction in VP requirements compared to baseline | – | Significant reduction in VP requirements compared with baseline |
Other results | Significant reduction in IL-6 | Significant reduction in IL-6 | IL-6 reduction in the HP group compared with no HP | – |
Safety | Modest reduction in platelet count (< 10%) and albumin (< 5%) | No AE | 1 drop in platelets in the treatment group | No AE |
Huang et al. 2010 [56] | Huang et al. 2013 [57] | |
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Study design | RCT | RCT |
Study population (n) | 44 sepsis or septic shock patients | 46 ALI/extra-pulmonary sepsis patients |
EAA assessment | – | – |
Prescribed dose | HP for 2 h for 3 days | HP for 2 h for 3 days |
Survival | • ICU mortality 12.5% in HA vs 45.0% in the controls (p = 0.02) • Hospital mortality 37.5% in HA vs 50.0% in the controls (p = 0.81) • 28-day mortality 45.8% in HA vs 55.0% in controls (p = 0.47) | • ICU mortality 24% in HA vs 57.14% in the controls (p = 0.02) • 28-day mortality 28% in HA vs 66.7% in the controls (p = 0.009) |
Length of ICU stay (days) | 12.4 ± 3.1 in HA vs 19.5 ± 4.0 in controls (p = 0.03) | 15.5 ± 4.0 in HA vs 19.4 ± 3.1 in controls (p = 0.04) |
Hemodynamics | Significant reduction in VP dose in the HA group vs increase in the control group (p = 0.01) | Significant reduction in VP dose in the HA group vs increase in the control group (p = 0.032) |
Other results | Significant difference in IL-8 and IL-6 levels between the two groups at day 3 (p = 0.03 and 0.01, respectively) | Significant difference in IL-1 and TNF-a in BAL fluid between the two groups (p = 0.02 and 0.04, respectively) |
Safety | • 1 patient with fever in the HA group • Transient reduction in platelet counts in the HP group | – |
Yaroustovsky et al. 2009 [60] | Ala-Kokko et al. 2011 [61] | Adamik et al. 2015 [62] | |
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Study design | Observational | Case series with matched controls | Observational |
Study population (n) | 13 Gram-negative sepsis | 24 septic shock patients and endotoxaemia. | 62 septic shock and suspected Gram-negative |
EAA assessment | – | More than 0.3 considered endotoxaemia | EA [0.70 EA units (0.66–0.77)]. |
Prescribed dose | Two sessions with a maximum duration of 120 min/patient Alteco adsorber (n = 6) and toraymyxin (n = 7) | 2-h LPS HP | LPS elimination + ST vs ST 1–2 sessions |
Timing | – | Within 36 h | Within 24 h |
Survival | – | – | No effect |
Length of ICU stay | – | – | No effect |
Hemodynamics | Improved MAP | Decreased VP | Significant improvement in the treatment group |
Other results | Decrease in endotoxin and procalcitonin levels | Decreased endotoxin levels | Decreased endotoxin levels |
Safety | Low platelets, two patients requiring transfusion but no bleeding |
Hemoperfusion is a well-tolerated and feasible technique. There is no robust evidence for the use of HP in sepsis; however, some studies suggest a trend toward hemodynamic improvement and decreased mortality with its use. |
Coupled plasma filtration adsorption
Terminology
Technical aspects
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Blood flow rate (Qb): typically, 150–220 ml/min (max 250 ml/min).
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Plasma flow rate: 17–20% of the blood flow rate (35–40 ml/min).
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Ultrafiltration rate: max 2500 ml/h (equivalent to 35 ml/kg/h in a 70 kg patient).
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Replacement fluid (Qr): usually in post-dilution mode.
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Duration: daily for five days lasting for at least 10 h/day.
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Anticoagulation: the typical anticoagulant used is heparin, but citrate has been used safely [63] and may represent an attractive alternative given the high rate of clotting with CPFA.
The evidence
CPFA is feasible but evidence supporting its effectiveness to date is limited. Furthermore, it is expensive, labor-intensive, and associated with multiple technical issues that often lead to under-treatment. Well organized staff training programs are required when considering the utilization of this technique. |
Adverse events (the pitfalls)
Adverse events, such as exposure to extracorporeal circuit, antibiotic removal, loss of beneficial molecules, electrolyte imbalances, increased cost, and increased work load, should be carefully monitored. |