In-house Production of Dialysis Solutions to Overcome Challenges during the COVID-19 Pandemic

Abstract

Background The coronavirus disease 2019, known as COVID-19, has affected >30 million people globally, leading to more than 900,000 deaths. 1 Many healthcare systems have faced significant challenges in providing care for overwhelming numbers of patients due to resource constraints. The United Kingdom (UK) is one of the most affected countries, and by September 17th, 2020, 381,614 people were confirmed COVID-19 positive, 41,705 had died, and 13,710 had been admitted to critical care. 1 , 2 Acute kidney injury (AKI) was reported in 25-78% of critically ill patients and approximately 25% required renal replacement therapy (RRT).2, S1-S3 London was the epicenter for infection in the UK and as cases surged, there was an unprecedented increase in demand for RRT. This demand rapidly outstripped commercial availability of RRT fluids, consequently leading to critical shortages in some parts of the world including India, New York, and London. 3 , 4 ,S4 In response, the UK National Health Service (NHS) centralised the procurement process in order to oversee the supply chain and to allocate resources proportionately. However, ultimately NHS procurement was only able to allocate fluids based on the available supply rather than on the overall patient need, which resulted in significant pressure on clinical services. Existing renal and critical care services worked closely together to provide renal support, alternate modes of dialysis were explored and in some instances, patients were transferred to centres with greater RRT capacity. Indications for dialysis were also reviewed to allocate RRT in the most efficient manner. During the peak period, provision of renal support was adjusted daily, due to changes in patient numbers, dynamic changes in the supply chain, and availability of fluids and consumables. Between March 3rd and June 13th, 2020, 331 critically ill COVID patients were admitted to the expanded critical care units at Guy’s & St Thomas’ NHS Foundation Trust (GSTT). At the peak, there were 130 patients in ICU of whom 44 required RRT. At this point, 34 continuous renal replacement therapy (CRRT) machines were available, but there was a major shortage of RRT fluids. Despite various actions, fluid shortages meant that CRRT capacity was reached and a contingency working group was formed to develop a program for the in-house production of dialysis solutions. The aim of this paper is to report our experience of the manufacture and use of in-house dialysis solutions during the pandemic in critically ill patients with severe AKI. This will assist preparations for future surges in both resource-rich and resource-poor countries. Summary of Methods On April 16th, 2020, an emergency multi-disciplinary working group was formed with representation from pharmacy, renal critical care nurses, and medical staff, to produce dialysis fluid for continuous venovenous haemodialysis (CVVHD) in-house. The formula, composition and electrolyte concentration of the two selected dialysis solutions compared with commercial fluids are shown in Table 1 and 2 ; Formula 1 (low bicarbonate solution) and Formula 2 (high bicarbonate solution). To minimise manipulations, the GSTT formulation did not contain any potassium (K), magnesium (Mg) or glucose. Calcium was not added either, in order to prevent precipitation with bicarbonate and to use the fluid as calcium-free dialysate with RCA. Nursing and medical staff protocols were adopted to ensure patient safety including the need for at least one arterial blood gas, including pH, bicarbonate (HCO3), sodium (Na), potassium (K), ionised Ca (iCa) concentration, and glucose measured every 2-4 hours. Serum magnesium and phosphate concentrations were measured routinely every day. Table 1 Fluid composition of each formula Compositions Formula 1 Formula 2 Sodium chloride 0.9% 2 L 2.5 L Sodium bicarbonate 1.26% 0.5 L - Sodium bicarbonate 8.4% - 0.1 L Sterile water for injections 0.5 L 1 L Total 3 L 3.6 L Table 2 Comparison of electrolyte components, volume, and osmolarity between commercial fluids and the GSTT Formula 1 and 2 Electrolyte concentration (mmol/L) Fluids compatible with citrate-based anticoagulation Fluids compatible with non-citrate anticoagulation Fluid based on GSTT Formula 1 Fluid based on GSTT Formula 2 CiCa® K2 CiCa® K4 Prism0Cal® (Baxter) PureflowTM (NxStage) MultiBic® (Fresenius) Prismasol® (Baxter) Accusol® (Nikkiso) PureflowTM (NxStage) Na+ 133 133 140 140 140 140 140 140 128 135 K+ 2 4 2-4 0-4 0-4 0-4 0-4 0-4 - - Mg2+ 0.75 0.75 0.5-0.75 0.75 0.5 0.75 0.5 0.5-0.75 - - Ca2+ - - 0 0 1.5 1.25-1.75 1.75 0-1.5 - - HCO3 - 20 20 22 25 35 32 35 35 25 28 Cl- 116.5 118.5 108-120.5 108.5-120.5 111-113 109-113 109.5-113.5 109-113 102.7 107 PO4 2- - - - - - - - - - - Glucose 5.55 5.55 6.1 5.55 5.55 5.55 5.55 5.55 - - Volume (L) 5 5 5 5 5 5 5 5 3 3.6 Theoretical osmolarity (mosm/L) 278 282 286-296 286-294 292-300 292-300 292-300 292-300 256 270 AbbreviationsNa+, sodium; K+, potassium; Mg2+, magnesium; Ca2+, calcium; HCO3-, bicarbonate; Cl-, chloride; mOsm; milliosmole; PO42-, phosphate; L, litre GSTT has an approved aseptic preparation unit, used primarily for the preparation of bespoke adult parenteral nutrition (PN) solutions. This RRT fluid production process entailed the aseptic filling of PN bags from bulk sterile solutions in a European Union (EU) Good Manufacturing Practice (GMP) Grade A environment.S5 The time taken for the preparation of each bag was 4 minutes, and 80 minutes for each batch. In line with the department’s standard procedures, a stability test protocol was developed to confirm solution stability over a 7-day period. (Supplementary Table S1) There was capacity to produce up to 60 bags of 3.6 L of GSTT formulation RRT fluid during working hours. The critical care pharmacy team worked closely with the critical care renal specialist nurses, and the pharmacy manufacturing team to ensure judicious production and to minimise waste. Fluid manufacturing requirements were assessed every two to three days depending on projection of ongoing needs. Here, we report the evaluation undertaken after the first two weeks of fluid production (April 17th to May 1st, 2020). To assess clinical efficacy, we evaluated changes of serum electrolytes (Na, K, calcium (Ca), magnesium (Mg), bicarbonate (HCO3), acid-base status [pH, base excess (BE)] at baseline and 2, 4, and 6 hours after RRT initiation of all sessions. We further categorised patients according to whether they had received RRT with fluid based on Formula 1 versus Formula 2, and citrate versus non-citrate anticoagulation. For assessment of safety aspects, we evaluated the proportions of patients who developed arrhythmias including atrial fibrillation, ventricular tachycardia, ventricular fibrillation, and significant metabolic disturbances as specified by departmental protocols (serum K <3.5 mmol/L, serum iCa <1.0 mmol/L, serum Mg <0.7 mmol/L, metabolic alkalosis defined as pH >7.5, BE >5, or HCO3 concentration >30 mmol/L, and blood glucose <4 mmol/L), and requirement for additional electrolyte supplementations. Results Between 17th April and 14th May 2020, a total of 880 GSTT formulation dialysis bags were manufactured. We audited the use of 186 bags of fluid in 25 patients (total 42 sessions) between 17th April and May 1st, 2020. Fluids based on Formula 1 and Formula 2 were used in 13 (31.0%) and 29 sessions (69.0%), respectively. Thirty (71.4%) and 12 (28.6%) sessions were delivered using RCA and systemic heparin, respectively. The median duration for using K0 GSTT bags was 5 hours (interquartile range (IQR) 2-8; range 1-23) and the median number of bags per session was 4 (IQR 2-5; range 1-15). The median blood flow rate was 100 mL/min (IQR 80-150; range 60-300), and median prescribed dose was 26.67 mL/kg/hr (IQR 20.62-35.17; range 12.73-53.40). Clinical data When using GSTT produced fluid, serum potassium concentrations fell from 5.21 ± 0.63 to 4.33 ± 0.37 mmol/L over 6 hours (p < 0.001). There were also significant increases in pH, HCO3 -, BE, and decrease in chloride over 6 hours but no significant changes in pCO2, sodium, lactate, iCa, glucose or magnesium. (Table 3 , Figure 2 ) Table 3 Changes of electrolytes, acid-base status, and glucose from baseline until 6 hours (n=42) Hour 0 (n=42) 2 (n=40)a 4 (n=24)a 6 (n=21)a p value pH 7.35 ± 0.08 7.37 ± 0.07∗ 7.36 ± 0.08** 7.38 ± 0.08*** 0.002 * pCO2 [kPa] 6.37 ± 1.51 6.18 ± 1.10 6.66 ± 1.70 6.46 ± 1.28 0.75 Na [mmol/L] 141.31 ± 5.17 141.59 ± 4.07 140.84 ± 3.65 141.13 ± 2.92 0.65 K [mmol/L] 5.21 ± 0.63 4.80 ± 0.51∗ 4.50 ± 0.38** 4.33 ± 0.37*** <0.001 Cl [mmol/L] 101.38 ± 3.00 101.22 ± 2.84 100.69 ± 2.76 99.66 ± 2.40*** <0.001 HCO3 [mmol/L] 25.49 ± 3.10 25.31 ± 5.01 27.44 ± 3.02** 27.46 ± 3.10*** 0.02 BE -0.33 ± 3.26 0.56 ± 3.42∗ 1.70 ± 3.21** 2.03 ± 3.31*** <0.001 Lactate [mmol/L] 1.32 ± 0.50 1.38 ± 0.38 1.38 ± 0.46 1.34 ± 0.42 0.84 iCa [mmol/L] 1.13 ± 0.09 1.12 ± 0.06 1.11 ± 0.07 1.12 ± 0.04 0.48 Glucose [mmol/L] 9.84 ± 2.90 9.25 ± 3.11 8.60 ± 2.44 8.50 ± 2.14 0.17 Mg [mmol/L] 1.22 ± 0.22 - - 1.13 ± 0.28b 0.15 ∗ p < 0.05 for time 0 vs 2; **p < 0.05 for time 0 vs 4; ***p < 0.05 for time 0 vs 6 a Laboratory data was not obtained after switching to commercial fluids b Mg was measured once daily. Therefore, the values represent the levels at 24 hr. There were no missing data for magnesium levels.; Abbreviations: pCO2, partial pressure of carbon dioxide; Na, sodium; K, potassium; HCO3, bicarbonate; Cl, chloride; Mg, magnesium; iCa, ionised calcium; BE, base excess Figure 1 Departmental guideline for administration of Guy’s & St Thomas’ NHS Foundation Trust (GSTT) dialysis solutions based on serum potassium; The dialysis bags were switched to 2 K0 bags towards the end of each RRT session in order to ensure the lowest acceptable potassium levels when RRT was discontinued and to prolong the time until RRT was necessary again. Figure 2 Changes of potassium (1A), pH (1B), bicarbonate (1C), and base excess (1D) at baseline (n=42), 2 (n=40), 4 (n=24), and 6 (n=21) hours Hypomagnesaemia developed in 1 session and three episodes of hypocalcaemia. Magnesium and calcium were administered as an ‘’as required’’ prescription in 16 and 4 from 42 sessions, respectively. Metabolic alkalosis developed in 8/42 sessions and was more common in patients receiving citrate (RCA) and fluid based on Formula 2 (Na 135/HCO3 28). (Supplementary Table S2 and S3, Supplementary Figure S1 and S2) When alkalosis occurred, there were three implemented troubleshooting strategies. First, blood flow rate was decreased to reduce citrate load. Second, we switched the fluid bags to K4 commercial solutions. Third, we used a K0 GSTT bag and a K4 commercial bag in combination to reduce the total bicarbonate concentration. All methods corrected metabolic alkalosis successfully unless it was suspected to be secondary to significant clogging in the circuit, in which case the treatment was stopped. There was mild and transient metabolic acidosis in one patient receiving non-citrate anticoagulation, which was rapidly corrected after switching to K4 solutions. Hypoglycaemia and arrhythmias related to the RRT solution were not seen. Stability and sterility All results passed the standard assays for stability and bacteriostatic sterility at 4°C and 25°C for 7 days. (Appendix 1, Supplementary File) Discussion This evaluation has clearly confirmed the safety, feasibility and efficacy of in-house dialysis fluid production for the management of critically ill patients requiring RRT. The fluids had satisfactory electrolyte concentrations, sterility, and stability over 7 days at room temperature. In particular, as regard efficacy, hyperkalemia, which was a major clinical problem in the reported cohort of COVID-19 critically care patients, was corrected. The most common side effect was metabolic alkalosis, especially with RCA and fluids based on Formula 2 (high bicarbonate solution). During the COVID-19 pandemic, several options were utilised to compensate for shortages of RRT fluid and consumables. 5 ,S6-S7 The use of RRT was based on the patients’ needs, local expertise and availability of staff and equipment. PIRRT for a duration of 8-12 hours permitted one machine to be used for 2-3 patients per day. In two of our ICUs with reverse osmosis systems, IHD was provided for patients who were haemodynamically stable. Although acute peritoneal dialysis (PD) is another option as less infrastructure and equipment are required and anticoagulant is not needed 6 , 7 , PD was not an option due to lack of experience in our centre and a high proportion of critically ill patients who required ventilation in the prone position. Other strategies included optimisation of vascular access and blood flow rate, intensified anticoagulation to prolong filter life, and adjustment of RRT dose once metabolic control was achieved to conserve RRT fluids. Production of in-house fluids is common in settings where CRRT consumables and fluids are not always available or in health care systems where resources are limited, and expensive commercial RRT fluids are not an option. We decided to pursue this option as a rescue strategy to maintain RRT capacity during the COVID-19 super-surge. Although we were able to manufacture fluids in bulk quantities, our limitation was the number of bags that could be produced daily balanced by the high number of patients requiring RRT. As a result, we remained partially dependent on the supply of commercial fluids. In addition, our relatively basic RRT fluids which did not contain any magnesium or calcium meant that more frequent monitoring and supplementation was required. As expected, this increased the bedside workload and associated clinical concern, in particular, for bedside nurses with varying RRT experience, who were already working in a stressful environment during pandemic. To offset this, the renal critical care nurses and the renal critical care physicians provided enhanced support to the clinical teams. This facilitated physicians’ and nurses’ knowledge and understanding of the effects of the dialysis solutions on serum electrolytes, acid-base balance, glucose, and their interactions with citrate with protocols to make adjustments to accommodate new bags. Overall, the introduction of in-house dialysis solution required significant training and constant feedback from the clinical team under close supervision within a strong clinical governance process. Our assessments confirmed that the GSTT RRT fluid formulations achieved significant reductions in serum potassium concentrations. Although this was a desired effect, we acknowledge that acute fluctuations in serum potassium can cause deviations in transmembrane potential of cardiac and skeletal muscle and might lead to arrhythmia and paralysis.S8 An increase in serum bicarbonate concentration can also stimulate potassium shift into cells and lower serum potassium further.S9 Previous observational studies found an increased risk of arrhythmia or death in chronic haemodialysis patients when using lower dialysate K.S10-S14 In contrast, some studies reported a decreased risk of mortality in patients with serum K >5 mmol/L who used dialysate containing < 2 mmol/L of K concentrations.S15,S16 We selected only hyperkalemic patients with an average baseline serum potassium of 5.2 mmol/L, and instructed the clinical staff to monitor electrolytes as frequently as every 2 hours so that the K0 bags could be changed promptly to K4 bags once serum potassium levels fell. In addition, the dialysate flow rate is only ∼50 mL/min during PIRRT and ∼30 mL/min during CVVHD in a 60-kg patient, as opposed to 500-800 mL/min in intermittent hemodialysis, which may cause less aggressive potassium removal. Later, we adjusted the prescription by hanging 1 bag of K0 and 1 bag of K4 together on the balancing scale. We did not observe any serious episodes of hypokalemia or cardiac arrhythmias. Hypomagnesemia is also a potential side effect of using magnesium-free dialysis fluid. It is a well-known risk factor of arrhythmia and has potentiating effects on hypokalemia as it promotes intracellular potassium shifts.S17 Magnesium removal during hemodialysis increases with lower magnesium in dialysateS18, but in our study hypomagnesemia occurred in only one session. Hypoglycemia did not occur in our patients. In contrast, hyperglycemia was common, as previously reported in the literature.S19 Fluids based on Formula 2 caused more alkalemia. This may be due to the bicarbonate concentration being 28 mmol/L in our fluids combined with citrate administration in patients whose acid-base was normal. Decreasing the blood flow rate can also reduce the citrate load and prevent alkalemia. The possibility of low osmolality and the risk of hypotension was considered with fluids based on Formula 1, but we did not observe any hyponatremia or hemodynamic instability. It is important to acknowledge that other formulae for in-house production of dialysis fluid are available in the literature, some of which contain higher sodium and bicarbonate concentrations than ours. 8 ,S21-S27 (Supplementary Table S4) The electrolyte concentrations in our fluids remained stable over 7 days at 4 and 25 ◦C. Fortunately, our hospital is equipped with an aseptic unit which allowed us to produce the fluids in a sterile environment. In settings where aseptic technique cannot be ensured, the RRT fluid bags should be safe to stay at room temperature for 24 hours with a monitoring protocol similar to ours. We successfully used the in-house produced fluids for four weeks until the number of COVID-19 patients declined and the supply of commercial fluids was sufficient. When reflecting back on our experience and planning for a possible second wave, we are confident that our process was safe and efficient, and the protocol was feasible and effective at both patient and organisational level. Specialist clinical oversight and frequent monitoring were essential to avoiding complications. In preparation for a future crisis, we are now developing training modules on different RRT modalities, RRT prescriptions, monitoring, and complication management for nursing and medical staff, including junior doctors. Other strategies to prepare for a future RRT surge include the installation of additional reverse osmosis points to increase IHD capacity in critical care. Another technique is to produce RRT fluids with IHD machines. 9 , S28 This process may allow greater volumes of fluid to be produced, and at a lower cost. However, the environment in which the fluid is produced may not be conducive to asepsis. Moreover, the IHD cartridges containing the electrolyte mix are not designed for this purpose and regulatory approval would have been needed. In conclusion, we present our experience of manufacturing in-house aseptic RRT fluid during the COVID-19 pandemic as a rescue strategy when faced with shortage of commercial RRT fluids. Indeed, we have confirmed the safety, feasibility and efficacy of in-house dialysis fluid production for the management of critically ill patients requiring RRT. Other healthcare systems and other critical care centres may need to consider this option in time of crisis and these data will hopefully be useful to the clinical teams. Disclosures All authors declared no conflicts of interest.