Published online Sep 16, 2023. doi: 10.12998/wjcc.v11.i26.6073
Peer-review started: April 21, 2023
First decision: June 14, 2023
Revised: July 4, 2023
Accepted: July 14, 2023
Article in press: July 14, 2023
Published online: September 16, 2023
Processing time: 139 Days and 23.9 Hours
The mortality rate from septic shock in patients with hematological malignancies (HMs) remains significantly higher than that in patients without HMs. A longer resuscitation time would definitely be harmful because of the irreversibly immunocompromised status of the patients. Shortening the resuscitation time through continuous renal replacement therapy (CRRT) with oXiris® would be an attractive strategy in managing such patients.
To explore the effects of CRRT and oXiris® in shortening the resuscitation time and modifying the host response by reducing inflammation mediator levels.
Forty-five patients with HM were diagnosed with septic shock and underwent CRRT between 2018 and 2022. Patients were divided into two groups based on the hemofilter used for CRRT (oXiris® group, n = 26; M150 group, n = 19). We compared the number of days of negative and total fluid balance after 7 d of CRRT between the groups. The heart rate, norepinephrine dose, Sequential Organ Failure Assessment (SOFA) score, and blood lactic acid levels at different time points in the two groups were also compared. Blood levels of inflammatory mediators in the 26 patients in the oXiris® group were measured to further infer the possible mechanism.
The average total fluid balance after 7 d of CRRT in the oXiris® group was significantly lower than that of patients in the M150 hemofilter group. The SOFA scores of patients after CRRT with oXiris® therapy were significantly lower than those before treatment on day 1 (d1), d3 and d7 after CRRT; these parameters were also significantly lower than those of the control group on d7. The lac level after oXiris® therapy was significantly lower than that before treatment on d3 and d7 after CRRT. There were no significant differences in the above parameters between the two groups at the other time points. In the oXiris® group, procalcitonin levels decreased on d7, whereas interleukin-6 and tumor necrosis factor levels decreased significantly on d3 and d7 after treatment.
CRRT with oXiris® hemofilter may improve hemodynamics by reducing inflammatory mediators and playing a role in shortening the resuscitation period and decreasing total fluid balance in the resuscitation phases.
Core tip: oXiris® is a high permeability polyacrylonitrile-based membrane with enhanced endotoxic blood adsorption and cytokine removal; it can be used either in continuous venovenous hemofiltration or continuous venovenous hemodiafiltration. In this study, we explored its effects of shortening the resuscitation time and modifying the host response by reducing levels of inflammatory mediators.
- Citation: Wang J, Wei SR, Ding T, Zhang LP, Weng ZH, Cheng M, Zhou Y, Zhang M, Liu FJ, Yan BB, Wang DF, Sun MW, Cheng WX. Continuous renal replacement therapy with oXiris® in patients with hematologically malignant septic shock: A retrospective study. World J Clin Cases 2023; 11(26): 6073-6082
- URL: https://www.wjgnet.com/2307-8960/full/v11/i26/6073.htm
- DOI: https://dx.doi.org/10.12998/wjcc.v11.i26.6073
The mortality rate from septic shock in patients with hematological malignancies (HMs) is significantly higher in the disease-related immunocompromised state or its management[1]. Septic shock is a subset of sepsis, clinically identified as a requirement for vasopressors to maintain the mean arterial blood pressure (MAP) ≥ 65 mmHg despite adequate fluid resuscitation and a lactate level > 2 mmol/L[2,3]. It is useful to consider different phases of fluid management in patients with septic shock over the course of acute illness, which are the resuscitation, optimization, stabilization, and evacuation phases[4]. However, patients with HM admitted to the intensive care unit (ICU) have an increased risk of hospital-acquired infection, which can deteriorate the patient’s condition and lead to high mortality[5]. Shortening the resus
This retrospective cohort study was conducted in the ICU of Hebei Yanda Hospital in China between January 1, 2018 and January 1, 2022. All patients were treated at the Ludaopei Hebei Yanda Hospital (a special hematological hospital) for HM before being diagnosed with septic shock and admitted to the ICU. Blood purification, as a standard approach to manage septic shock, was implemented as a host response modifier, using either the oXiris® membrane (observation group, n = 26) or the standard M150 hemofilter (AN69 membrane, control group, n = 19). All data were obtained from the electronic medical records of Hebei Yanda Hospital. This study was approved by the Ethics Committee of the hospital according to Chinese legislation.
Demographic data (sex and age), underlying disease, duration after the primary treatment, Acute Physiology and Chronic Health Evaluation II score on the day of admission to the ICU, infection site, possible pathogen, whether mechanical ventilation was used, length of ICU stay, survival, or death in the ICU were recorded. Blood, sputum, urine, and cerebrospinal fluid samples were obtained for bacterial cultures. We compared the days with negative balance (output > input) and total fluid balance (total liquid input minus total liquid output) 7 d after CRRT between the groups. The heart rate (HR), norepinephrine (NE) dose, Sequential Organ Failure Assessment (SOFA) score, and lactate blood levels at different time points in the two groups were also compared. Blood levels of inflammatory mediators [procalcitonin (PCT), interleukin (IL)-6, tumor necrosis factor (TNF)-α] in the 26 patients in the oXiris® group were evaluated to further infer the possible mechanism. Three days were needed to obtain a negative balance for the oXiris® group and 7 d for the control group. Renal therapy modality (CVVH or CVVHDF), the prescribed dialysis dosage, anticoagulant (citrate, heparin, or none), total duration of RRT during the ICU stay, and the number and duration of CRRT sessions performed with oXiris® membrane. The time in hours between ICU admission and the initiation of blood purification with the oXiris® membrane was also recorded.
The inclusion criteria were patients who: (1) Were diagnosed with HM; (2) were in septic shock on admission (met the diagnostic criteria of sepsis 3.0[2]); (3) received CRRT treatment (oXiris® filter or M150 filter) after admission; and (4) signed the informed consent, or their representative family members did. The exclusion criteria were as follows: (1) Failure to meet the inclusion criteria; and (2) ICU stay time < 48 h. The oXiris® group comprised 26 patients who met the inclusion criteria and underwent CRRT using the oXiris® membrane as a hemofilter. The control group included 19 patients who met the inclusion criteria but underwent CRRT using a standard M150 hemofilter (AN69 membrane).
All patients received standard treatment based on the Sepsis Bundle[3], including initial fluid resuscitation while pursuing source control, obtaining further laboratory results, and attaining more precise measurements of their hemodynamic status. All patients received organ function support (including invasive and noninvasive mechanical ventilation). The underlying condition (HM) of all patients was determined by the chief director of the original hematological department.
A temporary hemodialysis catheter in the femoral vein (12 Fr-20 cm for adults and 8.5 Fr-11 cm for children; Baihe Medical, Guangzhou, China) or internal jugular vein (11.5 Fr-15 cm for adults; Baihe Medical) was inserted under echographic guidance. CRRT was performed using either CVVHDF or CVVH. The adsorbing membrane oXiris® (Baxter, USA) or the M150 hemofilter (AN69 membrane; Baxter) was used through a Prismaflex CRRT system (Baxter) for the observation and control groups, respectively. Blood flow rates were designed to be 150–180 mL/min for adults and 50–100 mL/min for children, and the prescribed dialysis doses were in the range of 25–30 mL/kg/h based on tolerance. Citrate was used as an anticoagulant in the dialysis circuit via continuous infusion. The filters were changed either after clotting or after 72 h.
SPSS analyses were performed using IBM SPSS Statistics for Windows version 25. Normal distribution data are represented as mean ± SD and non-normal distribution data are represented by the quartile [p50 (p25, p75)]. Differences between the two groups were compared by independent sample t test; differences at different time points within a group were compared by repeated measurement analysis of variance; and multiple comparisons were made using the Bonferroni method. Differences between the two groups were compared using the nonparametric Mann–Whitney U test; differences at different time points within a group were compared using the nonparametric Friedman analysis; and multiple comparisons were made using the Bonferroni correction. The χ2 test was used to compare the differences in numerical data, and the Mann–Whitney U test was used to compare the differences in non-normal distribution data; for all analyses, P < 0.05 was considered statistically significant.
Overall, 45 patients were included in this study, with 26 in the observation group and 19 in the control group (Table 1). In the observation group, 69.23% (18 patients) were admitted after hematopoietic stem cell transplantation (HSCT), 23.08% (6 patients) after chemotherapy, and 7.69% (2 patients) after chimeric antigen receptor T-cell immunotherapy (CAR-T). Blood cultures tested positive for bacteria in 13 cases (50%), severe pneumonia in eight (30.77%), liver abscess in two (7.69%), severe acute pancreatitis in two (7.69%), and splenic abscess in one (3.85%). Nineteen patients (73.08%) were supported by invasive mechanical ventilation and seven (26.92%) by either a high-flow nasal cannula (HFNC) or face mask. The length of ICU stay ranged from 3 to 87 d and 17 patients (65.38%) survived in the ICU (mortality rate 34.6%).
| oXiris® group (n = 26) | CRRT group (n = 19) | χ2 | P value | |
| Management before | 0.309f | 1 | ||
| HSCT | 69.23 (18) | 68.42 (13) | ||
| Chemotherapy | 23.08 (6) | 19.23 (5) | ||
| CAR-T | 7.69 (2) | 5.26 (1) | ||
| Source of infection | 4.218f | 0.592 | ||
| Positive blood culture | 50 (13) | 63.15 (12) | ||
| Severe pneumonia | 30.77 (8) | 26.32 (5) | ||
| Liver abscess | 7.69 (2) | |||
| Severe acute pancreatitis | 7.69 (2) | |||
| Splenic abscess | 3.85 (1) | 5.26 (1) | ||
| Skin soft tissue infection | 5.26 (1) | |||
| Respiratory support | 0.002 | 0.964 | ||
| Invasive ventilation | 73.08 (19) | 73.6 (14) | ||
| HFNC or face mask | 26.92 (7) | 26.4 (5) | ||
| APACHE II | 26.5 (20.75, 32.25) | 29.5 (22.0, 31.25) | -0.431z | 0.667 |
| Outcome | ||||
| ICU stay (d) | 9.5 (5.75, 22.5) | 10.5 (6.5, 24.0) | 0z | 1 |
| Mortality (%) | 34.60 | 57.80 | 2.409 | 0.121 |
In the control group, 13 patients (68.42%) were admitted to the ICU after HSCT, five patients (19.23%) were treated with chemotherapy, and one (5.26%) was treated with CAR-T before ICU admission. Blood cultures tested positive for bacteria in 12 cases, severe pneumonia in five, skin soft-tissue infection in one, and splenic abscess in one. Of the 19 patients, 14 (73.6%) received invasive mechanical ventilation, whereas the others received either an HFNC or facemask oxygen. The length of ICU stay for these patients ranged from 3 to 49 d. Of the 19 patients, 11 died and eight survived, resulting in a mortality rate of 57.8% (Table 1).
Among the 26 patients in the oXiris® group, 18 received CVVH and eight received CVVHDF; 25 patients received citrate anticoagulant and only one did not receive any anticoagulation treatment. The start-up time of oXiris® was 0.5–48 h, and the number of oXiris® membranes used was 1–4. The total duration of the oXiris®–CRRT ranged from 24 to 215 h. Among the 19 patients in the CRRT group, 15 received CVVH and four received CVVHDF. Anticoagulation therapy was administered to 19 patients. The start-up time for CRRT was 1–28 h and the number of CRRT membranes used was 1–5. The total duration of oXiris®–CRRT therapy was 21–256 h (Table 2).
| 0.530 (χ2) | oXiris® group (n = 26) | CRRT group (n = 19) | χ2 | P value |
| CRRT | 0.530 | 0.467 | ||
| CVVH | 18 (69.2) | 15 (78.9) | ||
| CVVHDF | 8 (30.8) | 4 (21.1) | ||
| citrate | 96.15 (25) | 100 | 0.747f | 1 |
| No anticoagulation | 3.65 (1) | 0 | 0.747f | 1 |
| Time between ICU admission and initiation of blood | 5 (3, 21.25) | 15 (3, 22) | -0.761z | 0.447 |
| Total CRRT hours | 58 (48, 88.5) | 86 (39, 122) | -0.726z | 0.468 |
| Sessions | 2 (1, 2) | 2 (1, 3) | -1.141z | 0.254 |
We measured the fluid balance of patients treated with oXiris® and those in the control group during the first 7 d after CRRT commencement. We found that the oXiris® group had negative fluid balance from day 3 (d3) (273.55 ± 981.09 mL), whereas the control group reached a negative fluid balance on d7 (Figure 1). The total fluid balance in the oXiris® group was 213.54 ± 2243.22 mL compared with that of the control group, which was 3347.58 ± 4743.07 mL. The total fluid balance in the oXiris® group was significantly lower than that in the CRRT group (t = 3.034, P = 0.006) (Figure 2). The proportion of negative balance on d3 in the oXiris® group was 46.2%, and the proportion of negative balance on d3 in the CRRT group was 26.3%. The proportion of patients with a negative balance on d4 in the oXiris® group was 57.7%, and the proportion of negative balance on d4 in the CRRT group was 26.3%. On d4 of blood purification, the proportion of patients with a negative balance in the oXiris® group was significantly higher than that in the CRRT group (P = 0.036, Table 3).
The MAP of all patients was maintained above 65 mmHg during both types of treatment. The HR, NE dose, lactate levels, and SOFA scores of patients after CRRT with oXiris® therapy were significantly lower than those before treatment (HR: F = 6.743, P = 0.004; NE: H = 3 0.865, P < 0.001; SOFA: F = 7.864, P = 0.002) on d1, d3 and d7 after CRRT. The lactate levels of patients were significantly lower after CRRT with oXiris® therapy than before treatment (H = 21.963, P < 0.001) on d3 and d7 after CRRT. The HR, NE dose, and SOFA score of the oXiris® group were significantly higher than those of the control group on d7 (HR: t = 3.621, P = 0.001; NE: z = 2.931, P = 0.003; SOFA: t = 3.096, P = 0.004). There were no significant differences in the above indices between the two groups at other time points, and there were no significant differences in the lactate levels between the two groups at any of the specified time points. There were no significant differences in the above indices between different time points in the CRRT group (HR: F = 0.686, P = 0.566; NE: H = 3.488, P = 0.322; SOFA: F = 1.461, P = 0.24; lactate: H = 2.836, P = 0.418) (Figure 3).
The procalcitonin (PCT) before treatment was 15 ± 21 ng/mL; however, 7 d after treatment, it decreased to 3 ± 5 ng/mL (t = 2.235, P = 0.004). After oXiris® treatment, IL-6 and TNF-α levels were significantly reduced at 3 d (IL-6: t = 4.766, P < 0.001; TNF-α: t = 3.369, P < 0.001) and 7 d (IL-6: t = 4.805, P < 0.001; TNF-α: t = 3.998, P < 0.001) after treatment (Table 4).
Despite advances in the identification and treatment of sepsis, the outcome remains poor in patients with HM. Research published by Manjappachar et al[8] examined the effect of septic shock on patients with HM. They found that the mortality rate was 67.8% at 28 d and only 19.4% of the patients remained alive after 90 d[8]. Sepsis management includes three major aspects: infection control, hemodynamic stabilization, and host response modulation. Extracorporeal blood purification, using different systems to remove excess mediators and/or endotoxins, has been proposed as a host response modification method for the management of septic shock[9]. To date, a few studies have shown that some adsorption materials (polymyxin adsorption material[10,11], cytosorb filter[12], AN69 ST[13], and oXiris® filter[14]) affect septic shock treatment. The oXiris® membrane is a product based on the AN69 hydrogel structure. Several retrospective observational studies and two prospective observational studies have demonstrated the benefits of oXiris®[13,15]. Case data from these observational studies were mostly collected while the patients were under anesthesia or in the surgical intensive care[16]. Most of the results have confirmed that oXiris® endotoxin adsorption can effectively remove endotoxins and cytokines, reduce the inflammatory response, improve hemodynamics and the SOFA score when used during treatment of septic shock[12,17]. In a French two-center observational study, 31 patients with septic shock who were treated with oXiris® showed significant improvements in the hemodynamics and lactate levels, especially patients with abdominal or Gram-negative bacterial infections [18]. In a single-center study, CRRT with an oXiris® blood filter improved hemodynamic parameters in 35 patients with sepsis and severe renal insufficiency. The NE dose requirement, HR, and lactate levels decreased significantly [12,17,19,20]. In the current study, the oXiris®-endotoxin adsorption device was used in patients with septic shock and HM. In the observation arm, we found improved hemodynamics, as previously reported. The NE dose requirement, HR, and lactate levels decreased significantly (Figure 3). Moreover, we found that with the same septic shock protocol (international guidelines for the management of sepsis and septic shock 2021)[3], CRRT with oXiris® hemofilter resulted in negative fluid balance 4 d earlier than that by conventional treatment (Figure 1). The total fluid balance after 7 d of management was significantly lower in the observation group than in the control group (Figure 2). We infer that this may be a clinical sign after modifying the host response effectively. A positive fluid balance at 3 d is associated with significantly increased mortality[20]. Patients admitted to the ICU are at increased risk of developing hospital-acquired infection. A diagnosis of cancer alone increases the risk of sepsis by 3–5-fold, which further increases the risk of nosocomial infection, subsequently deteriorating results and leading to high mortality[5]. Therefore, it is particularly valuable for immunocompromised patients.
Studies have shown that the SOFA score can be an effective indicator for assessing the prognosis of HM as there may be a strong association between the mortality rate of patients admitted to the ICU and HM[21]. A retrospective cohort study conducted in China also found that the initial SOFA score on the day of admission to the ICU, coupled with the changes in the SOFA score during admission, was associated with survival outcomes, with a downward trend in the SOFA score predicting better patient outcomes[22]. Shum et al[23] found that patients with septic shock who were treated with oXiris® had a significant decrease in the SOFA scores at 48 h. Similarly, Adamik et al[24] found that the SOFA scores decreased from 14 to 7 at 3 d after oXiris® treatment. Our study demonstrated that the SOFA scores declined significantly on d3 and d7 post-treatment (Figure 3). PCT, IL-6 and TNF-α levels were significantly elevated before treatment. After oXiris® treatment, IL-6 and TNF-α levels were significantly lower than before treatment and PCT level in the blood was significantly decreased (Table 4). Turani et al[14] found that the use of the oXiris® filter significantly reduced the levels of circulating endotoxins IL-6 and IL-10. Broman et al[25] found significant reductions in endotoxin, IL-6, IL-8, TNF-α, and interferon-γ levels after treatment using oXiris® filter compared with a conventional filter.
The main limitations of the present study were its retrospective design and small number of study subjects. The others include: (1) No comparison of the changes in endotoxin levels before and after oXiris® treatment; since endotoxin activity was not measured in this study, the changes in endotoxin levels before and after oXiris® treatment could not be compared; (2) different treatments; the study subjects included in this study received different types of treatment, such as HSCT, chemotherapy, or CAR-T, perhaps representing different endotypes of septic shock; and (3) no evaluation of the life expectancy of the oXiris® filter. Currently, some experts suggest that the filter should be replaced within 24 h to achieve optimal results. Shum et al[23] used an oXiris® filter for 61 h, which effectively improved hemodynamics and organ function. Turani et al[14] applied each set of filters for approximately 24 h in their study. In our study, the mean time for each filter was 42 h. Further research is required to determine the optimal time for each filter and the overall optimal number/duration of treatments.
CRRT with an oXiris® hemofilter may be used as a host response modulation method in patients with septic shock and HM. This may improve the hemodynamic parameters by reducing the levels of inflammatory mediators. Clinically, it might play a role in shortening the resuscitation period and decreasing the total fluid balance in the resuscitation phase, thus reducing edema and decreasing the rate of hospital-acquired infection.
The mortality rate from septic shock in patients with hematological malignancies (HMs) remains significantly higher than that in patients without HMs.
Continuous renal replacement therapy (CRRT) with oXiris® might shorten the time from resuscitation to fluid negative balance. It may also improve hemodynamic parameters and decrease the blood levels of inflammatory mediators.
This study aimed to explore the effects of CRRT and oXiris® in shortening the resuscitation time as well as a modifier for the host response by reducing levels of inflammation mediators.
Patients with HMs who were diagnosed with septic shock and underwent CRRT were divided into two groups based on the hemofilter used. The days with negative balance and total fluid balance after 7 d of CRRT were compared between the groups. The heart rate, norepinephrine dose, Sequential Organ Failure Assessment (SOFA) score, and blood lactic acid levels at different time points in the two groups were also compared.
The average total fluid balance after 7 d of CRRT in the oXiris® group was significantly lower than that of patients in the M150 hemofilter group, and the SOFA scores of patients after CRRT with oXiris® therapy were significantly lower than those before treatment on day 1 (d1), d3 and d7 after CRRT; these parameters were also significantly lower than those of the control group on d7. Lactate levels after CRRT with oXiris® therapy were significantly lower than those before treatment on d3 and d7 after CRRT. In the oXiris® group, procalcitonin levels decreased on d7, and interleukin-6 and tumor necrosis factor- levels reduced significantly on both d3 and d7 after oXiris® treatment.
CRRT with oXiris® hemofilter might improve the hemodynamic parameters and play a role in shortening the resuscitation period, thus decreasing the total fluid balance in the resuscitation phase.
CRRT with an oXiris® hemofilter may be used as a host response modulation method in patients with septic shock and HM. This may improve hemodynamic parameters by reducing the levels of inflammatory mediators.
Provenance and peer review: Unsolicited article; Externally peer reviewed.
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Specialty type: Hematology
Country/Territory of origin: China
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P-Reviewer: de Vries PS, United States; Nathaniel T, United States S-Editor: Liu JH L-Editor: Kerr C P-Editor: Xu ZH
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