key: cord-294079-px9c20il
authors: Chua, Horng-Ruey; Laren, Graeme Mac; Choong, Lina Hui-Lin; Chionh, Chang-Yin; Khoo, Benjamin Zhi En; Yeo, See-Cheng; Sewa, Duu-Wen; Ng, Shin-Yi; Choo, Jason Chon-Jun; Teo, Boon-Wee; Tan, Han-Khim; Siow, Wen-Ting; Agrawal, Rohit; Tan, Chieh-Suai; Vathsala, Anantharaman; Tagore, Rajat; Seow, Terina Ying-Ying; Khatri, Priyanka; Hong, Wei-Zhen; Kaushik, Manish
title: Ensuring Sustainability of Continuous Kidney Replacement Therapy in the Face of Extraordinary Demand: Lessons From the COVID-19 Pandemic
date: 2020-06-04
journal: Am J Kidney Dis
DOI: 10.1053/j.ajkd.2020.05.008
sha: 
doc_id: 294079
cord_uid: px9c20il

With the exponential surge in coronavirus disease 2019 (COVID-19) patients worldwide, the resources needed to provide continuous kidney replacement therapy (CKRT) for patients with acute kidney injury or kidney failure may be threatened. This article summarizes subsisting strategies that can be implemented immediately. Pre-emptive weekly multi-center projections of CKRT demand based on evolving COVID-19 epidemiology and routine workload should be made. Corresponding consumables should be quantified and acquired, with diversification of sources from multiple vendors. Supply procurement should be stepped up accordingly, so that a several-week stock is amassed, with administrative oversight to prevent disproportionate hoarding by institutions. Consumption of CKRT resources can be made more efficient by optimizing circuit anticoagulation to preserve filters, extending use of each vascular access, lowering blood flows to reduce citrate consumption, moderating the CKRT intensity to conserve fluids, or running accelerated KRT at higher clearance to treat more patients per machine. If logistically feasible, earlier transition to intermittent hemodialysis with online generated dialysate, or urgent peritoneal dialysis in selected patients, may help reduce CKRT dependency. These measures, coupled to multi-center collaboration and a corresponding increase in trained medical and nursing staffing levels, may avoid downstream rationing of care and save lives during the peak of the pandemic.

Level 10 Medicine Office, National University Health System, Tower Block, 1E Kent Ridge Road, (S) 119228, Republic of Singapore.

Email: horng_ruey_chua@nuhs.edu.sg

The coronavirus disease 2019 (COVID-19) pandemic has led to a tragic loss of lives and the exponential rise in infections has overwhelmed healthcare systems with a surge in demand for critical care, along with continuous kidney replacement therapy (CKRT) for patients with acute kidney injury (AKI) or kidney failure. The reported incidence of KRT in ICU or mechanically-ventilated patients with COVID-19 ranges from 16-23% [1] [2] [3] [4] . The pandemic has placed unprecedented demands on the supply of CKRT machines and consumables, which is worsened by the global lockdown and disrupted supply chains. The provision of CKRT in an austere environment poses profound challenges in that traditional evidence-based management needs to be balanced with resource limitations, and pre-emptive planning has to be flexible based on the rapidly changing disease epidemiology and logistical considerations.

Our workgroup of nephrologists and intensivists from the 3 public healthcare clusters in Singapore have outlined strategies to ensure the medium-term sustainability of CKRT in the ICU during the peak of the COVID-19 pandemic. These strategies could be implemented immediately and would remain relevant for future contingency planning during similar healthcare crises. Specifically, we aimed to: (i) develop projections regarding the demand for CKRT that are revised weekly in accordance with prevailing rates; (ii) improve efficiency of existing care practices to avoid future rationing; (iii) optimize stocks of consumables by trimming current consumption and diversifying sources, while preventing hoarding; (iv) ramp up clinical and nursing training but maintain realistic workforce awareness; and most importantly, (v) collaborate widely at a national and regional level, and stay in close communication despite the social disconnect forced by COVID-19 (Fig.1) .

We first examined the annual consumption of CKRT fluids and estimated the current usage in the 8 publicly-funded acute care hospitals in Singapore, based on routine rates and a total capacity of 9,404 hospital beds 5 . We factored in another 586 acute-care beds in the National Centre for Infectious Diseases, which attends to the majority of hospitalized COVID-19 cases in Singapore. We projected incident COVID-19 cases per week based on current epidemiology 6 and inferred a corresponding CKRT incidence of 1% 1 , with an average 6 days of CKRT 7 . This allowed us to estimate the assets and consumables for standard CKRT support, and to predict the critical threshold of incident COVID-19 cases beyond which the CKRT capacity would be exceeded (Table.1 ).

We have diversified our sources of CKRT machines from multiple vendors to ensure a continuity of supply. In Singapore, these include the Prismaflex (Baxter, Lund, Sweden), multiFiltrate (Fresenius Medical Care, FMC, Homburg, Germany), Omni (B.Braun, Melsungen, Germany), Aquarius (Nikkiso, Langenhagen, Germany), and HF440 (Infomed, Geneva, Switzerland). Oversight of national demand is maintained to avoid disproportionate hoarding with respect to service load among institutions.

Different types of CKRT machines utilize different protocols and fluids for RCA.

These include the 0.5% citrate solution (diluted citrate concentration of 18 mmol/L) paired with an isonatremic, calcium-free, low bicarbonate solution 8 ; and 4% trisodium citrate (concentrated citrate of 136 mmol/L) paired with a low sodium, low bicarbonate, and calcium-free solution 9 . In the event that the fluids for either RCA regimens become depleted, an alternative in the form of anticoagulant-citrate-dextrose-A (ACDA) solution (containing at low volume is circuit-compatible with conventional isonatremic solution; the latter runs as a post-filter replacement if it contains calcium. Prescribers need to draft new protocols on alternative RCA regimens and initiate immediate clinical training in preparation for use of new machines.

Most machines allow common connector compatibility and cross-usage of fluids from various vendors without special adaptors, but there are exceptions in that certain machine types require specific fluids, limiting flexibility. Conventional CKRT fluids are mostly used in non-RCA circuits and contain physiological concentrations of electrolytes, including sodium 140 mEq/L, chloride 109 mEq/L, calcium 3 mEq/L, magnesium 1 mEq/L, and bicarbonate 35 mEq/L 11 . Some fluids include low quantities of organic anions such as lactate. CKRT fluids contain potassium at either 0, 2, or 4 mEq/L. Interchangeable conventional fluids should be actively sourced to maintain supply and connector compatibility to available machines. It is best to keep a consistent practice with regard to fluid potassium content to avoid its misadministration. Attention should be given to the glucose content because it affects caloric calculation and nutritional management during CKRT 12 . Pharmacy-compounded CKRT fluids reduce the dependency on commercially available options but intensive safety checks are essential 13, 14 .

CKRT filters and lines may be specific for certain machine types based on unique connectors; this restricts their diversification. Most current filter membranes are synthetic and high-flux. Prismaflex utilizes a filter made from a copolymer membrane of acrylonitrile and sodium methallylsulfonate (AN69) that is conjoined with lines. FMC and Nikkiso machines incorporate filter membranes made from polysulfone; the filters come separate from the lines, making the connection less restrictive, but the priming time may be longer. Filter membrane surface areas range from 0.9 to 1.9 m 2 for adult CKRT and institutions must work with the vendors to ensure a supply of filter sizes that correspond to the commonest range of body weight encountered in their practice. Certain filter membranes putatively aid immunoadsorption of cytokines 15, 16 ; it is unknown if these would be beneficial in COVID-19 patients, and their use should be reserved for specific indications or clinical trials.

Administrative oversight is vital to ensure adequate, diversified stocks of both tunneled and non-tunneled vascular catheters for KRT, as well as catheter sizes appropriate for various venous sites. Different catheter guidewire rigidity or dilatation techniques may affect the end-user competency in catheterization. Experienced proceduralists should be tasked with handling new catheter types so as to allow trainee operators to use catheters that they are familiar with. A common procurement process for ICUs and dialysis centers within the same institution would avoid duplication of efforts and excessive demand.

To ensure service sustainability, all domains of CKRT practice must be reviewed to ensure that adequate but rational care is delivered to current patients, with minimal compromise in service (Box 2).

Vascular access is an important determinant for delivery of efficient CKRT. A good access minimizes complications during insertion, limits the risk of catheter-related infections and thrombosis, and provides adequate uninterrupted blood flow for CKRT. Clinicians should optimize each vascular access to conserve resources, but remain mindful of unexplained leukocytosis and elevated inflammatory markers that suggest catheter-related infection, given that CKRT may mask fever 17 . It is prudent to ensure at least 7 days of use per non-tunneled vascular catheter, within which period the catheter colonization or infection rate is low 18, 19 . Systematic vascular catheter change in absence of complications is best avoided, as there is no clear threshold duration beyond which the risk of catheter-related bloodstream infection increases significantly in the ICU 18 . Choosing the most appropriate catheter site and size upfront minimizes downstream catheter dysfunction and interrupted CKRT, especially in COVID-19 patients on prone ventilation for extended hours daily.

Femoral venous access does not necessarily worsen the risk of malfunction during prone ventilation as compared with internal jugular venous access 20 , but the latter would be easier to monitor for bleeding or dislodgement.

Evidence of fibrinolytic therapy with alteplase or urokinase for catheter malfunction is extrapolated from maintenance hemodialysis and tunneled catheter studies 21 . While safety and efficacy is unclear in the context of CKRT, fibrinolytic therapy may provide rapid salvage of dysfunctional catheters, is non-invasive, and arguably leads to fewer vascular complications and lesser use of consumables than new catheterization. Extended femoral venous catheterization for CKRT and guidewire exchange of dysfunctional vascular catheters over an optimal sterile field can be performed with very low colonization or infection risk 19 . This helps conserve central venous sites, which is important because KRT may continue for weeks in AKI survivors 22 . Additionally, CKRT circuits may be combined in parallel with extracorporeal membrane oxygenation in patients 23 . For patients without COVID-19 who could be readily transferred for fluoroscopy, an initial tunneled vascular catheter over traditional non-tunneled-first approach is feasible and more efficacious for KRT 24 ; this helps conserve non-tunneled catheter stocks for COVID-19 patients. Existing arteriovenous access may be used for CKRT in patients with kidney failure; vigilance is advised for needle dislodgement, extravasation, and access hematoma 25 .

Measures to improve efficiency of CKRT fluid usage could potentially save 30% of cumulative consumption and help counter-balance the increase in demand (Table 1 and Fig. 2). The accepted intensity of CKRT is 25 mL/kg/h for most AKI patients in the ICU 26 ; this is subject to individual variations due to illness severity, catabolism, and acid-base and electrolyte derangements. There is a general consensus to prescribe approximately 30 mL/kg/h to achieve the desired CKRT dose in view of circuit downtime 27 ; a higher initial CKRT intensity may be associated with greater improvements in patients' hemodynamics and vasopressor requirements 28 . Concerns about the CKRT fluid supply, however, should prompt clinicians (if not required by severe hyperkalemia or acidosis) to order relatively lower dialysate and/or replacement fluid rates initially and up-titrate to achieve the desired intensity rather than the reverse. Furthermore, the net ultrafiltration augments the effluent rate, which determines the clearance. As CKRT progresses over days and the patient's kidney function improves, adequate clearance could be maintained at a CKRT intensity under 20 mL/kg/h 29 . Replacement fluid rate could also be reduced in tandem with increased ultrafiltration rate to maintain a constant effluent dose. Antibiotic and antiviral drug dosing need to be correspondingly adjusted with the changes in intrinsic kidney function and KRT dose to optimize the antimicrobial efficacy with adequate drug clearance. Individualized treatment goals and frequent reviews of the prescription could further reduce unnecessary fluid consumption.

Anticoagulation-free CKRT allows 12-16 hours of filter-life on average 30, 31 ; in conditions of shortage, this represents dangerously excessive use of filters, particularly given that dedicated filters are often needed for each machine type. The currency of contraindications to circuit anticoagulation must be actively reviewed and the longevity of filter targeted to a minimum of 2 days.

In Singapore, most ICUs adopted the RCA protocol that uses 0.5% citrate solution, which also serves as a replacement fluid contributing to at least half of the CKRT intensity and buffering capacity. With conventional blood flow settings and a citrate dose of 3.0 to 3.5 mmol per liter of blood, citrate consumption exceeds 1.5 L/h; the paired bicarbonate-based solution that contains potassium and magnesium is often maintained in proportion to the former for biochemical equilibrium. The resulting CKRT intensity usually exceeds 30 mL/kg/h to avert citrate accumulation. Reducing the blood flow towards 100 mL/min attains a more favorable citrate dose over total citrate delivery and reduces the metabolic burden, but a diffusive based therapy is preferred to avoid a high filtration fraction (Fig. 2) . In non-COVID-19 patients, citrate dose may even be lowered to 2.5 mmol/L, which is non-inferior to higher citrate dosing for an optimal filter life in general 32 .

In addition, we suggest a balance between RCA and heparinization to allow proportionate consumption of both. Importantly, premature filter clotting is commonly observed in COVID-19 patients 33 . This is postulated to be, in part, due to a hypercoagulable state, and systemic anticoagulation is frequently necessary to prolong filter life and manage thromboembolic complications 34, 35 . Monitoring anti-Xa activity is suggested during treatment with unfractionated heparin due to the numerous interactions with inflammatory proteins that interfere with activated partial-thromboplastin time prolongation 36 . A combined anticoagulation strategy with RCA-CKRT deployed concurrently to heparinized extracorporeal membrane oxygenation has been described in critically ill patients, with good filter life and no increased bleeding events 37 . Non-anticoagulation measures such as a predominant diffusive-based CKRT versus convective clearance would reduce circuit failures 38 . The optimal blood flow for circuit patency is unclear 39 , but needs to be adjusted for an appropriate filtration fraction in hemofiltration.

Purchasing CKRT machines is limited by supplier inventory and the substantial cost.

The continuous nature of CKRT implies a ratio of one patient to one machine, which becomes unsustainable as demand surges. It may be possible to treat 2 patients per machine within a 24-hour period by compressing the run of KRT to 10-12 hours at correspondingly higher clearance to compensate for efficacy 40, 41 . This accelerated KRT could be run as hemodiafiltration to optimize both dialysate and replacement fluid pumps and to accommodate the doubled fluid consumption rate. Admittedly such therapy would consume at least one filter per patient-treatment; moreover, the higher ultrafiltration rate could induce hemodynamic instability. Although the strategy saves on the nursing hours and machines, avoids prolonged circuit anticoagulation, and reduces cumulative heparin consumption, it does not save on effort, filters, and fluids. Antimicrobial administration would need to be staggered to be delivered post treatment, and the dose moderated with transition from CKRT. Therapy may even be staggered according to pre-determined treatment goals as not all patients would require an augmented solute clearance even if the duration is shortened, and KRT could be terminated once targets are reached (such as the case for targeted correction of hyperkalemia and acidosis in patients with kidney failure). Ultrafiltration could be geared towards a projected negative balance required for the day and achieved in the initial hours of therapy. This approach can be adopted in patients with relatively improved stability, lower vasoactive drug requirements, and less complex metabolic derangements.

Clinicians could allow an earlier transition to intermittent hemodialysis using online generated dialysate, but the latter will also be subject to resource constraints, including water supply, drainage, and reverse osmosis machines. The nursing requirement with intermittent hemodialysis is less compared with that of CKRT (Table.1 ).

In selected patients with AKI, peritoneal dialysis (PD) may be advantageous over extracorporeal KRT 42 . Similar mortality has been reported in both 43 . Technical simplicity, minimal infrastructural requirements, lack of requirement for anticoagulation, and less nursing time make PD especially attractive in pandemics. Flexible PD catheters are preferred over rigid catheters due to a higher risk of complications and peritonitis associated with the latter, and the high dialysate flow rates achieved with the former 44 Manual PD exchange remains an option, but PD is best delivered using an automated cycler to optimize staff time and usage of personal protective equipment. Icodextrin dwell during prone ventilation alternating with cycler usage when supine may meet fluid removal and clearance targets, whilst overcoming drainage issues and alarms.

While recognizing the difficulties in clearance measurement in the context of a pandemic, titration to best possible solute and volume balance is essential. Weekly Kt/V urea of 3.5, which matches the dose of daily hemodialysis, is recommended 46 . With a dialysate to plasma urea ratio of 0.6 in one hour 47, 48 , 30-40 L of daily PD exchange volume, may be required in a 70 kg patient. In some patients, weekly Kt/V urea of 2.1 may be acceptable 46, 49 .

Non-PD trained aides or volunteers could also be trained specially to deliver manual PD exchanges in service exigencies 50, 51 .

A CKRT program cannot be implemented without the integral contribution of nurses.

Projections of staffing needs in tandem with increasing CKRT demand is detailed in Table. 1, and the training needs to start pre-emptively. Nursing staff have to monitor circuit dynamics, titrate volume management, ensure metabolic stability during RCA, and perform infection control 52 . The complexity increases with diversification of machines, platforms, filters, fluids, and RCA protocols. A close collaboration between critical care and nephrology nursing is highly desirable. It may be more efficient to have a core group of nursing supervisors to oversee machine assignments, perform the initial setup, and train a larger pool of bedside nurses to monitor ongoing CKRT. Involvement of the lead nurses, along with physicians, in drafting new protocols would provide concurrent education to rapidly increase everyone's domain knowledge. If physicians and nurses from departments other than the ICU and nephrology will be needed, particular care should be given to developing easily accessible and simplified protocols, as well as audiovisual learning aides that are accessible in the ICU or hospital intranet.

Many large hospitals run several ICUs and CKRT machines are often forwardallocated to individual ICUs for routine deployments. In the context of a pandemic, demands may become unpredictable, and there is a need for responsive allocation (and re-distribution) of machines to areas experiencing a surge in patient load. It is vital to share information across institutions regarding patient-level CKRT needs, as well to understand the supply chain that vendors employ so as to pre-empt threats to resource availability at the national and regional level. A centralized machine and patient census would help administrators coordinate, track, and optimize utilization. To minimize therapy downtime due to technical issues, pre-emptive machine maintenance is necessary despite the movement restrictions in force. The usage of consumables and resupply should be tracked weekly to allow a greater lead time to respond to any supply chain disruptions.

It is imperative that critical care and nephrology teams work together to address shortfalls in life-saving medical treatments exposed by the pandemic. CKRT provision is only a part of the end-to-end management of patients with critical illness and kidney diseases.

Upstream management to optimize volume balance and lung-protective ventilation may help moderate AKI severity in patients with acute respiratory distress syndrome, and prevent deterioration to the point that KRT is required. Many survivors of KRT-requiring AKI develop chronic kidney disease 53, 54 , and long-term management needs to be planned for them. A careful review of current practice patterns with good clinician oversight of resource limitations could potentially save lives by preventing an undesired rationing of care during the peak of a pandemic.

Support: None. Financial Disclosure: Dr Chua reports prior research funding from Baxter in an investigator-initiated trial on CKRT. Dr Kaushik reports speaker fees from Baxter and Fresenius Medical Care. The remaining authors declare that they have no relevant financial interests.

Peer Review: Received April 25, 2020. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form May 27, 2020.

Hirsch JS, Ng JH, Ross DW, et al. Acute kidney injury in patients hospitalized with COVID-19. Kidney Int. 2020.

Ministry of Health Singapore. Beds in inpatient facilities and places in non-residential long-term care facilities. Resources & Statistics 2019.

https://www.moh.gov.sg/resources-statistics/singapore-health-facts/beds-in-inpatientfacilities-and-places-in-non-residential-long-term-care-facilities. Accessed 17 April 2020.

Ministry of Health Singapore. COVID-19 situation report.

https://www.moh.gov.sg/docs/librariesprovider5/2019-ncov/situation-report---24-apr-2020.pdf. Accessed 24 April 2020.

Intensive CKRT: continuous kidney replacement therapy; mM: mmol/L; PBP: pre-blood pump; Qb: blood flow rate; RCA: regional citrate anticoagulation; UF: ultrafiltration.

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Assumptions used for calculating consumption levels in the absence of conservation strategies are shown in the top half of Box 1. ACDA: anticoagulant-citrate-dextrose-A solution; CKRT: continuous kidney replacement therapy; HD: intermittent hemodialysis; IU: international units; Qb: blood flow rate

Box 1. Assumptions and Conservation Strategy Practices for Projections of CKRT Needs Assumptions for calculating consumption under standard conditions • 50% RCA circuits; 50% circuits using conventional / non-RCA fluids • Protocols used for RCA circuits: ACDA (10%)