Controversies in fluid therapy: Type, dose and toxicity

Table 1 Overview of the analogy of prescribing fluid therapy and prescribing a drug

Steps for prescribing a drug	Prescribing an oral hypoglycemic medication	Prescribing fluid therapy
Define the clinical problem	Diabetes mellitus	Hypovolemia or other fluid responsive state
Specify the therapeutic objective	Lower blood glucose	Restore absolute/relative fluid deficit
Verify the suitability of the drug	Class of oral hypoglycemic agent	Crystalloid, colloid or blood product
Write a prescription to start the drug	Order written by MD, verified and dispensed by pharmacy	Order written by MD, verified by pharmacy, blood bank or RN, administered by RN
Monitor therapeutic response of the drug	Blood glucose or hemoglobin A1C, evidence of adverse effect/ toxicity	Monitor hemodynamic profile and end-organ perfusion, evidence of dose-response toxicity
Write an order to discontinue	Order written by MD, verified by pharmacy	Order written by MD, administered by RN

Adapted from Raghunathan et al[58].

Table 2 Summary of studies comparing isotonic saline to balanced crystalloid solutions

Study	Design	Population	Solutions	Outcome
McFarlane et al[59]	RCT	Elective hepatobiliary/pancreatic surgery	0.9% saline vs PL-148	Iatrogenic metabolic acidosis with 0.9% saline
Wilkes et al[47]	RCT	Major abdominal surgery	0.9% saline vs Hartmann's (in HES)	Iatrogenic metabolic acidosis with 0.9% saline
O'Malley et al[48]	RCT	Kidney transplant recipients	0.9% saline vs RL	Iatrogenic metabolic acidosis and hyperkalemia with 0.9% saline
Yunos et al[56]	Prospective before-and-after	Critically ill patients	Chloride-rich vs chloride-poor fluid strategy	More acidosis with chloride-rich; more alkalosis and reduced cost with chloride-poor
Chowdbury et al[26]	RCT (cross-over)	Healthy volunteers	0.9% saline vs PL-148 (2 L infusion)	↑Δ [Cl-]; ↑ Strong ion difference; ↓ RBF; ↑ weight gain; ↑ extravascular volume; ↑ time to micturation
Chua et al[49]	Retrospective	Critically ill with DKA	0.9% saline vs PL-148	More rapid resolution of acidosis with PL-148
Shaw et al[55]	Retrospective	Major abdominal surgery	0.9% saline vs PL-148	↑ Major infection; ↑ composite of complications; ↑ blood transfusions; and ↑ RRT with 0.9% saline
Yunos et al[57]	Prospective before-and-after	Critically ill patients	Chloride-rich vs chloride-poor fluid strategy	↑ AKI (KDIGO stage II/III); ↑ RRT with chloride-rich strategy

Adapted from Raghunathan et al[58]. RCT: Randomized clinical trial; 0.9% saline: Normal saline; PL: Plasmalyte; RL: Ringers lactate; RBF: Renal blood flow; DKA: Diabetic ketoacidosis; AKI: Acute kidney injury; HES: Hydroxyethyl starch; RRT: Renal replacement therapy; KDIGO: Kidney disease improving global outcomes; FO: Fluid overload; FB: Fluid balance.

Table 3 Studies in critically ill patients describing the association with fluid overload and worse outcome

Study	Design	Population	Exposures	Outcomes
Pediatric Studies
Goldstein et al[33]	Retrospective	Pediatric critically ill starting CRRT	% FO	↑ % FO associated with ↑ mortality
Foland et al[60]	Retrospective	Pediatric critically ill starting CRRT	% FO	↑ % FO associated with ↑ organ dysfunction + mortality
Sutherland et al[31]	Retrospective	Pediatric critically ill starting CRRT	% FO	↑ % FO associated with ↑ mortality
Arikan et al[30]	Retrospective	Pediatric critically ill starting CRRT	% FO	↑ % FO associated with ↓ lung function
Adult Studies
Payen et al[61]	Post-hoc prospective	Adult critically ill septic patients	FB	↑ FB associated with ↑ mortality
Murphy et al[62]	Retrospective	Adult critically ill ALI patients	AIFR + CLFM	↑ Survival for ↑ AIFR + ↑ CLFM
Bouchard et al[63]	Post-hoc prospective	Adult critically ill AKI patients	% FO > 10%	↑ FB associated with ↑ mortality
Wiedemann et al[36]	RCT	Adult critically ill with ALI	Conservative vs liberal fluid management strategy	↑ MV-free days; ↑ ICU-free days with conservative strategy
Fulop et al[64]	Retrospective	Adult critically ill starting CRRT	VRWG	↑ VRWG associated with ↑ mortality
Boyd et al[65]	Post-hoc analysis from VASST	Adult critically ill septic patients	Quartiles of FB + CVP at 12 h and 4 d	↑ FB at 12 h and 4 d associated with ↑ mortality; CVP < 8 at 12 h ↓ mortality
Grams et al[66]	Post-hoc FACCT	Adult critically ill with ALI + AKI	FB + diuretics	↑ FB associated with ↑ mortality
Heung et al[67]	Retrospective	Adult critically ill starting CRRT	% FO	↑ % FO associated with ↓ kidney recovery
Bellomo et al[68]	Post-hoc RENAL	Adult critically ill with AKI	FB	↑ FB associated with ↑ mortality

Adapted from Raghunathan et al[58]. ALI: Acute lung injury; AIFR: Adequate initial fluid resuscitation; CLFM: Conservative late fluid management; VRWG: Volume-related weight gain; AKI: Acute kidney injury; CVP: Central venous pressure; ICU: Intensive care unit; RCT: Randomized clinical trial.

Table 4 Summary of randomized trials of hydroxyethyl starch resuscitation in severe sepsis/septic shock and kidney outcomes

Ref.	RCT type	n(HES/CON)	Population (n)	HES fluid	Control fluid	Kidney parameters	RRT (OR; 95%CI)
Schortgen et al[50]	Multi-centre	129 (65/64)	Severe sepsis/ septic shock	6% (200/0.62)	3% gelatin	↑ AKI ↑ oliguria, ↑ peak SCr	1.20 (0.5-2.9)
Molnár et al[69]	Single centre	30 (15/15)	Septic shock	6% (200/0.60)	3% gelatin	NR	NR
McIntyre et al[70]	Multi-centre	40 (21/19)	Septic shock	6% (200/0.50)	0.9% NS	No difference	3.00 (0.3-31.6)
Brunkhorst et al[42]	Multi-centre	537 (262/275)	Severe sepsis/septic shock	10% (200/0.5)	RL	↑ AKI	1.95 (1.3-2.9)
Guidet et al[23]	Multi-centre	196 (100/96)	Severe sepsis/septic shock	6% (130/0.4)	0.9% NS	No difference	NR
Perner et al[6]	Multi-centre	798 (398/400)	Severe sepsis/septic shock	6% (130/0.42)	Ringer’s acetate	↑ AKI	1.35 (1.01-1.8)
Myburgh et al[5]	Multi-centre	7000 (3315/3336)	Sepsis (27.4%) (1921/7000)	6% (130/0.4)	0.9% NS	↑ RRT	1.21 (1.00-1.45)

RCT: Randomized clinical trial; HES: Hydroxyethyl starch; CON: Control; NS: Normal saline; RL: Ringer’s lactate; AKI: Acute kidney injury; RRT: Renal replacement therapy; NR: Not report.