Plasma-Lyte 148: A clinical review

Table 2 Summary of the Plasma-Lyte 148 clinical trials

Ref.	Title	Objectives	Patient numbers	Findings
Liskaser et al[19]	Role of pump prime in the etiology and pathogenesis of CPB-associated acidosis	RCT that compared the development of metabolic acidosis in patients on CPB who had either Hemaccel- Ringer’s Solution, or PL 148 as the pump prime fluid	n = 22	All patients developed a metabolic acidosis when the pump prime fluid was delivered Participants who received Hemaccel-ringer’s solution developed a hyperchloremic metabolic acidosis, however participants who received PL 148 developed acidosis as a result of an increase in unmeasured ions, likely acetate and gluconate The acidosis was reversed more quickly with PL 148 compared to NS
Yunos et al[24]	The biochemical effects of restricting chloride-rich fluids in intensive care	This study evaluated the acid base effects of administration of chloride-restricted fluids to critically ill patients, compared with unrestricted fluid management	n = 1644	Restriction of chloride rich fluids was associated with a reduction in metabolic acidosis (P < 0.001), standard base excess (P < 0.001) and severe acidemia (P < 0.001) The intervention was associated with a greater incidence of severe metabolic alkalosis (P < 0.001)
Shaw et al[25]	Major complications, mortality, and resource utilization after open abdominal surgery: NS compared to PL	This observational study compared the post-operative complications, in-hospital mortality and resource utilization after abdominal surgery between patients who received either NS or PL 148 fluid therapy on the day of surgery	n = 31920	Patients who received PL 148 had lower rates of in-hospital mortality (P < 0.001) and major complications (including renal failure requiring dialysis (P < 0.001), post-operative infection (P < 0.006), blood transfusions (P < 0.001), electrolyte disturbance (P < 0.046) and acidosis investigation (P < 0.001) and intervention (P = 0.02)
Aksu et al[31]	Balanced vs unbalanced crystalloid resuscitation in a near-fatal model of hemorrhagic shock and the effects on renal oxygenation, oxidative stress, and inflammation	Animal study in which rats were induced into hemorrhagic shock, and were then resuscitated with either no fluid, PL 148 or NS	n = 6	Both PL 148 and NS restored blood pressure during resuscitation NS was associated with hyperchloremia (P < 0.001) and metabolic acidosis (P < 0.05) PL 148 restored acid base balance more effectively than NS PL 148 was associated with improvement in renal oxygen consumption occurred compared to NS (P < 0.05) Systemic inflammation and oxidative stress were similar with NS or PL 148
Chowdhuryet al[32]	A randomized, controlled, double blind crossover study on the effects of 2L infusions of NS and PL on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers	The authors used MRI to compare the renal blood flow of healthy male volunteers following a 2L infusion of either PL 148 or NS	n = 12	NS was associated with hyperchloremia (P < 0.0001) and metabolic acidosis (P < 0.025) NS was associated with a decrease in a reduction in mean renal artery flow velocity (P = 0.045) and renal cortical tissue perfusion (P = 0.008), findings not observed after PL 148
Young et al[35]	Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the Intensive Care Unit: The SPLIT randomized clinical trial	A double blind, cluster randomized, double-crossover trial conducted in 4 intensive care units. The primary aim was to determine the effects of PL compared with NS on renal complications	n = 2278	No differences in the incidence of acute kidney injury (P = 0.77) No differences in mortality (P = 0.40)
Omron et al[42]	A physicochemical model of crystalloid infusion on acid-base status	In this study, authors used a simulated human model in a standard physiological state to compare the effect of 5 different fluids with varying SID values on the acid-base status of the human model when infused up to 10 L	n = 1	Solutions with a SID greater than 24.5 mEq/L resulted in a progressive metabolic alkalosis Solutions with a SID less than 24.5 mEq/L resulted in a progressive metabolic alkalosis PL 148 (SID of 50 mEqu/L) caused a progressive metabolic alkalosis when administered in high volumes
Davies et al[50]	Plasma acetate, gluconate and interleukin-6 profiles during and after CPB: A comparison of PL 148 with a bicarbonate-balanced solution	In this study, acetate levels were compared in elective cardiac surgical patients who received either PL 148 or a bicarbonate- balanced crystalloid as the priming fluid for their cardiopulmonary bypass	n = 30	PL 148 was associated with supraphysiological plasma concentrations of acetate (P < 0.0005) and gluconate (P < 0.0005) after institution of CPB Gluconate levels remained persistently elevated at the end of CPB Plasma concentrations of acetate did not completely return to normal levels until 4 h post separation from CPB There were no significant differences in concentrations of IL-6 between the two priming fluids
Traverso et al[58]	Fluid resuscitation after an otherwise fatal hemorrhage: I. Crystalloid solutions	An animal model in of hemorrhagic shock comparing four crystalloid solutions (NS, Ringer’s lactate, Plasmalyte-A, and Plasmalyte-R) to prevent death after a fatal hemorrhage	n = 116	Ringers lactate provided the best survival when compared to saline and PL After analyses of arterial blood gas values, biochemistry variables, and hemodynamic metrics such as heart rate and aortic pressure, Ringers lactate was considered the most superior crystalloid solution (P value: not stated)
Morgan et al[74]	Acid-base effects of a bicarbonate-balanced priming fluid during cardiopulmonary bypass: comparison with PL. A randomised single-blinded study	In this RCT, the authors compared the acid- base effects of a bicarbonate- balanced trial crystalloid with those of PL when administered as a 2-L prime in patients undergoing elective cardiac surgery	n = 20	PL 148 was associated with a metabolic acidosis (P = 0.0001) and an increased strong ion gap secondary to a surge of unmeasured anions (likely acetate and gluconate)
Yunos et al[75]	Association between a chloride-liberal vs chloride-restrictive IV fluid administration strategy and kidney injury in critically ill adults	This study assessed the rates of kidney injury in patients admitted to ICU who received only chloride- restricted fluids such as PL 148 or Hartmann’s solution compared to those that also received fluids that were high in chloride concentration, including NS	n = 1533	The incidence of acute kidney injury decreased significantly in patients who received a chloride-restrictive fluid plan compared to those who received fluids high in chloride concentration (P < 0.001) No differences in hospital mortality, hospital or ICU length of stay were observed
Mahler et al[76]	Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis	In this prospective single centre study, patients admitted to the emergency department in diabetic ketoacidosis were resuscitated over at least 4 h with either NS or PL 148, and their serum chloride and bicarbonate levels were monitored and compared	n = 45	Resuscitation with NS was associated with higher serum chloride concentrations (P < 0.001) and lower bicarbonate concentrations (P = 0.020) Resuscitation with PL 148 prevented hyperchloremic metabolic acidosis
Chua et al[77]	PL 148 vs NS for fluid resuscitation in diabetic ketoacidosis	In this retrospective study, the authors compared the plasma biochemistry, hemodynamic and glycemic control in patients admitted to the ICU for management of ketoacidosis who were resuscitated primarily with PL 148 or NS over the first 12 h	n = 23	PL 148 was associated with less hyperchloremia and a more rapid improvement in metabolic acidosis than those who received NS (P < 0.05) PL 148 improved hemodynamic measures including an improved mean arterial pressure at 2-4 h, and higher cumulative urine output at 4-6 h compared the NS group (P < 0.05) No differences were observed in glycemic control or length of stay in ICU based
Shin et al[83]	Lactate and liver function tests after living donor right hepatectomy; a comparison of solutions with and without lactate	A randomised controlled compared the acid- base status, lactate levels and liver function tests in patients undergoing hepatectomy for liver transplant who received PL 148 or Hartmann’s solution	n = 104	Immediately post hepatectomy, donors who received PL 148 had significantly lower lactate levels (P = 0.005), lower bilirubin concentrations (P < 0.001), shorter prothrombin time (P = 0.009), and higher albumin levels compared to the Hartmann’s group There were no significant differences between the groups in albumin, bilirubin, or prothrombin times on post-operative day 5 There were no significant differences in complications or duration of hospital stay
Weinberg et al[84]	The effects of PL 148 vs Hartmann’s solution during major liver resection: a multicentre, double blind, randomized controlled trial	Multicentre RCT investigating the biochemical effects of Hartmann’s solution or PL 148 in patients undergoing major liver resection. Primary outcome: Base Excess immediately after surgery. Secondary outcomes: changes in blood biochemistry and hematology	n = 60	Base excess similar in both groups at completion of surgery (P = 0.17) Postoperatively patients receiving Hartmann’s solution were more hyperchloremic (P = 0.01) and hyperlactatemic (P = 0.02) Patients receiving PL 148 had higher plasma magnesium levels (P < 0.001) and lower ionized calcium levels (P < 0.001) No significant differences in pH, bicarbonate, albumin and phosphate levels PT and aPTT were significantly lower in the PL 148 group (P < 0.001, P = 0.007)
MacFarlane et al[85]	A comparison of PL 148 and NS for intra-operative fluid replacement	RCT that compared the pre-op and post-operative acid base status of patients who received either NS or PL 148 whilst undergoing major hepatobiliary or pancreatic surgery	n = 30	Intra-operatively, NS was associated with increased plasma concentrations of chloride (P < 0.01), decreased levels of bicarbonate (P < 0.01), and an increased base deficit (P < 0.01), compared to PL 148 Less blood loss and higher postoperative hemoglobin in the PL 148 group) (P = 0.03) Total complications were more frequent in the Hartmann’s group (P = 0.007) Hyperchloremic metabolic acidosis occurred in patients receiving NS but not in those receiving PL 148
Hadimioglu et al[87]	The effect of different crystalloid solutions on acid-base balance and early kidney function after kidney transplantation	A blinded RCT investigating the effects of NS, lactated Ringer’s, or PL 148 on changes in acid-base balance, potassium and lactate levels during kidney transplantation. Urine volume, serum creatinine, and creatinine clearance were recorded on postoperative days 1, 2, 3 and 7	n = 60	Patients receiving NS had lower pH levels, and higher chloride levels (P value not stated) Lactate levels increased significantly in patients who received Ringer’s lactate (P value not stated) No significant changes in acid-base measures or lactate levels occurred in patients who received PL 148 Potassium levels were not significantly changed in any group The best metabolic profile was maintained in patients who receive PL 148
Kim et al[88]	Comparison of the effects of NS versus PL on acid-base balance during living donor kidney transplantation using the Stewart and base excess methods	RCT compared the effects of NS and PL 148 on acid-base balance and electrolytes during living donor kidney transplantation using the Stewart and base excess methods	n = 60	Significantly lower values of pH, base excess, and effective strong ion differences during the post-reperfusion period in the NS group (P < 0.05) Hyperchloremic metabolic acidosis present in the NS group (P < 0.05) No differences between the groups in early postoperative graft function (P = 0.3)
Potura et al[89]	An acetate-buffered balanced crystalloid vs NS in patients with end-stage renal disease undergoing cadaveric renal transplantation: a prospective randomized controlled trial	RCT that evaluated the impact of NS vs a chloride-reduced, acetate-buffered crystalloid on the incidence of hyperkalemia during cadaveric renal transplantation. The incidence of metabolic acidosis and kidney function were secondary aims	n = 150	The incidence of hyperkalemia differed by less than 17% between groups (P = 0.56) Use of balanced crystalloid resulted in less hyperchloremia (P < 0.001) and metabolic acidosis (P < 0.001) Significantly more patients in the NS group required administration of catecholamines for circulatory support (P = 0.03)
Smith et al[99]	Cost-minimization analysis of two fluid products for resuscitation of critically injured trauma patients	A retrospective cost-minimization analysis evaluating fluid and drug acquisition costs, materials and nurse labor costs, and costs associated with electrolyte replacement in patients who received PL 148 or NS	n = 46	Substitution of PL 148 for NS for fluid resuscitation during the first 24 hours after trauma was associated with decreased magnesium replacement requirements (P < 0.001) and a net cost benefit to the institution
Smith et al[100]	Does saline resuscitation affect mechanisms of coagulopathy in critically ill trauma patients? An exploratory analysis	An exploratory analysis of a subset of subjects enrolled in a randomized trial comparing the effect of resuscitation with PL 148 and NS on acidosis and electrolyte abnormalities	n = 18	Patients receiving NS were more acidemic at 6 h (mean pH saline 7.31 vs PL 148; base excess NS -5.3 mmol/L vs 0.6 mmol) (P value: not stated) Kinetics time was shorter (P = 0.06) and alpha angle was significantly greater (P = 0.008) in the PL 148 group NS did not alter endogenous thrombin potential: (P > 0.1) for all variables
Song et al[101]	The effect of 0.9% saline vs PL 148 on coagulation in patients undergoing lumbar spinal surgery; a randomized controlled trial	This study compared the effect of PL 148 to NS on coagulation assessed by rotation thrombo-elastometry (ROTEM) and acid-base balance in the aforementioned patients	n = 50	Patients receiving NS developed a transient hyperchloremic acidosis (P < 0.05) Coagulation assessed by ROTEM analysis and the amount of blood loss was similar between the groups: (P > 0.1 for all variables)
Young et al[102]	Saline vs PL in initial resuscitation of trauma patients: a randomized trial	RCT that evaluated the acid-base status of patients who were resuscitated with either PL or NS for the first 24-h post major trauma	n = 46	Significantly greater improvement in base excess (estimated difference 4.1 mmol/L) and less hyperchloremia (estimated difference 7 mmol/L) in patients who were resuscitated with PL compared to those resuscitated with NS (P value: not stated)
Story et al[103]	Cognitive changes after saline or PL 148 infusion in healthy volunteers: a multiple blinded, randomized, crossover trial	Randomized, crossover, blinded study of healthy adult volunteers. On separate days, participants received 30 mL/kg over 1 h of either NS or PL. Primary endpoint: reaction time index after infusion - a validated metric of cognitive function	n = 25	NS was also associated with greater metabolic acidosis (P < 0.001) NS was also associated with higher serum chloride levels (P < 0.001) No difference in measures of cognition after infusions of PL 148 or NS (P = 0.39)
Noritomi et al[104]	Impact of PL 148 pH 7.4 on acid-base status and hemodynamics in a model of controlled hemorrhagic shock	After controlled hemorrhagic shock was induced, animals were resuscitated with NS, Ringer's lactate solution or PL 148	n = 18	Resuscitation with all three fluids restored cardiac output, and urinary output Resuscitation with PL 148 and Hartmann’s Solution both resulted in a reduction in chloride concentration, and increased base excess Resuscitation with NS was associated with an increased chloride concentration (P = 0.018), reduction of base excess (P = 0.042) and a metabolic acidosis (P = 0.045)

PL 148: Plasma-Lyte 148; NS: Normal saline 0.9%; RCT: Randomized clinical trial; CPB: Cardiopulmonary bypass; PT: Prothrombin time; aPTT: Activated partial thromboplastin time; SID: Strong ion difference; ICU: Intensive care unit; IL: Interleukin.