An Overview of the Properties of Iv Fluids

Bapen Conference 2009 13th October 2009 Cardiff International Arena

‘Salt of the earth or a drop in the ocean’ An overview of the properties of iv fluids

Peter Gosling BSc MSc PhD FRCPath

Consultant Clinical Scientist Honorary Senior Clinical Lecturer University Hospital Birmingham UK

Potential conflicts of interest declaration: In receipt of two grants from Bayer Diagnostics to study microalbuminuria in critical illness and surgery, and two grants from Fresenius- Kabi to study the effects of hydroxyethyl starch in vascular surgery Crystalloids and Colloids: is there really a debate ? Crystalloids

Definition: crystalloids are salt solutions containing electrolytes or easily metabolised small molecules such as glucose

Properties: Crystalloid solutions are isotonic with plasma at the time of intravenous administration, but in the case of glucose solutions, they become hypotonic in vivo as the glucose is metabolised.

Primary Uses: 1. To provide free water (dextrose) 2. To replace lost electrolytes (salt solutions) 3. To provide a vehicle for i.v. delivery of drugs Crystalloids and Colloids: is there really a debate ? Crystalloids

Definition: crystalloids are salt solutions containing electrolytes or easily metabolised small molecules such as glucose Ad hoc uses for salt solutions: Properties: Crystalloid solutions are isotonic with plasma at the Poortime man’s of intravenous volume expander administration, (10-20% but stays in the in vasc.case space)of glucose solutions, they become hypotonic in vivo as the glucose is metabolised. An i.v. fluid for the unthinking e.g. ‘normal saline’ must be safe

Colloids

Definition: A colloid solution contains molecules which are large enough to be retained by the vascular endothelium

Properties: A colloid has the property of trapping water: e.g. 1 gram of albumin binds18 grams of water.

The ability of a colloid solution to remain in the vascular space depends upon: 1. Molecular size (30kD up to >500kD) 2. Rate of degradation 3. Permeability of the endothelium

Primary use: To fill the depleted vascular compartment Capillary permeability of different tissues

Pore sizes for capillary walls in various tissues Tissue Large pore Small pore Ratio large to small diameter nm diameter nm pores Subcutaneous 20.0 5.0 1:3000

Skeletal muscle 22.0 6.0 1:3600

Brain …….. 0.4 ………

Intestine 20.0 4.6 1:6400

Liver 33.0 9.5 1:50

Lung 20.0 8.0 1:200

Adapted from Aubrey Taylor Scanning EM: normal endothelial cell junction McDonald DM, Thurston G, Baluk P.Endothelial gaps as sites for plasma leakage in inflammation. Microcirculation 1999; 6:7-22

X 40,000 Scanning EM: 1 minute after substance P Capillary inflammation (microalbuminuria) during burns/surgery/trauma

SIRS - Organ Failures

Vascular permeability (Microalbuminuria)

Normal

Pre op Induct ‘injury’ 2h 6h 12h 24h Distribution of Infused Solutions

Plasma Interstitial fluid Intracellular fluid

Colloids 0.9% NaCl 5% Dextrose

0% 20% 40% 60% 80% 100%

Courtesy of Dileep Lobo Distribution of Infused Solutions

Plasma Interstitial fluid Intracellular fluid

Remember: The ability of colloids to remain in the vascular space depends upon: 1. Molecular size (30kD up to >500kD) 2. Rate of degradation 3. Permeability of the endothelium Colloids 0.9% NaCl 5% Dextrose

0% 20% 40% 60% 80% 100%

Courtesy of Dileep Lobo Chemical and Physical Properties of Crystalloids Fluid Sodium Chloride Potassium Osmolarity mmol/L mmol/L mmol/L mosm/L Normal 140 95 4 295 plasma 0.9% 154 154 0 308 saline Ringers 130 109 4 273 lactate Hartmanns 131 111 5 275

Plasmalyte 140 98 5 294

7.5% 1283 1283 0 2566 saline Effects of 2000 mL acute fluid loading in 10 volunteers. Blind cross over trial (Lobo et al Br J Surg 2001)

10 volunteers

5 given 2L 0.9% saline 5 given 2L 5% dextrose

2 week interval

5 given 2L 5% dextrose 5 given 2L 0.9% saline

Effects of Saline Loading

(Ab)normal saline • Hyperchloraemic metabolic acidosis Na 154 mmol/L • Hyperosmolar states Cl 154 mmol/L • Stimulation of ADH - fluid retention • Chloride causes renal vasoconstriction – fluid retention • Nausea, vomiting, abdo pain, hyperventilation, headaches, thirst

Hartmann AF, Senn MJE 1932 J Clin Invest 11:337-44 Waters JH et al Anesthesiology 2000:93:1184-7 Williams EL et al Anesthesia & Analgesia 1999;88:999-1003 Skellett S et al. Arch Dis Child 2000;;83:514-6 Healey MA et al J Trauma;45:894-9 Hypertonic Saline Solutions

Fluid Composition mmol/L mmol/250mL

Hypertonic saline 7.5% NaCl 1283 321

Hypertonic saline 6% Dextran 70 kDa 1283 321 with dextran in 7.5% saline RescueFlow (Vitaline)

Hypertonic HES 6% HES 200 kDa 1232 308 HyperHES in 7.2% saline (Fresenius-Kabi)

Normal sodium intake only 70 mmol/24h Hypertonic Saline - Mechanisms of Action

1. Bio Physical Effects (clinical and animal studies) Osmotic mobilization of cellular water into the circulation Reduction of haematocrit and viscosity In brain reduces ICP and draws fluid from cerebral oedema (HSD gives 10 times volume expansion of Ringer's)

Increased preload for about 30 minutes Hyperosmotic vasodilation - reduces afterload

BETTER PERFUSION ! Hypertonic Saline - Mechanisms of Action

2. Anti inflammatory effects (animal studies)

Decreases neutrophil endothelial cell interaction

Reduces capillary leak

Less interstitial oedema

Better organ function

Early administration is essential for benefit Chemical and Physical Properties of Colloids

Fluid Sodium Chloride Mean Mol. Duration COP mmol/L mmol/L weight of vol. mmHg expan. Normal plasma 140 95 - - 25

Gelofusine 145 120 30,000 2h 27

Albumin 154 154 68,000 3-4h 13 5% Pentastarch 154 154 200,000 12-24h 50 10%

Tetrastarch 140 118 130,000 6h 38 6% Half glucose molecules substituted with HES, substitution =0.5 Characteristics of different hydroxyethyl starch preparations Adapted from Anesthesiology: 2005; 103:654-660

Tetra

Penta

Heta

‘Hepta’

‘Hepta’ Structure of hydroxyethyl starches

HES substituted glucose molecules can be 40 to 70% Structure of hydroxyethyl starches

Amylase

C2 to C6 substitution ratio Characteristics of different hydroxyethyl starch preparations Adapted from Anesthesiology: 2005; 103:654-660

Tetra

Penta

Heta

‘Hepta’

Fluids for volume expansion Saline 58 D 5 times more needed than HES colloids Large sodium, chloride and water load

Hyperchoraemic acidosis Fluid retention Interstitial oedema Properties of resuscitation fluids

Ringers lactate 5 times more needed than HES colloids Less sodium, less chloride, better excreted than saline

Interstitial oedema still a risk if given in large volumes Properties of resuscitation fluids

Gelatine 30,000 Da Volume expansion lasts 1-2 hours Larger volume required than for HES Sodium, chloride and water load Properties of resuscitation fluids

Pentastarch 200 kD Volume expansion lasts 6-18 h 0.5 substitution Compared with crystalloid- only + - or gelatine less Na Cl and H2O

Anti-inflammatory, less capillary leak Repeated infusions risk of accumulation Properties of resuscitation fluids Tetrastarch 130 kDa 0.4 substitution Volume expansion lasts 6-8 h Smaller volumes needed than cryst. gelatine

Now in balanced electrolyte solution

Gone after 12 h

Anti-inflammatory, less capillary leak No accumulation claimed Advantages of HES for fluid resuscitation

• Better vascular retention than gelatins, albumin or crystalloid alone

• Less extravascular Na+ & water - less oedema

• Better kidney, gut and lung function

• Reduction of cytokine inflammation Side effects of HES administration

• Osmotic like nephrosis after high dose

• Retention in reticuloendothelial system

• Pruritis after chronic administration

• Coagulopathy Normal oncotic pressure (22 mmHg)

Filtration (Blood) pressure

Normal oncotic pressure Effects of oncotic pressure on glomerular filtration NORMAL ONCOTIC PRESSURE Normal renal function

Normal urine output High oncotic pressure (e.g. 40 mmHg)

Filtration (Blood) pressure

High oncotic Effects of oncotic pressure on pressure glomerular filtration HIGH ONCOTIC PRESSURE e.g. starch load with insufficient water Oliguria - renal impairment

Low urine output

Stopped after 537 patients recruited due to high incidence of renal dysfunction and hypoglycaemia VISEP Study Design

Conventional insulin therapy Intensified insulin therapy

Blood glucose is adjusted by using human Blood glucose is adjusted by using human insulin (Actrapid®) in the range between 180- insulin (Actrapid®) in the range between 80- 200 mg/dl (10,0-11,1 mmol/l) 110 mg/dl (4,4–6,1 mmol/l)

CrysConv CollConv CrysInt CollInt

Crystalloid-based Crystalloid-based Colloid-based volume volume replacement Colloid-based volume volume replacement replacement replacement Volume replacement is Volume replacement is Volume replacement is Volume replacement is performed by performed by performed by using exclusively using performed by using exclusively using 10% HES (Hemohes® 10% HES (Hemohes® crystalloids crystalloids 10%) until reaching the (Sterofundin®). 10%) until reaching the (Sterofundin®). maximum daily dose of maximum daily dose of 20 ml/kg BW. 20 ml/kg BW.

Ringer’s lactate 10% 200/0.5 HES in 0.9% Saline VISEP Study: Amount of crystalloids

Amount of crystalloids infused:

Crystalloids (n = 275) HES (n = 262) min max median min max median

0 – 24 h 500 33,507 3,787 146 13,000 2,400 0 – 48 h 500 40,568 5,960 100 20,024 3,400

HES 10% 200 kD Not enough crystalloid in some patients Major risk of hyperoncotic state VISEP Study: Amount of HES infusions

40 HES (n = 262) Overdose % n BW/day / 20 22 ml/kg BW At least at one day 38.2 100 ml Hemohes / kg ml Hemohes Within first 24 h 28.2 74

0 - 24h 24 - 24h

38% Patients overdosed HES 10% 200 kD: high risk of hyperoncotic acute renal failure VISEP Study: Reasons for renal impairment

¾ Study design: Ringers versus HES in 0.9% saline – choride nephrotoxicity ¾ Volume therapy with HES 10% (HES 200/0.5) with insufficient free water in some patients

¾ HES 200/0.5 administered in some patients with contraindication – renal impairment

¾ HES 200/0.5 has been overdosed in 38% patients Eur J Anaesthesiol. 2008 May 20:1-9. Safety of HES 130/0.4 (Voluven(R)) in patients with preoperative renal dysfunction undergoing abdominal aortic surgery: a prospective, randomized, controlled, parallel-group multicentre trial. Godet G et al. Paris, France. 6% 130 0.4 hydroxyethyl starch; n = 32 3% gelatin; n = 33.

Crit Care Med. 2007;35:2740-6. Influence of volume therapy with a modern hydroxyethylstarch preparation on kidney function in cardiac surgery patients with compromised renal function: a comparison with human albumin. Boldt J et al , Ludwigshafen, Germany.

6% 130kD 0.4 hydroxyethyl starch (130 kD 0.4); n = 25 5% human albumin; n = 25 Minerva Anestesiol. 2006;72:655-64. The effects of hydroxyethyl starch solution in critically ill patients. Palumbo D et al , Naples, Italy. PATIENTS Critically ill with sepsis INTERVENTION Hydroxyethyl starch 6% ( 130/0.4) n=10 Albumin 20% n = 10 To maintain PCWP 15 - 18 mmHg RESULTS: Compared with 20% albumin group, HES treated patients showed increased cardiac index (CI), right ventricular ejection fraction (RVEF), oxygen consumption index (VO(2)I), oxygen delivery index (DO(2)I), PaO2/FiO2 ratio (P<0.05). APACHE II score decreased significantly only in HAES treated group (P<0.05), HES versus Gelatine: Renal function in Aortic Surgery

Serum creatinine lower in Voluven group

Voluven Gelofusine eloHES

140

120

100

80 0.0009 0.0384 0.0074 0.0414 0.0123 60 n = 20

40 Median serum creatinine umol/L creatinine serum Median 20

123456 Days

Mahmood A, Gosling P, Vohra RK. Rittoo D, Gosling P, et al Cardiovasc Br J Surg 2007;94:427-33. Surg. 2002;10:128-33. Lung function during AAA

Rittoo D, Gosling P, et al Br J Anaesth. 2004;92:61-6 Effect of Ringers Lactate, Saline and HES 130 on inflammation and endothelial activation in elderly major abdominal surgery

Boldt, Intens Care Med 2004

Saline

Ringers Lactate Anti inflammatory effects of hydroxyethyl starch

Clinical studies show reduced expression of pro inflammatory cytokines and adhesion molecules

In vitro and animal studies suggest attenuation of endothelial cell response to activated neutrophils And finally…. Give fluid for a reason!

To correct serious hypovolaemia • Effective colloid to fill vascular space. One part starch to two parts balanced crystalloid. Avoid overdose! • Red blood cells • Clotting factors/platelets for haemostasis Give fluid for a reason!

To replace electrolyte losses • For small scale resuscitation or replacement use balanced electrolyte solution (Hartmann’s or Ringers) • Avoid 0.9% saline except for extreme Na+ Cl- deficits To provide free water • Give enough water as 5% dextrose iv or enterally. This is to excrete urea and sodium and replace insensible losses. • In critical illness measure urine electrolytes to ensure natriuresis and urine volume is adequate for solute load STOP! when resuscitation or replacement completed Thank you for listening [email protected]

Before a patient can recover they have to excrete all the fluid and electrolytes we give them