IV Fluid Choice - An ICU Perspective

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IV Fluid Choice - An ICU Perspective

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  • Good morning, am Vincent Chan a senior registrar in Emergency and Intensive care medicine and today I will be talking about IV fluid Choice an ICU Perspective
  • Iv fluids are a corner stone of medical treatment – particular emergency and intensive care
    There are numerous varieties of iv fluids just like the purported 57 varieties Heinz beans
    There has been a lot of debate with regards to the relative safety of colloids and the Cochrane reviews at the time
    3 key studies with regards to Colloids have been large multicentre RCT performed in Australian and new Zealand intensive care units and scandanavia have caused Cochrane to review their recommendations
  • Strictly speaking iv fluids include crystalloids, Colloids and blood
    However for the purpose of this talk it was be confined to Crystalloids and colloids
    The use of blood products and transfusion triggers deserve a separate talk
  • Crystalloids are a solution of sterile water with added electrolytes
    Colloids have the added component of a colloid which is a substance microscopically dispersed thought out the solution, that does not freely diffuse across a semipermeable membrane
    The theoretical advantage is that colloids can raise the intravascular volume quicker using less volume than crystalloids
  • This is a rather busy looking table but it demonstrates the different compositions of different colloids and crystalloids
  • Iv fluids have been a main stay of modern medical treatment, just as long as the antibiotic era and it has been assumed that they are a safe and effect means of iv fluid resusicatation
    Starting in 1989 there have been several meta-analysis which have questioned the safety of colloids
    A Cochrane review in 1998 questioned the safety of albumin in critically ill patients
    They analysed 30 rcts involving 1419 patients and stated that for every 17 critically ill patients treated with albumin that there is one additional death – IE Number dead to kill 17
    Thhs caused a large amount of concerns n Australian and new Zealand intensive care units as Albumin was used extensively and they felt certain that 1 out of 17 patients didn’t die as a result of albumin, therefore this required resolution thought a large mutli-centre rct
  • So the Australian and new Zealand intensive care society did the SAFE Study – Saline versus albumin fluid evaluation trial
    To evaluate the safety of albumin vs Normal saline on a large heterogeneous population of intensive care patients which numbered 6997 with a few notable exceptions
    This was almost 5 times the number of patients in the 30 RCTS that Cochrane has meta-analysed
  • The SAFE study showed that there was no overall difference in outcomes
    But trauma patients who received Albumin were more likely to die particularly traumatic brain injuries
    Conversely patients with severe sepsis had a trend towards increased survival
  • This the the table for sub group analysis in the SAFE Study
  • The other colloid of note is Hydroxyethyl starch it’s a derivative of Maize
    And had become of the most prevalent colloids in intensive care world wide
    Particularly in Europe with caution regards to colloids such as Gelofusin which contain Beef protein – (BSE and religious concerns)
    Hydroethyl starch has been around for a while – which also means off patent
    The newer generations Voluven and Voluyte which are licensed by TGA are characterised by a lower molecular weight and low c2/c6 ratio – which is theoretically less harmful to patients than earlier generations
  • The whole safety issue of Hydroethylstarch really came into question with the Boldt affair
    He was the chief anasetheties and professor Extraordinaire at the Ludwigshafen Hospital in Germany
    He was the leading advocate of HES with 11 publications purporting to its alleged superiority to other colloids in surgical settings
    His publications were important in submissions to regulatory authorities including the TGA and also in Meta-analysis
    The Cochrane review in 2007 of colloids versus crystalloids for fluid resuscitation in critically ill patients showed no significant difference in patient safety.
    However in 2011 it all came undone – Bolds admitted to falsifying data, falsifying signatures of co-authors, failure to obtain ethical approval thislead to the retraction of many of the publications purporting to the safety of Hydroxyethyl starchs
    He is definitely not the guy to do your 4-10 with!!!
  • So the whole question about the safety of HES need to be addressed
    First of the rank was The 6S trial which is a Scandinavian critical care trials group they performed a multicentre parallel group ( ie non-crossover) each group receives the allocated treatment exclusively) blinded clinical trial to assess the effect of HES compared with Ringers Lactate with severe sepsis
    There were a total of 798 septic patients randomised
  • The 6S group demonstrated that there was a significant risk of death or dependency on dialysis at day 90
    The number need to harm was 13
  • Following hot on the trial of the 6S trial was the Chest trial this was performed by the ANZICS along similar line to the SAFE study and it was also published in the NEJM in 2012
    This involved 7000 heterogeneous ICU patients in Australia and new Zealand
    Who were randomly assigned to receive fluids resuscitation with either HES or Saline
    The big difference to the 6S study is that the chest study has a maximum dose of 50ml/kg day of HES which was the maximum permissible dose by the TGA
    The 6S study being a parallel group meant that patients received Hes or ringers lacate exclusively
  • The chest trial showed that there was no significant difference in mortality at 90 days
    But did show that patients who received HES were more likely to require renal replacement therapy
    So in conclusion 6% HES does not have any clinical benefit compared with saline
  • So this begs the question which colloid
    The short answer to this is 4% albumin except in trauma and head injuries and my experience in RPH and SCGH iCu bares this out as the colloid of choice
    I have to put a big question mark with regards to Gelofusin which seems sufficiently different to HES in that it is mainly eliminated unchanged through the kidneys however a large RCTS would be necessary
  • With regards to Crystalloids Normal saline remains the default for most situations with some notable exceptions,
    However there is a move in intensive care, to move to more physiological crystalloids, such as Hartmann's lacated ringers and plasma lyte
    Particular in reducing hyperchloraema and metabolic acidosis – the most common emergency patients afflicted by this are the DKA patients
    But for the time being there is a distinct lack of high level evidence with regards to crystalloid choice
  • THE Anzics is looking into this and its worthwhile to note that they have another catchy named study called SPLIT in progress which compares normal saline and Plasma lyte in intensive care patients. This is a pilot study, but I have no doubt that in a few years which should be able to answer the question as to which is the most appropriate Crystalloid in critically ill patients
  • IV Fluid Choice - An ICU Perspective

    1. 1. IV Fluid Choice - an ICU perspective (With 2 Cautionary stories about Cochrane Meta-analysis) Dr Vincent Chan Senior Registrar in Emergency and Intensive Care Medicine 17th April 2014
    2. 2. Introduction • Iv fluids are a cornerstone treatment of emergency and intensive care medicine • There are numerous varieties of iv fluids however their relative safety is under debate particularly with colloids • 2 Cochrane meta-analyses demonstrated increased risk of harm with IV albumin and no increase in harm with IV Hydroxyethyl starches compared with crystalloids • 3 Large randomised Control trials in Australian, New Zealand and Scandinavian intensive cares units have proved Cochrane wrong
    3. 3. Crystalloid, Colloid and Blood Products • Strictly speaking IV fluids include Crystalloid Colloid and Blood • This talk will be confined to Crystalloids and Colloids • Use of blood products and transfusion triggers deserve a separate discussion in itself
    4. 4. Crystalloid and Colloids • Crystalloids are predominately based on a solution of sterile water with added electrolytes to approximate the mineral content of human plasma. • Colloids are often based on crystalloid solutions, thus containing water and electrolytes, but have the added component of a colloidal substance that does not freely diffuse across a semipermeable membrane • Colloids can raise the intravascular volume quicker and using less volume than using crystalloids
    5. 5. Variations in Colloids and Crystalloids Formulations Solution pH Na+ Cl- K+ Ca++ Lactate Glucose Osmolality Other 0.9% normal saline 5.0 154 154 0 0 0 0 308 0 Hartmann/CSL 5-7 131 112 5 2 28 0 255 0 Plasma lyte 7.4 140 98 5 0 0 0 294 27mmol Acetate 23mmol Gluconate 5% dextrose in water (D5W) 4.0 0 0 0 0 0 50 g/L 252 0 .45% normal saline with dextrose (D51/2 NS) 4.5 77 77 0 0 0 50 g/L 406 0 Albumin (4%) 6.7-7.3 140 128 0 0 0 0 260 40 g/L albumin Albumin (20%) 6.4-7.3 48-100 130-160 0 0 0 0 130 200 g/L albumin Hetastarch 6% 5.5 154 154 0 0 0 0 310 60 g/L starch Pentastarch 10% 5.0 154 154 0 0 0 0 326 100 g/L starch Dextran-40 (10% solution) 3.5-7.0 154 154 0 0 0 0 311 100 g/L dextran Dextran-70 (6% solution) 3.0-7.0 154 154 0 0 0 0 310 60 g/L dextran Haemaccel 3.5% 7.4 145 145 5 6.25 0 0 293 35 g/L gelatin Gelofusine 7.4 154 125 0 0 0 0 308 40 g/L gelatin
    6. 6. Safety of Colloids • It has been assumed over the past 60 years that both colloids and crystalloids are safe and effective means of intravenous fluid resuscitation • The safety of colloids was first questioned by a rudimentary meta-analysis performed by Velanovich in 1989. (1) • Subsequently in the BMJ in 1998 a systematic review questioned the safety of colloids in general[2] and a Cochrane Review in 1998, questioned specifically the safety of albumin. [3] • This can only be resolved by a large randomised control trial 1. Velanovich V. Crystalloid versus colloid fluid resuscitation: a meta-analysis of mortality. Surgery. 1989;105:65-71 2. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomized trials. BMJ. 1998;316:961-964. 3. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ. 1998;317:235-240
    7. 7. The SAFE (Saline versus Albumin Fluid Evaluation) trial • Conducted by the Australia and New Zealand Intensive Care Society's Clinical Trials Group (ANZICS-CTG) between 2001 and 2003 • Published NEJM May 2004 • Double blind prospective multi-centre randomised controlled trial • Determine the effect of fluid resuscitation with either 4% Albumin or N/saline on mortality in a heterogeneous population of Intensive care Patients • Excluded patients – Burns, plasmapheresis, cardiac bypass surgery and liver transplant • Randomized 6997 critically ill patients requiring fluid resuscitation to receive 4% albumin or Normal Saline
    8. 8. The SAFE (Saline versus Albumin Fluid Evaluation) trial • There was no overall difference in outcome according to whether patients received colloids or crystalloids (relative risk for death with colloid use = .99, 95% confidence interval .91-1.09, P = .87). • Prospective Subgroup Analysis • Trauma Patients appeared to be more likely to die if they received colloids and this was statistically true for those patients with traumatic brain injury compared with trauma patients as a whole (relative risk for death = 1.62, 95% confidence interval 1.12-2.34, P = .009). • Severe Sepsis trends toward a reduction in death for who received colloids (relative risk = .87, 95% confidence interval .74-1.02). • ARDS no statistically significant difference
    9. 9. Subgroups Identified in the Saline vs Albumin Fluid Evaluation Study Outcome Albumin Saline RR (95% CI) P Value Trauma 13.6% 10.0% 1.36 (.99-1.86) .06 (81 of 596) (59 of 590) Severe sepsis 30.7% 35.3% .87 (.74-1.02) .09 (185 of 603) (217 of 615) ARDS 39.3% 42.4% .93 (.61-1.41) .72 (24 of 61) (28 of 66)
    10. 10. Hydroxyethyl Starch • Derived from Maize Starch • Hydrolysed amylopectin in the C2 C3 and C6 units of the macromolecules • Eliminated only through the kidneys as the products of endogenous hydrolysis • C2 units impairs hydrolysis more effectively than one in position C6 • Charactered by • mean molecular weight in Daltons • C2/C6 ratio • Voluven and Volulyte • New generation low molecular weight and low C2/C6 Ratio HES 130/0.42 • Most commonly used colloid in intensive care units globally
    11. 11. The Boldt Affair • Joachim Boldt MD PHD • Chief Anaesthetist at Ludwigshafen Hospital in Rhineland Germany • Leading Advocate of Hyroxyethyl starch (HES) • Prolific submitting on average 1 paper a month • 11 papers demonstrated a relative reduction in mortality with HES • Some have been cited in manufacturers product information sheets, submissions to regulatory authorities, clinical trial protocols and Meta-analysis. • Cochrane review in 2007 with regards to Colloids versus crystalloids for fluid resuscitation in critically ill patients analysed 55 studies concluded that there was no significant difference • Discovered in 2011 to have published 101 articles of which 89 papers did not have institutional review board approval • Lead to dismissal from post, multiple article retractions and ongoing criminal investigations
    12. 12. THE 6S Trial: Hydroxyethyl Starch 130/0.42 versus Ringer's Acetate in Severe Sepsis • Published NEJM July 2012 • 6S trial Group Scandinavian Critical Care Trials Group • Multicentre parallel group blinded clinical trial • Conducted between 2009 and 2011 in Denmark, Norway, Finland and Iceland • To assess the effect of HES 130/0.4 compared with a balanced crystalloid solution on mortality and end stage kidney failure in patients with severe sepsis. • 798 patients with Severe Sepsis • 398 randomised to HES 130/0.42 for fluid resuscitation • 400 randomised to Ringers Acetate group
    13. 13. The 6S Trial: Hydroxyethyl Starch 130/0.42 versus Ringer's Acetate in Severe Sepsis • HES 130/0.42 significantly increased the risk of death or dependence on dialysis at day 90, as compared with Ringer's acetate. • HES 130/0.42 increased the absolute risk of death at 90 days by 8 percentage points, corresponding to a number needed to harm of 13. • Similar results were observed in analyses adjusted for risk factors and in the subgroups of patients with shock or acute kidney injury at the time of randomization.
    14. 14. CHEST Trial: Hydroxyethyl starch or saline for fluid resuscitation in intensive care. • Crystalloid versus Hydroxyethyl Starch Trial (CHEST) • Australian And New Zealand Intensive Care Society Clinical Trial Groups • Published NEJM Nov 2012 • Multicentre, prospective, blinded, parallel-group, randomized, controlled trial conducted in 32 hospitals in Australia and New Zealand conducted between 2009 and • 7000 patients intensive care patients who required fluid resuscitation over and that required for maintenance or replacement fluids • 3500 assigned to receive 6% HES (130/0.4) max dose of 50ml/kg day then open label 0.9% Saline • 3500 patients assigned to receive 0.9% N/Saline
    15. 15. CHEST Trial: Hydroxyethyl starch or saline for fluid resuscitation in intensive care - Conclusion • There was no significant difference in mortality at 90 days in ICU patients who received 6% HES (130/0.4) in 0.9% saline and those who received 0.9% saline alone for fluid resuscitation. • The effect on mortality did not differ significantly in six predefined subgroup pairs: Acute Kidney Injury, Sepsis, Trauma, Traumatic Brian injury, APACHE Score and receiving HES before Randomisation • However more patients who received resuscitation with HES were treated with renal-replacement therapy • 6% HES does not have any clinical benefit compared with Saline in ICU patients
    16. 16. Which Colloid? • 4% albumin is generally safe • Small advantage in Sepsis • Except in trauma and head injuries • Hydroxyethyl Starch • No benefit over Normal Saline • Increased mortality with Severe Sepsis • More likely to require Renal Replacement Therapy • Gelofusin • Modified Gelatine of bovine origin – Succinylated • Gelatine derivatives are mainly eliminated unchanged through the kidney • Produced in BSE-free countries • No large RCTS
    17. 17. Which Crystalloid? • Normal Saline is the default fluid for most situations • Exceptions: • Hartmann's for Burns • Hypertonic Saline in Intracranial Hypertension • Blood products in severe blood loss • There is a move in intensive care to use of more physiological crystalloids such as Hartmann's, lactated ringers and Plasma lyte • Particularly in reducing hyperchloraemia and metabolic acidosis • Diabetic Ketoacidosis – high risk • However there is a distinct lack of high-level evidence with regards to crystalloid choice
    18. 18. SPLIT Study: 0.9% saline vs. Plasma Lyte® 148 for fluid therapy in intensive care trial • Australian and New Zealand Intensive Care Society Clinical Trials Group • The study hypothesis is that routinely using Plasma Lyte® 148 for fluid therapy instead of 0.9% saline will reduce the risk of developing acute kidney failure • Pilot Randomised multicentre trial recruiting 2000 Patients • In Progress
    19. 19. QUESTIONS?

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