Getting smart with fluids in the critically ill. NOR AZIM MOHD YUNOS Jeffrey Cheah School of Medicine & Health Sciences Monash University Malaysia

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1 Getting smart with fluids in the critically ill NOR AZIM MOHD YUNOS Jeffrey Cheah School of Medicine & Health Sciences Monash University Malaysia

2 Isotonic Solutions and Major Adverse Renal Events Trial Major adverse kidney event within 30 days: composite of death from any cause new renal-replacement therapy persistent renal dysfunction ( of creatinine 200% of baseline)

3 SMART 2018

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7 Overview Fluid therapy: how it began The rethinking of crystalloids Fluids: to push or to pull, that is the question The headache that is capillary leak

8 Fluid therapy: how it began The rethinking of crystalloids Fluids: to push or to pull, that is the question The headache that is capillary leak

9 The first intravenous fluids 1830 First intravenous use of water 1831 Saline plan for cholera proposed 1832 First saline infusion 1832 First successful saline infusion Herman & Jaehnichen injected 6 oz of H 2 O into a patient. Died 2 hours later. O Shaughnessy: injection of highly-oxygenated salts into the venous system Latta injected 6 pints of ½ [soda & subcarbonate soda] in 30 min. Patient died. Latta s 2nd patient received 330 cm 3 of fluid over 12 h. Patient survived.

10 Further milestones 1876 Ringer s solution Sydney Ringer s observation of different effects of electrolytes on frog s heart 1932 Hartmann s solution Alexis Hartmann s search for gastroenteritis treatment. Sodium lactate added to Ringer s solution (compound sodium lactate)

11 Fluid therapy: how it began The rethinking of crystalloids Fluids: to push or to pull, that is the question The headache that is capillary leak

12 Thomas Latta % saline Sodium Chloride Bicarbonate 16 0 Why then is 0.9% saline the normal saline? Jakob Hambuger s 1890 s study of osmosis: in 0.9% saline, mammalian erythrocytes least likely to lyse - indifferent saline described as normal for mammalian blood

13 Tohoku J Exp Med 1923 But if we strictly trace the action of ion, we have to say that 0.85% solution is not normal, the average saline content of blood being 0.6%, so that naturally there will be some disturbance of isoionia

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15 Plasma 0.9% saline Hartmann s Plasma-Lyte148 Sterofundin ISO Contents of crystalloids Na mmol/l Cl mmol/l K mmol/l Ca mmol/l Mg mmol/l Lactate mmol/l Gluconate mmol/l 23 Acetate mmo/l Malate mmol/l 5 Osmolarity mosm/l Osmolality mosm/kg

16 Unbalanced Plasma 0.9% saline Hartmann s Plasma-Lyte148 Sterofundin ISO Contents of crystalloids Na mmol/l Cl mmol/l K mmol/l Ca mmol/l Mg mmol/l Lactate mmol/l Gluconate mmol/l 23 Acetate mmo/l Malate mmol/l 5 Osmolarity mosm/l Osmolality mosm/kg

17 Balanced Plasma 0.9% saline Hartmann s Plasma-Lyte148 Sterofundin ISO Contents of crystalloids Na mmol/l Cl mmol/l K mmol/l Ca mmol/l Mg mmol/l Lactate mmol/l Gluconate mmol/l 23 Acetate mmo/l Malate mmol/l 5 Osmolarity mosm/l Osmolality mosm/kg

18 Nothing is perfect Hypotonicity of some balanced solutions Precipitation & coagulation with calcium in Hartmann s Lactate (pre-infusion: > 20 x plasma concentration) Concerns in liver failure, hyperlactatemia & hyperglycemia Acetate (pre-infusion: up to 1,000 x plasma concentration) Negative inotropy & vasodilatation with acetate use in high volume CRRT

19 Yunos et al. Crit Care Med 2011 Prospective open-label sequential study Crit Care Med month control Chloride-Liberal 0.9% saline 4 % succinylated gelatin 4% albumin in saline Hartmann solution Plasma-Lyte % albumin 6 month washout period 6 month intervention Chloride-Restrictive Hartmann solution Plasma-Lyte % albumin

20 Control (21694 measurements) Intervention (19807 measurements) p Severe hypochloremia, Cl < 90 mmol/l, n (%) 205 (0.9%) 287 (1.4%) < Severe hyperchloremia >114 mmol/l, n (%) Cl 1353 (6.2%) 465 (2.3%) < Severe dyschloremia, n (%) 1558 (7.2%) 752 (3.7%) < SBE < -5 mmol/l, n (%) 1964 (9.1%) 1185 (6.0%) < SBE > 5 mmol/l, n (%) 5500 (25.4%) 6491 (32.8%) < 0.001

21 6 month control Chloride-Liberal 0.9% saline 4 % succinylated gelatin 4% albumin in saline Hartmann solution Plasma-Lyte % albumin 6 month washout period Yunos et al JAMA 2012; 308: month intervention Chloride-Restrictive Hartmann solution Plasma-Lyte % albumin

22 RRT use: Chloride-liberal: 78 patients (10%; 95%CI, 8.1%-12%) Chloride-restrictive: 49 patients (6.3%; 95%CI, 4.6%-8.1%) p = 0.005

23 Multi-centre, cluster-randomized, double cross over trial 4 ICUs in New Zealand. 2,278 patients Cluster-randomized to receive alternating seven week blocks of blinded 0.9% saline or Plasma-Lyte 148 Primary outcome: AKI based on RIFLE criteria

24 SPLIT Trial Both groups received a median of 2L of study fluid with most fluid administered on first ICU day

25 SPLIT Trial: Acute Kidney Injury

26 SPLIT Trial Well conducted, excellent adherence to protocol. > 99% patients analysed Critiques: A feasibility study, sample size not calculated. Cluster design. Study population (> 50% elective surgeries) might not reflect population at risk of AKI > 90% of patients were exposed to IV fluids pre-enrolment, with majority receiving buffered crystalloid Exposure of 2L of fluid throughout ICU stay was too low to have an impact

27 Isotonic Solutions and Major Adverse Renal Events Trial Major adverse kidney event within 30 days: composite of death from any cause new renal-replacement therapy persistent renal dysfunction ( of creatinine 200% of baseline)

28 SMART 2018

29 SMART 2018

30 SMART 2018

31 SMART 2018

32 SMART Trial The most comprehensive balanced solutions vs saline trial to date Critiques: Single center, cluster design Open label Lactated Ringer s solution and Plasma-Lyte A evaluated together The use of composite outcomes

33 SMART 2018

34 Intravenous fluids are ubiquitous in ICU Millions of liters administered across the world annually Slight difference in outcomes matters to thousands of patients Hyperchloraemic acidosis with saline resuscitation is confirmed For patients at high risk of AKI like the critically ill and septic, the choice of crystalloids may make a difference No single clinical study has shown unbalanced 0.9% saline to be superior to balanced solutions If 0.9% saline is a new solution today, would the FDA approve?

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36 Australia & New Zealand IV fluid patterns: vs Percentage change between and % Saline CSL Plasma-Lyte 19%* p = % 10% 7%* p = % 0% -10% -30% -4% -11%* p = % Unbalanced: Balanced -12%* p = % -19%* p < % -70% -67%* p = % Saline CSL* Acetate* U to B Ratio* Total Crystalloid 20% albumin 4% albumin* Gelofusin HES* N to A Ratio Total Colloid* Total Fluid Types of Intravenous Fluid

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38 PLUS trial Plasma-Lyte 148 versus Saline Study (PLUS) Blinded RCT. 40 centres. ANZICS. Estimated enrolment: 8,800 patients Inclusion criteria: NICE-Sugar criteria plus need for fluid resuscitation All cause mortality at 90 days 1500 patients already enrolled Expected completion: June 2020

39 BaSICS Balanced Solution vs Saline in Intensive Care Study Brazilian Research in Intensive Care Network (BRICNET) Multi-centre, blinded, RCT (2x2 factorial design) Estimated enrolment: 11,000 patients Plasma-Lyte vs. Saline; Fast Infusion (999 ml/h) vs. Slow Infusion (333 ml/h) All-cause mortality at 90 days. Harmonized with PLUS for individual patient data meta-analysis

40 Fluid therapy: how it began The rethinking of crystalloids Fluids: to push or to pull, that is the question The headache that is capillary leak

41 Crit Care Med 2006; 34: Cohort, multi-centre observational study. 198 ICUs in 24 European countries. 3,147 pts Fluid therapy

42 Crit Care Med 2011; 39: Multi-centre RCT: Vasopressin in Septic Shock Trial (VASST) 778 patients. Septic shock & 5 mcg/min noradrenaline Retrospective review of IV fluids in first 4 days of care Patients stratified into 4 fluid balance quartiles : Quartile 1 Quartile 4 (dry) (wet) Fluid therapy

43 Crit Care Med 2011; 39: Fluid therapy

44 Unpublished data 3 month prospective observational study on fluid balance Fluid Balance Non-fluid overload patients (n=225) Fluid Overload patients (n=32) p-value # Daily fluid balance (Median, IQR) (ml/kg/day) Median Daily fluid Balance (ml) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day ( ) ( ) ( ) ( ) ( ) 31.0 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) <0.001 <0.001 <0.001 < <

45 ICU Mortality

46 Secondary Outcome: Mechanical Ventilation free days Non-fluid overload (n=190) Fluid overload (n=27) Crude regression coefficient, B a, (95% CI), p-value Adjusted regression coefficient, B b, (95% CI), p-value Mechanical Ventilator free days 25 ( ) 17 ( ) ( , ) P< (-8.219, ) P=0.02 B a = crude regression coefficient; B b = Adjusted regression coefficient 33 patients had missing mechanical ventilation data

47 Subgroup Analysis: 4 fluid groups <8ml/kg/day (n=149) 8-20ml/kg/day (n=76) 20-30ml/kg/day (n=17) 30ml/kg/day (n=15) Mortality n (%) 11 (7.5) 7 (9.7) 5 (29.4) 8 (53.3) Crude Odds Ratio, 95% (CI), p-value 1.00 (ref) Adjusted Odds Ratio, 95% (CI), p-value 1.00 (ref) ( ) P= * ( ) P= ( ) P= * ( ) P= ( ) P< # ( ) P=0.003 *Adjusted for mean fluid balance, age, BMI, APACHE II, SOFA, PRE-ICU fluid # Adjusted for mean fluid balance, SOFA

48 Fluids are drugs: type, dose & toxicity Malbrain et al. 2014

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54 J Crit Care Litre over 120 min Cardiac Output 1 Litre over 30 min

55 Fluid therapy: how it began The rethinking of crystalloids Fluids: to push or to pull, that is the question The headache that is capillary leak

56 Glassford Korean J Crit Care Med 2016

57 Glycocalyx Endothelium Journal of Anesthesia 2015

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61 Schott et al 2016

62 Fluid therapy: how it began The rethinking of crystalloids Fluids: to push or to pull, that is the question The headache that is capillary leak

63 Fluid therapy is an important, complex, and poorly researched area of everyday clinical practice that is often delegated to the most junior members of clinical teams. Increasingly the evidence suggests it can affect important outcomes, including mortality. Liu B, Finfer S BMJ Editorial BMJ 2009;338:b2418

64 Rome wasn t built in a day, but they were laying bricks every hour John Heywood

65 THANK YOU