Evaluation of the safety and efficacy of extracorporeal carbon dioxide removal in the critically ill using the PrismaLung+ device

Background Several extracorporeal carbon dioxide removal (ECCO2R) devices are currently in use with variable efficacy and safety profiles. PrismaLung+ is an ECCO2R device that was recently introduced into clinical practice. It is a minimally invasive, low flow device that provides partial respiratory support with or without renal replacement therapy. Our aim was to describe the clinical characteristics, efficacy, and safety of PrismaLung+ in patients with acute hypercapnic respiratory failure. Methods All adult patients who required ECCO2R with PrismaLung+ for hypercapnic respiratory failure in our intensive care unit (ICU) during a 6-month period between March and September 2022 were included. Results Ten patients were included. The median age was 55.5 (IQR 41–68) years, with 8 (80%) male patients. Six patients had acute respiratory distress syndrome (ARDS), and two patients each had exacerbations of asthma and chronic obstructive pulmonary disease (COPD). All patients were receiving invasive mechanical ventilation at the time of initiation of ECCO2R. The median duration of ECCO2R was 71 h (IQR 57–219). A significant improvement in pH and PaCO2 was noted within 30 min of initiation of ECCO2R. Nine patients (90%) survived to weaning of ECCO2R, eight (80%) survived to ICU discharge and seven (70%) survived to hospital discharge. The median duration of ICU and hospital stays were 14.5 (IQR 8–30) and 17 (IQR 11–38) days, respectively. There were no patient-related complications with the use of ECCO2R. A total of 18 circuits were used in ten patients (median 2 per patient; IQR 1–2). Circuit thrombosis was noted in five circuits (28%) prior to reaching the expected circuit life with no adverse clinical consequences. Conclusion(s) PrismaLung+ rapidly improved PaCO2 and pH with a good clinical safety profile. Circuit thrombosis was the only complication. This data provides insight into the safety and efficacy of PrismaLung+ that could be useful for centres aspiring to introduce ECCO2R into their clinical practice.


Background and rationale
Acute respiratory failure is one of the most common indications for admission of patients to the intensive care unit (ICU).Many of these patients require the assistance of invasive mechanical ventilation (IMV) in the management of respiratory failure.A strategy of preventing ventilator induced lung injury (VILI) by reducing inspiratory pressures and the driving pressure on IMV has been shown to reduce mortality [1,2].The current standard of care in treating patients with acute hypoxic respiratory failure is to use low tidal volume (< 6 ml/kg predicted body weight) ventilation [3].One of the effects of such a ventilation strategy is the development of hypercapnia and related respiratory acidosis.Several recent studies have highlighted the adverse effects of hypercapnia when associated with lung protective ventilation [4][5][6][7][8].Based on the evidence from these studies, hypercapnia should be avoided or actively treated when associated with lung protective ventilation.
There are several minimally invasive extracorporeal carbon dioxide removal (ECCO 2 R) devices that are currently available for the management of patients with severe hypercapnic respiratory failure [9][10][11][12][13].Most of these devices provide partial respiratory support as compared to extracorporeal membrane oxygenation (ECMO), where total respiratory support can be provided.These devices are mainly used to remove CO 2 from the blood to provide lung protective ventilation [14,15].Most of these less invasive devices are efficient in clearing CO 2 but do not provide significant oxygenation [12,13,16].The cannulas used to access blood vessels are smaller (13-16 F) in low-flow ECCO 2 R devices but can be cannulas similar to ECMO in highflow devices.The anticoagulation targets are similar to other extracorporeal devices, such as renal replacement therapy circuits and ECMO devices.A recent study, however, observed a higher incidence of bleeding and haemolysis with low-flow ECCO 2 R devices [17].
The use of minimally invasive ECCO 2 R devices was reported in several studies with satisfactory clearance of carbon dioxide [9][10][11][12]18].However, some studies reported a higher incidence of complications such as haemolysis, bleeding, and inadequacy of obtaining satisfactory carbon dioxide clearance with the use of lowflow devices ECCO 2 R devices [17,[19][20][21].
One of the newer devices is called PrismaLung+ [22], which was recently introduced to clinical practice.Pris-maLung+ is a low flow venovenous ECCO 2 R device that can provide CO 2 removal with or without simultaneously providing renal replacement therapy.

Aims and objectives
This study aimed to evaluate the safety and efficacy of ECCO 2 R with PrismaLung+ in mechanically ventilated critically ill patients.

Ethics approval
The human research ethics committees of Peninsula Health reviewed the study proposal and waived the requirement for a full ethics committee application (QA/89504/PH-2022-330245).This was because the study was seen as a retrospective audit of data routinely collected for patient care and not experimental research.Consent from individual patients was not required, since the research was limited to the use of information previously collected during normal care and the patients were not identifiable.
All mechanically ventilated patients with acute or acute-on-chronic hypercapnic respiratory failure, managed with ECCO 2 R over a period of 6 months (March 2022 to September 2022) in our hospital were included.

ECCO 2 R with PrimaLung +
PrismaLung+ (Fig. 1) is a novel low flow venovenous device that integrates renal and respiratory extracorporeal supports.A detailed description of this device is provided elsewhere [23,24].It incorporates a gas exchange membrane made of polymethylpentene hollow-fiber mats, into Prismax (Baxter Healthcare Pty Ltd.) renal replacement system with or without the use of a haemofilter within the circuit [24].Pris-maLung+ has a larger gas exchange membrane surface area (0.8 m 2 ) as compared to the earlier version of Pri-maLung+ with a lower surface area (0.35 m 2 ) making this a more effective device [24].The total priming volume of the circuit is 273 mL.

Patient management on ECCO 2 R
Access to blood flow was obtained by a 13F doublelumen catheter either via a femoral or jugular vein.Catheter insertion was performed using real-time ultrasound guidance.Heparin was used for anticoagulation, aiming for an Activated Partial Thromboplastin Time (APTT) of 50-70 s.Blood flow was established at a rate of 200 mL/ min to 250 mL/min.Oxygen was used as sweep gas.The sweep gas flow was gradually increased to 10 L/min to provide effective ECCO 2 R.After lung recovery, ECCO 2 R weaning was initiated by down-titrating sweep gas flow and thereby reducing the amount of CO 2 removal to zero.After confirming adequate respiratory function, ECCO 2 R was disconnected from the patient at the discretion of the treating intensivist.
Low tidal volume (≤ 6 mL/kg ideal body weight), and low-pressure ventilation were targeted for all patients included in this study, with no pre-specified protocol on the mode of IMV.Asthmatic patients were mechanically ventilated with a low tidal volume (5-6 mL/kg), a low respiratory rate (10-12 breaths/min), and a short inspiratory time associated with prolonged expiratory time to avoid dynamic hyperinflation.

Indications for the use of ECCO 2 R
Patients were managed with ECCO 2 R at the discretion of the treating intensivist if the patient was receiving IMV but could not be ventilated with lung protective ventilation (tidal volumes ≤ 6 mL/kg of ideal body weight) due to hypercapnic respiratory failure (respiratory acidosis (pH < 7.25 and pCO 2 > 55 mmHg).

Contraindications to ECCO 2 R
• Contraindication for limited anticoagulation (Heparinisation to achieve an APTT of 50-70 s or an activated clotting time (ACT) of 150-180 s).• Platelet count of less than 75,000/mm 3 .
• Patients who had established treatment limitations (i.e., not for cardiopulmonary resuscitation, or admitted to ICU for palliative care or organ donation purposes, not for intubation, mechanical ventilation, and not for continuous renal replacement therapy in ICU).

Primary outcome measure
CO 2 clearance and improvement in pH with the use of ECCO 2 R.

Secondary outcome measures
• Complications associated with ECCO 2 R • Survival to weaning from ECCO 2 R, ICU and hospital discharge.
Complications: Classified as patient-related or device-related. Patient-related:

Results
A total of ten patients received ECCO 2 R during the study period.The demographic, diagnosis, and outcome data are presented in Table 1.A summary of the patients, including duration of ECCO 2 R, complications, survival and the cause of death is presented in Table 2. Figure 2 shows changes in pH and PaCO 2 before initiation and at successive time points.Figure 3 shows changes in minute ventilation and peak inspiratory pressure before initiation and at successive time points.therapy.The minute ventilation showed a reduction by day 1 of ECCO 2 R initiation.A reduction in peak inspiratory pressures was noted on day 2 after the initiation of ECCO 2 R.There were no bleeding complications noted with the use of ECCO 2 R, but two patients required blood transfusions (one patient received four units and the other two units) largely due to loss of blood due to circuit changes and haemodilution.There were no other patientrelated complications.A total of 18 circuits were used in ten patients (median 2 per patient; IQR 1-2).Circuit thrombosis was noted in five circuits (28%) that required replacement of the circuit prior to reaching the expected circuit life.It was due to a lack of anticoagulation at the time of initiation of ECCO 2 R, in one of these patients.No other device-related complications were noted.The survival to weaning of ECCO 2 R, ICU, hospital discharge, and cause of death are presented in Tables 1 and 2. Three patients required tracheostomy during their ICU course.All patients who survived were discharged home.

Key findings
In this 10-patient case series to assess the efficacy of PrismaLung+ in correcting hypercapnic acidosis, we found that ECCO 2 R significantly improved hypercapnic acidosis within 30 min and maintained normal pH and normocapnia throughout the therapy while reducing minute ventilation and inspiratory pressure.There were no patient-related complications associated with the use of this device.Circuit thrombosis within 72 h of initiating ECCO 2 R was noted in four patients and was the only device-related complication that was noted in this study.The factors that may have contributed included poor vascular access that was noted in one patient due to the catheter inserted in the jugular vein and inadequate anticoagulation in another patient.Experience with the use of the device may help reduce the incidence of such complications.

Relationship with previous studies
Several ECCO 2 R devices are currently in use with variable performances.PrismaLung+ is a novel device with the advantage of providing both ECCO 2 R and renal replacement therapy (RRT) with a single access catheter.The similarity of the device with RRT makes use of this device easier in intensive care units that currently use RRT.The results of our study in terms of CO 2 removal are comparable to other studies with higher blood flows (350-550 mL/min) [16,21].This is due to the fact that the larger surface area of the membrane offsets the relative lower blood flow rates of 200-250 mL/min that were able to achieve with PrimaLung+ [25].
Our indication for the use of PrismaLung+ was different from some of the recent studies, where ECCO 2 R devices were used to target ultra-protective ventilation [9,21].Targeting ultra-protective ventilation did not improve 90-day mortality and was associated with lower ventilation-free days in patients with a PaO2/FiO2 of less than 150 mmHg [21].Given these results, our aim was to first investigate if PrismaLung+ had the efficacy of removing CO 2 with comparably lower flow rates (200 to 250 mL/min) when the low tidal volume (≤ 6 mL/kg of ideal body weight) caused hypercapnic acidosis.Our results suggest that PrismaLung+ was effective in the removal of CO 2 and thereby correcting the hypercapnic Table 2 Summary of patients managed with PrismaLung+ acidosis associated with low tidal volume ventilation.The safety and efficacy of PrismaLung+ with ultralow tidal volume ventilation remain to be evaluated.
From the published data, ECCO 2 R devices while being effective in removing CO 2 , they have not been shown to improve survival, especially in patients with severe ARDS [9,21].Such patients with severe ARDS, are likely to benefit from VV ECMO [26].Patients with mild to moderate ARDS associated with hypercapnic acidosis may benefit from low-flow ECCO 2 R devices [16].
The published literature on the use of this device is limited [20,27,28], with only one study reporting on the exclusive use of PrismaLung+ in mechanically ventilated patients with hypercapnic acidosis [27].Similar to the results of our study, the study by Consales and colleagues reported a rapid correction of hypercapnic acidosis with no treatment-related complications [27].The study by Giraud and colleagues [20] reported that PrismaLung+ was not able to remove sufficient CO 2 , to correct hypercapnic acidosis in three patients with severe COPD.In our case series, two patients had COPD, and Pris-maLung+ satisfactorily improved hypercapnic acidosis.
In previous studies, low-flow ECCO 2 R devices were shown to have a higher proportion of haemolysis, bleeding, and membrane clotting as compared to high-flow ECCO 2 R devices [17,19].In our study, we did not find any similar clinical complications with PrismaLung+ such as bleeding or haemolysis other than the clotting of the circuit within 72 h after initiation of the ECCO 2 R in five circuits.

Study implications and future directions
This study provides preliminary data on the safety and efficacy of ECCO 2 R with PrismaLung+ in mechanically ventilated patients.Further data on the efficacy of this device is required to determine whether it will reduce tidal volumes and driving pressure and thus improve survival in patients with ARDS.

Strengths and limitations
Strengths: This study provides further evidence of the use of PrismaLung+ as an intervention to correct hypercapnic acidosis in patients receiving low tidal volume ventilation.The study results provide insights into the clinical efficacy and safety profile of the device that may help clinicians who may be considering the introduction of ECCO 2 R to their clinical practice.It reports data on physiological and patient-centred outcomes, especially the safety of this device.

Limitations
Our study included patients, in whom lower tidal volumes were used.The efficacy of this device to provide satisfactory CO 2 clearance in patients receiving ultralow tidal volumes was not evaluated in our study.We used an increase in serum bilirubin or anaemia that is not due to other obvious causes, as a marker of haemolysis.They may not be as sensitive as other investigations, such as haptoglobin or free haemoglobin for haemolysis.Given the single-centre experience of our study, the results may not be generalisable.

Conclusions
ECCO 2 R with the use of PrismaLung+ appears safe, and effective in correcting hypercapnic acidosis.This data provides insight into PrismaLung+ performance and potential complications that could be useful for centres aspiring to introduce ECCO 2 R into their clinical practice.Further studies are required to evaluate its use in reducing driving pressure and associated lung injury, which may contribute to an improvement in clinical outcomes, including a reduction in the duration of mechanical ventilation and the associated morbidity and mortality.

Fig. 3
Fig. 3 Changes in peak inspiratory pressure, minute ventilation, tidal volume and respiratory rate before initiation and at successive time points.Error bars represent 95% confidence intervals All analyses were performed using SAS software version 9.4 (SAS Institute, Cary, NC, USA) and SPSS version 22 (IBM SPSS, Armonk, NY).
using means and standard errors.To account for repeat measures, data were analysed using the PROC MIXED procedure in SAS with each patient treated as a random effect.Time was treated as a categorical variable to facilitate specific comparisons.A two-sided P < 0.05 indicated statistical significance.

Table 1
Table 3 shows mean changes in minute ventilation, peak inspiratory pressure, PaCO 2 , PaO 2 , pH, respiratory rate and tidal volume before initiation and at successive time points.A significant reduction in PaCO 2 and improvement in pH were noted within 30 min of initiation of ECCO 2 R.These clinically important changes persisted throughout the Summary of clinical characteristics and outcomes of patients receiving ECCO 2 R

Table 3
Mean changes in minute ventilation, peak inspiratory pressure, PaCO 2 , PaO 2 , pH, respiratory rate and tidal volume before initiation and at successive time points