CHAPTER 17
Intravenous Fluids and
Electrolytes
Jessica Spellman • Jack S. Shanewise
Total body water and electrolytes are divided between the
intracellular and extracellular compartments. The major
electrolytes in the intracellular compartment are potas-sium,
magnesium, calcium, and phosphate. The extracel-lular
compartment consists of the interstitial, plasma, and
transcellular fluid components, where sodium and chlo-ride
are the major electrolytes. Fluid movement between these
spaces, and thus the effect of fluid therapies, depends on
the levels of water, electrolytes, and colloid proteins among
them and the composition and permeability of the
membranes that separate them.
Total Body Fluid Composition
The adult body is composed of approximately 60% water,
with some variation with age and gender, as well as signifi-
cant variation among different tissues. For example, muscle
is about 75% water, whereas adipose tissue only 10%.
About two-thirds of total body fluid is intracellular and one-
third extracellular (Fig. 17-1). The intracellular compartment
is rich in potassium (the major cation), magnesium, cal-
cium, phosphate (the major anion), and proteins. Extracel-
lular volume (ECV) includes interstitial fluids (about 80% of
the ECV), plasma (about 20%), and transcellular fluids,
which are anatomically separate fluid spaces, such as the
intraocular, gastrointestinal, and cerebrospinal fluids, and
are not available for water and solute exchange with the re-
mainder of the ECV. Extracellular fluids are rich in sodium
(the major cation) and chloride (the major anion). These and
other small ions move freely between plasma and in-
terstitium in the extracellular compartment. The plasma also
contains proteins, such as albumin and globulins, which
create the colloid oncotic pressure. Plasma proteins are
prevented from freely moving from vascular to inter-stitial
space by the interplay of the vascular endothelial cells and
the endothelial glycocalyx layer (EGL) c oating the inside of
the vascular space. Macromolecule move-ment out of the
vascular space is dependent on the type of EGL pores and
endothelial cell junctions, which have
432
four phenotypes throughout the body. In the liver, spleen,
and marrow, sinusoidal capillaries have large EGL p ores
and open fenestrations allowing macromolecules to pass
between plasma and the interstitial space. The glomeruli
have open capillary fenestrations with the effective pore
size reduced by overlying EGL. Endocrine, choroid plexus,
and gut mucosa vascular endothelial cells have inducible
fenestrations. Nerve, muscle, connective tissue, and lung
have nonfenestrated or continuous capillaries so that lit-
tle transvascular filtration into the interstitium occurs in
these tissues. In states of inflammation, changes in the en-
dothelial cells and an increase in the number of large pores
in the capillaries increase the amount of protein passing
from vascular into interstitial spaces. The transcapillary es-
cape rate of albumin to tissues is normally 5% per hour but
can double during surgery and increase to 20% in sepsis.1
Fluid in the interstitial space is returned to the circulation
as lymph.2 The cell membrane prevents sodium, the pri-
mary extracellular cation, from moving into the cell, except
for a small amount by active pump transport, but isotonic
fluids containing sodium added to the vascular space are
distributed throughout the ECV so that only 20% of the
3
volume infused remains in the plasma.
Intravenous Fluid Types
Crystalloids
Crystalloids are fluid solutions containing ion salts and other
low-molecular-weight substances. Crystalloids can be
categorized based on their tonicity or osmotic pressure of
the solution with respect to that of plasma. Examples are
listed in Table 17-1. Administering large volumes of normal
saline (NS) c an result in hyperchloremic meta-bolic
acidosis.4 “Balanced” or “physiologic” crystalloid solutions
contain a composition approximating that of ex-tracellular
fluid but are usually slightly hypotonic because of lower
sodium concentration. Administering large vol-umes of
balanced salt solutions can result in hyperlactate-mia,
metabolic alkalosis, hypotonicity, and cardiotoxicity

FIGURE 17-1  Body fluid compartments with main ion distribution. ECF, extracellular fluid; ICF, intracellular fluid. (Reused from
Doherty M, Buggy DJ. Intraoperative fluids: how much is too much? Br J Anaesth. 2012;109:69–79, with permission.)
due to acetate. Calcium-containing balanced salt
solution may cause formation of microthrombi when
infused with citrate-containing banked blood.
Colloids
Colloid solutions contain macromolecules suspended in
electrolyte solutions. These macromolecules, such as plant
or animal polysaccharides or polypeptides, remain in the
plasma compartment longer than crystalloid solutions;
however, their distribution has been shown to be context
sensitive, with larger percentages of the volume admin-
istered remaining intravascular in hypovolemic patients as
compared to normovolemic patients.3 Semisynthetic colloid
solutions are metabolized and excreted and thus have a s
horter duration of effect than human albumin solutions.2
Examples are listed in Table 17-2.
Albumin (4% to 5%)
Albumin solution is produced from human blood and
suspended in saline. It is heat-pasteurized at 60°C f or
Chapter 17  • Intravenous Fluids and Electrolytes 433
10 hours to reduce viral transmission. It is expensive to
produce and distribute as compared to semisynthetic
col-loids and crystalloid solutions. The incidence of
5
anaphy-lactoid reactions to albumin is 0.011%.
The comparative effectiveness of fluid resuscitation with
colloid versus crystalloid has been a long-standing
controversy, which has been the subject of much recent
clinical research. In the Saline versus Albumin Fluid Eval-
uation (SAFE) study, a multicenter, randomized, double-
blind trial of 6,997 i ntensive care unit (ICU) patients, the
effect of fluid resuscitation with albumin 4% or NS was
evaluated. The primary outcome was death within 28 days.
There was no significant increase in mortality (p 5 .87). The
two groups also had similar rates of new single organ and
multiple organ failure (p 5 .85), days spent in ICU (p 5 .44),
days spent in hospital (p 5 .3), days of mechanical
ventilation (p 5 .74), and days of renal replacement therapy
(p 5 .41).6 In a p ost hoc analysis of the SAFE study, of 460
patients with traumatic brain injury, the primary outcome of
mortality was increased in the albumin-treated group
(33.2%) versus the NS group
 434 Part III   • Circulatory System
Table 17-1
Common Crystalloid Solutions
Osmolarity Calories Na1 Cl2 K1 Ca11 Mg11 Glucose Lactate Acetate Gluconate
Solution (mOsm/L) Tonicity pH (kcal/L) (mEq/L) (mEq/L) (mEq/L) (mEq/L) (mEq/L) (g/L) (mEq/L) (mEq/L) (mEq/L)
NS 308 Iso 5 154 154
D5NS 560 Hyper 4 170 154 154 50
D51/2NS 406 Hyper 4 170   77   77 50
LR 273 Iso 6.5   9 130 109 4 3 28
D5LR 525 Hyper 4.9 179 130 109 4 3 50 28
Plasmalyte 294 Iso 140   21 140   98 5 3 27 23
D, dextrose; LR, lactated Ringer’s; NS, normal saline.
From Warren BB, Durieux ME. Hydroxyethyl starch: safe or not? Anesth Analg. 1997;84:206–212.
 Table 17-2
Common Colloid Solutions
Osmolarity Na1 Cl2 K1 Ca11 Mg11 Lactate Acetate Octonate Malate
Fluid Trade Name Source (mOsm/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L)
Albumin 4% Albumex Human 250 148 128 6.4
donor
Albumin 5% Human 309 154 154
donor
HES 10% Hemohes Potato 308 154 154

Chapter 17 • Intravenous Fluids and Electrolytes 435

(200/0.5) starch
HES 6% Hextend Maize 304 143 124 3 5 0.9 28
(450/0.7) starch
HES 6% Voluven Maize 308 154 154
(130/0.4) starch
HES 6% Volulyte Maize 286 137 110 4 1.5 34
(130/0.4) starch
HES 6% Venufundin Potato 308 154 154 2.5 1 24
(130/0.42) starch
HES 6% Tetraspan Potato 296 140 118 4 5
(130/0.42) starch
HES, hydroxyethyl starch.
From Myburgh JA, Mythen MG. Resuscitatiouids. N Engl J Med. 2013;369:1243–1251.
436 Part III   • Circulatory System
(20.4%, p 5 .03).7 In an additional subgroup analysis of
1,218 patients with severe sepsis, albumin administration
was associated with a d ecreased risk of death as com-
pared to NS with an adjusted odds ratio of 0.71 (95% CI,
0.52–0.97; p 5 .03).8 A more recent multicenter, open-label,
randomized trial of 1,818 ICU patients with severe sepsis,
the Albumin Italian Outcome Sepsis study, of 20% albumin
and crystalloid versus crystalloid alone with pri-mary
outcome measure of death found no erence in survival at 28
or 90 days (p 5 .29).9
Semisynthetic Colloid Solutions
Solutions include hydroxyethyl starch (HES) s olutions,
succinylated gelatin, urea-linked gelatin–polygeline prep-
arations, and dextran solutions. HES, the most commonly
used semisynthetic colloid solutions, are created by at-
taching hydroxyethyl groups to carbons 2, 3, or 6 of the
glucose moieties of starches of sorghum, maize, or pota-
toes. HES solutions vary with respect to HES concentra-
tions (6% t o 10%), molecular weights (70 t o 670 kD a),
molar substitution ratios (0.3 t o 0.75), and crystalloid carrier
solutions. The concentration influences the initial volume
effect with 6% s olutions being iso-oncotic and 10%
solutions hyperoncotic. HES a re polydisperse with particles
in a wide range of molecular mass (dispersity is a measure
of the heterogeneity of sizes of molecules or particles in a
mixture); thus, the molecular weight is av-eraged by either
weight or number, with high molecular weight preparations
being associated with alterations in coagulation. The
substitution ratio indicates the average fraction of glucose
moieties bearing a hydroxyethyl group. HES can also be
named hexa- (0.6), penta- (0.5), or tetra-(0.4) starches for
this level of substitution. Substitution increases the solubility
of the starch in water and inhibits the destruction of the
starch by amylase, thus prolonging intravascular retention.
HES can also be categorized with respect to the pattern of
hydroxyethylation of the C2 and C6 carbon atoms.
Hydroxyethyl groups in the C2 position inhibit amylase
access to the starch more effectively than hydroxyethyl
groups at the C6 position; thus, high C2/C6 ratios would be
expected to hydrolyze more slowly. The maximum daily
dose of HES is limited to 20 to 50 mL/kg of body weight/day
but varies by solution.10
HES is removed from the circulation by redistribution
and renal excretion. Redistribution of HES results in tem-
porary storage in the skin, liver, and kidneys. Skin depo-
sition results in non–histamine-associated pruritus. After
hours, 23% of the total dose is interstitial and at 26 weeks,
trace amounts of HES are still detectable.6 HES molecules
with greater molecular weights and increased substitution
ratios tend to be stored more than those with more rapid
clearance and deposition appears to be dose-dependent.10
Renal excretion of HES o ccurs in two phases:
immediate glomerular fi ltration of HES p olymers less than
59 kDa and delayed glomerular filtration after HES
metabolism by plasma a-amylase. This amylase functions
as an endoamylase cleaving within the polyglucose chain
instead of acting at the ends of the molecule, resulting in
polydispersity and varying molecular weights of the
remaining HES molecules in the plasma. Thus, pharma-
cokinetic parameters of plasma clearance and half-life will
change over time, cannot be rigorously defined, and must
not be interpreted as efficacy half-lives or contrib-uting to
the pharmacodynamics of volume effect of HES solutions.11
Additionally, the hydroxyethyl groups re-tard hydrolysis of
the compound by amylases, allowing longer presence in the
plasma. Plasma levels of amylase are elevated after HES
administration for 72 hours, with-out evidence of increased
pancreatic production, owing to decreased renal elimination
of amylase as it remains complexed to HES. 5 The
pharmacokinetic profile of some HES solutions after single
dose and multiple infusions in healthy volunteers is
described in Tables 17-311 and 17-4,11 and in impaired
renal function in Table 17-5.12
HES compounds have effects on coagulation with
re-ductions in factor VIII, von Willebrand factor, and
plate-let function, although the exact mechanisms are
unclear. Coagulation effects are noted even when
used below rec-ommended maximum doses.
Solutions with more rapid degradation are associated
10
with less effects on coagula-tion. The incidence of
6
anaphylactoid reactions with HES use is 0.085%.
HES solutions carry a U.S. Food and Drug Administra-
tion black box warning with the following recommenda-tions:
Do not use HES solutions in critically ill adult patients
including those with sepsis and those admitted to the ICU;
avoid use in patients with preexisting renal dysfunction;
discontinue use of HES at the first sign of renal injury; need
for renal replacement therapy has been reported up to 90
days after HES administration, continue to monitor renal
function for at least 90 days in all patients; avoid use in
patients undergoing open heart surgery in association with
cardiopulmonary bypass due to excess bleeding; dis-
continue use of HES a rst sign of coagulopathy.13
The Crystalloid versus Hydroxyethyl Starch Trial
evaluated HES v ersus NS i n a m ulticenter, prospective,
blinded, parallel-group, randomized controlled trial of over
7,000 adult ICU patients.14 Patients were randomized to
receive either HES (6% [130/0.4] Voluven, Fresenius Kabi
Norge AS, Halden, Norway) solution or NS until ICU
discharge, death, or 90 days following randomization. Pri-
mary outcome was death 90 days after randomization, and
secondary outcomes were acute kidney injury, failure, and
treatment with renal replacement therapy. There was no
significant erence in mortality during the study period (18%
in the HES group and 17% in the NS group, p 5 .26) or renal
failure (HES g roup 10.4% a nd 9.2% NS g roup, p 5 .12);
however, significant erences in renal injury (34.6% HES
group and 38% NS group, p 5 .005) and renal replacement
therapy use (7% HES group, 5.8% NS group, p 5 .04) were
found. Additionally, HES was associated with significantly
more adverse events (0.3% vs. 2.8%, p ,.001).
 Chapter 17  • Intravenous Fluids and Electrolytes 437

Table 17-3
Pharmacokinetic Parameters after a Single Dose of Different Hydroxyethyl Starch Types in Healthy
Volunteers
HES Type Cmax t½/2 t½/2 t½/2central AUC∞ CL Infusion
(concentration) Dose (g) (mg/mL) (h) (h) (h) (mg h/mL) (mL/min) Time (min)
a b c
670/0.75 (6%) 0.6/kg 13 6.3 46.4 NA 926.0 0.98 20
d e
450/0.7 (6%) 30 7.8 NA 300 NA NA NA 60
200/0.62 (6%) 30 5.2 5.08 69.7 44.42 NA 1.23 30
200/0.5 (10%) 50 8.0 3.35 30.6 7.12 NA 9.24 30
f g
200/0.5 (6%) 30 6 NA NA NA NA 4.88  15
f g
200/0.5 (10%) 50 14 5.2 39.1 NA NA 6.38  15
h h
130/0.4 (6%) 26.3 3.7 1.39 12.1 1.55 14.3 31.4 30
130/0.4 (10%) 44.1 6.5 h h 1.82 28.8 26.0 30
1.54 12.8
a 
Mean for 0–8 hours.
b 
Mean for 7–10 hours.
c 
Calculated for 70 kg body weight.
d 
Product label declaration, however de facto similar to 670/0.75.
e 
For days 7–28 post-treatment.
f 
Mean for 0–24 hours.
g 
BLood letting of 400 mL prior to infusion.
h 
Model independent.
AUC∞, area under the plasma concentration-time curve from time zero to infinity; CL, total body clearance; Cmax, maximum plasma concentration; NA,
not available; t½a, initial/distribution half-life; t½b, terminal/elimination half-life; t½central, elimination half-life from the central compartment.
From Jungheinrich C, Neff TA. Pharmacokinetics of hydroxyethyl starch. Clin Pharmacokinet. 2005;44:681–699.

Table 17-4
Pharmacokinetic Parameters and Residual Plasma Concentrations after Multiple Infusions of Different
Types of Hydroxyethyl Starch in Healthy Volunteers
Plasma
Concentration AUC
24 h after Last t1/2b t1/2 (mg h/mL)
Cumulative Treatment Administration CL t1/2a
HES Type day 1 a
Dose (g) Period (mg/mL) (mL/min) (h) (h) (h) Last Day
450/0.7   90   3 days (3 3 30 g) 9.6 1 NA NA NA NA day1
b c
200/0.62 150   5 days (5 3 30 g) 7.8 0.983 0.568 11.6 211 508 day1
b c
200/0.5 250   5 days (5 3 50 g) 3.4 4.86 0.389 6.98 113 171 day1
200/0.5 250   5 days (5 3 50 g) 3.4 NA NA NA NA 62.6 96.2
70/0.5 250   5 days (5 3 50 g) 3.0 NA NA NA NA NA day1
130/0.4 500 10 days (10 3 50 g) 0.5 d e e f 32.8 35.7
22.8 1.14 9.1 NA
a 
Day 3, 5, or 10 according to length of treatment period.
b 
Three-compartment modelling.
c 
Taking days 1–5 into account.
d 
Day 1: 23.7; day 10: 21.8.
e 
Means from days 1 and 10.
f 
Not applicable for two-compartment modelling used; three-compartment modelling would yield a value of 33 hours.
AUC, area under the plasma concentration-time curve; CL, total body clearance; NA, not available; t1/2a, initial/distribution half-life, t1/2 ,
terminal/elimination half-life; t1/2 , terminal/elimination half-life in a three-compartment model; , indicates much greater than.
From Jungheinrich C, Neff TA. Pharmacokinetics of hydroxyethyl starch. Clin Pharmacokinet. 2005;44:681–699.
438 Part III   • Circulatory System

In the Efficacy of Volume Substitution and Insulin

Table 17-5 Therapy in Severe Sepsis multicenter, randomized trial
evaluating adult ICU patients with severe sepsis, patients
Pharmacokinetic Parameters after a Single Dose
were randomized to receive either intensive insulin ther-apy
of Hydroxyethyl Starch 6% (130/0.4) 500 mL in
or conventional insulin therapy in addition to either HES
Different States of Renal Insufficiency
10% pentastarch, HES 200/0.5, or lactated Ringer’s for fluid
resuscitation. Primary endpoints were death and mean
Renal Mean (CV %) score for organ failure. There were 537 p atients who were
Variable a (Geometric) 95% CI evaluated and the trial was stopped early due to increased
Group
severe hypoglycemia events in the intensive in-sulin therapy
AUC(0 inf) 15 30 41.1 (19.9) (33.4, 50.6) group, but the comparison between HES and lactated
(mg h/mL) 30 50 35.1 (13.9) (28.1, 43.8) Ringer’s was continued with all patients receiving
50 80 20.0 (6.8) (18.4, 21.8) conventional insulin therapy. HES therapy was associated
80 120 25.5 (21.3) (18.3, 35.4) with higher rates of acute renal failure (34.9%, 22.8% in the
All subjects 29.8 (34.4) (25.3, 35.0) lactated Ringer’s group, p 5 0.002) and renal replace-ment
Cmax (mg/mL) 15 30 4.68 (17.4) (3.90, 5.62)
therapy than lactated Ringer’s (18.3%, 9.2% lactated
30 50 4.37 (14.1) (3.50, 5.46)
50 80 3.48 (12.5) (2.99, 4.05) Ringer’s group).16
80 120 5.11 (25.4) (3.45, 7.57)
All subjects 4.34 (21.9) (3.91, 4.81)
Total plasma 1530 0.73 (20.3) (0.59, 0.90) Assessing Fluid
clearance 30 50 0.85 (12.8) (0.69, 1.05) Responsiveness
(L/h) 50 80 1.52 (6.9) (1.40, 1.65)
80 120 1.19 (21.3) (0.86, 1.65) Fluid responsiveness may be defined as a 15% i ncrease in
All subjects 1.02 (34.9) (0.87, 1.20) cardiac output following a 500-mL IV fluid bolus, in-dicating
Volume of 15 30 14.2 (18.4) (11.7, 17.2) that the patient is still on the ascending limb of the cardiac
distribution 30 50 15.4 (12.7) (12.7, 18.7) output/end diastolic volume curve, also re-
at steady 50 80 27.1 (6.6) (24.9, 29.5) ferred to as the cardiac function curve17 (Fig. 17-2). Fluid -
state (L) 80 120 19.9 (23.1) (13.8, 28.7) administration to a patient on the plateau part of the curve
All subjects 18.4 (31.2) (15.9, 21.3) may be of little benefit and result in adverse effects. Filling
Terminal half- 15 30 15.9 (8.8) (14.5, 17.4) pressure measures, particularly central venous pressure,
life (h) 30 50 15.5 (9.6) (13.3, 18.0)
50 80 15.9 (5.4) (14.8, 17.1)
80 120 17.2 (6.8) (15.4, 19.2)
All subjects 16.1 (8.1) (15.5, 16.7)
HES, hydroxyethyl starch, CV, coefficient of variation, CI,
confidence interval; AUC, area under the time
concentration curve; Cmax, peak concentration.
a
 Defined according to measurements of creatinine clearance
(mL/min/ 1.73 m2).
From Jungheinrich C, Scharpf R, Wargenau M, et al. The pharmacokinet-
ics and tolerability of an intravenous infusion of the new hydroxyethyl
starch 130/0.4 (6%, 500 mL) in mild-to-severe renal impairment.
Anesth Analg. 2002;95:544–551.

HES (6% [130/0.42] Tetraspan, B. Braun Melsungen AG,

Melsungen, Germany) has also been evaluated in a multi-
center, parallel-group, blinded, randomized trial of 798 adult
ICU patients with severe sepsis versus Ringer’s acetate in the
Scandinavian Starch for Severe Sepsis/Septic Shock trial. Pri-
mary outcomes measured were death or end-stage kidney
failure at 90 days. Death was greater at 90 days in the HES
group (51% vs. 43%, p 5 .03). One patient in each group had
end-stage kidney failure; however, in the 90-day period, 22% of
HES patients were treated with renal replacement therapy
15
versus 16% in the Ringer’s acetate group (p 5 .04).
FIGURE 17- 2  Schematic representation of Frank–Starling
relationship between ventricular preload and stroke volume. A
given change in preload induces a larger change in stroke
volume when the ventricle operates on the ascending portion of
the relationship (A, condition of preload dependence) than
when it operates on the flat portion of the curve (B, condition of
preload independence). (From Michard F, Teboul JL. Using
heart-lung interactions to assess fluid responsiveness during
mechanical ventilation. Critical care. 2000;4:282–289).
 Chapter 17  • Intravenous Fluids and Electrolytes
correlate poorly with blood volume, and changes in central
venous pressure have been shown to poorly predict he-
18
modynamic response to fluid challenge. Stroke volume
changes due to increases or decreases in right ventricular
preload may be used to assess fluid responsiveness. Posi-
tive pressure ventilation decreases right ventricular stroke
volume by decreasing venous return to the right heart and
increasing right ventricular afterload. The decrease in right
ventricular stroke volume is passed on to the left ventricle
over subsequent cardiac cycles and if the left ventricle is
preload dependent, decreases in the left ventricle stroke
volume will cause a decrease in the arterial pulse pressure.
These cyclic changes associated with positive airway pres-
sure are greater when the ventricles are functioning on the
steep, ascending portion of the cardiac function curve.
Variation in the arterial pulse pressure (PPV) can be de-
rived from analysis of the arterial pressure waveform and
variation greater than 12% to 13% is predictive of volume
responsiveness.19 Other measures of these positive pres-
sure–associated stroke volume changes include systolic
pressure variation of the arterial waveform, stroke volume
variation (SVV) derived from arterial pulse contour anal-ysis,
pleth variability index derived from pulse oximeter waveform
analysis, inferior vena cava diameter variation measured by
echocardiography, and descending aortic blood velocity
measured by esophageal Doppler. Measures dependent on
variations caused by positive pressure ven-tilation are
limited by the presence of arrhythmia, spon-taneous
breathing, tidal volume settings (8 mL/kg i deal body weight
19
minimum required for PPV and SVV), low
lung compliance (,mL/cm H 2O), increased abdomi-
20
nal pressure, and open chest surgery.
The end-expiratory occlusion test is useful in ventilated
patients with cardiac arrhythmias, mild amplitude sponta-
neous breathing activity, or low tidal volume positive pres-
sure ventilation. The test assesses the effect of a 15-second
interruption in the ventilation on cardiac preload.
A increase in pulse contour cardiac output (sensitivity
91%, specificity 100%) or pulse pressure (sensitivity 87%,
21
specificity 100%) is suggestive of volume responsiveness.
Passive leg raising maneuvers (PLR) can be used to as-
sess preload responsiveness in spontaneously breathing
patients with arrhythmias but is limited in patients with
intraabdominal hypertension. The test is performed in a
supine patient by elevating the legs to 45 d egrees while
assessing cardiac output or stroke volume over 30 t o
seconds. Cardiac output measures during PLR are more
accurate in predicting fluid responsiveness than arterial
22
pressure measurements during the maneuver.
Important Fluid Constituents
Magnesium
Magnesium is almost all intracellular in bone (53%), mus-cle
(27%), and soft tissues (19%), with less than 1% of total
439
body magnesium in the extracellular fluid and only 0.3% in
the plasma.23 Most intracellular magnesium is bound to
adenosine 5’-triphosphate and DNA, with less than 3%
being in solution and ionized immediately available for
intracellular magnesium homeostasis.24 Plasma magne-
sium level is normally 1.7 to 2.4 mg/dL, where it is found in
three states: ionized (62%), protein bound (33%), and
complexed to anions (5%).23 Given these distributions,
plasma magnesium measurements may not be represen-
tative of total body magnesium stores. Also, magnesium
measurements can be falsely elevated with hemolysis of the
blood sample, which releases the intracellular elec-trolytes.
Ingested magnesium is absorbed in the small intestines,
primarily the ileum (75%),24 via passive con-centration
effects and in the colon by active transcellular absorption. 25
Excretion occurs via the kidney with more than 95% of the
filtered magnesium being reabsorbed in the renal tubules,
with this mechanism effectively regulat-ing the plasma level.
Reabsorption occurs primarily (70%) in the ascending loop
of Henle via passive mechanisms with a small amount
occurring in both the proximal tubule via passive
mechanisms and distal convoluted tubules via active
mechanisms.24 Bone, as the primary store of total body
magnesium, provides a b uffer for plasma mag-nesium
levels through poorly understood mechanisms controlling
magnesium incorporation into bone by os-teoblasts and
removal by osteoclasts.25 Genetic mutations in colon
transport channels25 and loop of Henle junction proteins24
can both result in hypomagnesemia.
Role of Magnesium
Magnesium plays a key role in many biologic processes
including protein synthesis, neuromuscular function, and
nucleic acid stability. It is involved in adenosine 5
-triphosphatase function, antagonizes N-methyl-d-as-partate
(NMDA) glutamate receptors, inhibits catechol-amine
release, and is involved in the regulation of other
electrolytes. For instance, magnesium antagonizes the
uptake and distribution of calcium and modulates so-dium
and potassium currents thru nicotinic acetylcholine
receptors, NMDA receptors, and ion pumps, thus affect-ing
membrane potentials. Magnesium has antiarrhythmic
properties related to calcium channel antagonism.24 Intra-
venous (IV) magnesium administration can exert muscle-
relaxing effects, enhance nondepolarizing neuromuscular
blockers, attenuate muscle fasciculations and potassium
release with administration of succinylcholine, and precip-
itate skeletal muscle weakness in patients with Lambert-
Eaton syndrome and myasthenia gravis. It has been used to
reduce anesthetic requirements and attenuate cardiovascu-
lar effects of laryngoscopy and intubation. Magnesium has
been shown to vasodilate blood vessels in many vascular
beds (mesenteric, skeletal muscle, uterine, cerebral, coro-
nary, and the aorta). It also decreases blood–brain barrier
disruption and limits cerebral edema formation after brain
injury.26 Side effects of IV administration include burning
440 Part III   • Circulatory System
or pain on injection, drowsiness, nausea, headache, dizzi-
ness, muscle weakness, hypotension, and bradycardia.
Hypomagnesemia
Hypomagnesemia may result from dietary defi iency (as
seen in chronic alcoholism), gastrointestinal malab-
sorption or secretion (diarrhea, vomiting, laxative use),
renal losses (medication effects, nephrotoxic agents, -
endocrine disease, diabetic nephropathy), and chelation
(citrate binding in the case of massive transfusion). 24 It is
seen in as many as 11% of hospitalized patients and
65% of patients in the ICU. Clinical manifestations of
hypomag-nesemia result in cardiac and neuromuscular
disorders and include symptoms of nausea, vomiting,
weakness, convulsions, tetany, fasciculations, as well as
electrocar-diogram (ECG) abnormalities (prolonged PR
and QT intervals, diminished T-wave morphology,
torsades de pointes, and others) and accompanying
hypokalemia and hypocalcemia.
Hypermagnesemia
Hypermagnesemia is rare and most commonly occurs
with excessive administration of magnesium for thera-
peutic purposes. Clinical manifestations include QRS
widening, hypotension, narcosis, diminution of deep
tendon refle es, respiratory depression from paralysis
of muscles of ventilation, heart block, and cardiac
arrest. Immediate treatment of life-threatening
hypermagnese-mia is with calcium gluconate, 10 to 15
mg/kg IV, followed by diuretics or dialysis, along with
appropriate respiratory and circulatory support.
Preeclampsia
Magnesium appears to improve the clinical symptoms of
preeclampsia by causing systemic, vertebral, and uter-ine
vasodilation via direct effects on vessels as well as by
increasing concentrations of endogenous vasodila-tors
(endothelium-derived relaxing factor and calcitonin gene–
related peptide) and attenuating endogenous vaso-
constrictors (endothelin-1). Suggested dosing regimens of
magnesium sulfate based on randomized trial data are 4 g
IV loading dose over 10 to 15 minutes followed by infu-sion
of 1 g per hour for 24 hours or 4 g IV l oading dose with 10
g i ntramuscular (IM) followed by 5 g IM e very 4 hours for
24 hours. Many other dosing regimens exist. 27 Infusions or
repeat dosing should be combined with clini-cal monitoring
of urine output, respiratory rate, and deep tendon refle es.
Serum monitoring of magnesium levels should be
performed for signs of toxicity or renal impair-ment.
Magnesium crosses the placenta and may result in neonatal
lethargy, hypotension, and respiratory depres-sion if
administered for prolonged duration (more than 48 hours).24
In a Cochrane Summaries review, magnesium was shown
to decrease the risk of progression to eclamp-sia (RR, 0.41;
CI, 0.29–0.58), decrease the risk of placental abruption
(RR, 0.64; CI, 0.5–0.83), and increase caesarean
section (RR, 1.05; CI, 1.01–1.1) but does not clearly af-
fect maternal morbidity, stillbirth, or neonatal death or
neurosensory disability at age 18 months. Reductions in
maternal death were found to be nonsignificant.28
Cardiac Dysrhythmias
Excess magnesium blocks myocardial calcium influx re-
sulting in decreased sinus node activity, prolonged atrio-
ventricular (AV) conduction time, and increased AV node
refractoriness. Arrhythmias associated with hypomagne-
semia are often29 accompanied by hypokalemia. Normal-
ization of both electrolytes is recommended. 23 Magnesium
administration may decrease the incidence of severe
arrhythmia after myocardial infarction but use is limited by
the incidence of hypotension.24 Th re is no evidence that
magnesium infusion during human cardiopulmonary
resuscitation increases survival to hospital discharge; how-
ever, magnesium is recommended for patients with poly-
morphic wide complex tachycardia associated with familial
or acquired long QT syndrome (torsades de pointes). 30 For
digoxin-induced tachyarrhythmias in hypomagnesemic
patients, magnesium should be administered while await-
ing digoxin antibodies.24 Prophylactic administration of
magnesium during cardiopulmonary bypass has been
shown to decrease the incidence of postoperative atrial
fibrillation after coronary artery bypass graft urgery.
Analgesia
Magnesium has antinociceptive effects when admin-
istered IV or intrathecally, possibly due to inhibition of
calcium influx, antagonism of NMDA receptors, or
pre-vention of NMDA signaling. Data to support the
use of magnesium as an analgesic or for preventative
24
analgesia at this point is conflicting.
Asthma
Magnesium causes bronchodilatation via inhibition
of calcium-mediated smooth muscle contraction,
inhibi-tion of histamine release from mast cells, and
inhibition of nicotinic acetylcholine release. IV
magnesium (not inhaled) has been reported to
improve bronchodilatation when standard therapies
23,31
have failed; however, responses are variable.
Pheochromocytoma
Magnesium’s arteriolar-dilating effects combined
with re-duction in catecholamine release may be
beneficial in the management of patients with
pheochromocytoma prior to tumor excision and in
32,33
hemodynamic catecholamine crisis.
Calcium
As an important component of the skeleton, there is more
calcium in the body than any other mineral. The plasma
concentration of calcium is maintained between 4.5 and
 Chapter 17  • Intravenous Fluids and Electrolytes
5.5 mEq/L (8.5 to 10.5 mg/dL) by an endocrine control
system involving vitamin D, parathyroid hormone, and
calcitonin, which regulate intestinal absorption, renal
reabsorption, and bone turnover. Total plasma calcium
consists of calcium bound to albumin and proteins (40%),
calcium complexed with citrate and phosphorus ions
34
(9%), and freely diffusible ionized calcium (51%). It is
the ionized fraction of calcium that produces physiologic
effects and is normally 2 to 2.5 mEq/L. The ionized con-
centration of calcium depends on arterial pH, with acido-
sis increasing and alkalosis decreasing the
concentration. Additionally, plasma albumin binds
nonionized calcium, thus, in low albumin states, less
nonionized calcium is protein bound making more
available to return to stor-age sites, such as bone and
teeth. This may decrease the total plasma calcium, but
symptoms of hypocalcemia do not occur unless the
ionized calcium concentration is also decreased. Thus,
nonionized plasma calcium levels must be interpreted
with knowledge of the plasma albu-min concentration
and can be corrected according to the following formula:
corrected Ca11 (mg/dL) 5 measured Ca11 (mg/dL) 1 [0.8 3
(4.0 2 albumin (mg/dL)].35 How-ever, calculations to
correct serum nonionized calcium for hypoalbuminemia
36
may not be reliable in critically ill patients.
Role of Calcium
The majority of total body calcium (.99%) is present in bone
and provides the skeleton with strength and a reser-voir to
maintain the intracellular and extracellular calcium
concentrations. Calcium is important for neuromuscular
transmission, skeletal muscle contraction, cardiac muscle
contractility, blood coagulation, and intracellular sig-naling in
its function as a second messenger. In cardiac myocytes,
calcium regulates contraction, relaxation, and electrical
signals that determine rhythm and triggers hypertrophy via
calcineurin mechanisms.37 In vascular smooth muscle,
calcium induces a change in contractile state, increasing
and decreasing vessel diameter.38
Hypocalcemia
Hypocalcemia can result from decreased plasma concen-
tration of albumin, hypoparathyroidism, acute pancreati-tis,
vitamin D deficiency, chronic renal failure associated with
hyperphosphatemia, citrate binding of calcium (in the case
of transfused blood, particularly in hepatic fail-ure and
reduced citrate metabolism39,40 or use of citrate in dialysis
or plasmapheresis41), sepsis, and critical illness.41
Malabsorptive states rarely result in hypocalcemia as serum
levels are maintained by bone calcium stores. Symptoms of
hypocalcemia include neuromuscular ex-citability, including
muscle twitching, spasms, tingling, numbness, carpopedal
spasm, tetany, seizures, and car-diac dysrhythmias.42
Calcium can be administered by oral or IV route. IV
preparations include calcium chlo-ride which provides 27 mg
of elemental calcium/mL and
441
41
calcium gluconate which provides 9 mg. IV c
alcium chloride may cause local irritation and
necrosis if extrava-sated into the subcutaneous
tissues and therefore is best administered centrally.
Hypercalcemia
Hyperparathyroidism is the most important cause of
hypercalcemia and may be primary from parathyroid
adenoma (85%), parathyroid hyperplasia (10%) which may
be associated with multiple endocrine neoplasia syn-
dromes, or, rarely (,1%), parathyroid carcinoma. Second-ary
hyperparathyroidism results from abnormal feedback loops
present in renal failure and tertiary hyperparathy-roidism
from overactive responses to normal negative feedback
mechanisms. Malignancies, such as squamous cell lung,
breast, prostate, colon, adult T-cell, and multiple myeloma,
may result in release of parathyroid hormone– related
peptide from tumor cells, resulting in inappropri-ate
hypercalcemia.41 Malignancy-related hypercalcemia may
also result from osteolytic activity at sites of skeletal
metastases commonly seen in breast cancer, multiple my-
eloma, and lymphoma, and, rarely, malignancy-related hy-
percalcemia may result from tumor release of vitamin D.35
Hypercalcemia may be associated with benign familial
hypocalciuric hypercalcemia syndrome resulting from a
mutation in calcium-sensing receptors. Hypercalcemia is
also associated with granulomatous diseases such as sar-
coidosis, tuberculosis, leprosy, coccidioidomycosis, and
histoplasmosis and may result from excessive dietary sup-
plement or medication side effects as a result of diuretic or
lithium administration. Symptoms of hypercalcemia result
from smooth muscle relaxation in the gut (consti-pation,
anorexia, nausea, vomiting), decreased neuromus-cular
transmission (lethargy, hypotonia, confusion), renal effects
(polyuria, dehydration, nephrolithiasis), cardiac rhythm
abnormalities (QTc shortening, J waves following QRS
complex), as well as pancreatitis.41
Treatment of hypercalcemia depends on the exact eti-
ology but usually includes promoting renal excretion of
calcium with IV fluids and loop diuretics while avoiding
dehydration that would worsen any renal injury. Medica-
tions contributing to hypercalcemia should be discon-tinued
and parathyroidectomy performed if indicated.
Corticosteroids can be used to lower excessive calcium
levels by inhibiting the effects of vitamin D, reducing
intestinal absorption, and increasing renal excretion.
Hydrocortisone 200 to 400 mg IV per day for 3 to 5 days 41
or prednisone 40 t o 100 m g per day orally are recom-
mended treatments for hypercalcemia associated with
lymphoma and myeloma.35 IV bisphosphonates to inhibit
osteoclast bone resorption may be useful: pamidronate 60
to 90 mg IV or zoledronate 4 mg IV. Gallium nitrate 100 to
200 mg/mL/day IV infusion for 5 days is used to inhibit
osteoclastic bone resorption for paraneoplastic hypercal-
cemia refractory to bisphosphonate therapy.35 Calcitonin 4
to 8 International Units/kg subcutaneously or IM every
442 Part III   • Circulatory System
hours is less effective than bisphosphonates35 or gallium
41
nitrate and works by inhibiting bone resorption and in-
creasing renal calcium excretion. Mithramycin 25 mg/kg IV
blocks bone resorption by inhibiting osteoclast RNA
synthesis, but its use is limited by frequent dosing and
toxicity (renal, hepatic, and hematologic). 35 Hemodialysis
may also be used to treat acute, severe hypercalcemia.
Bone Composition
Bone is composed of an organic matrix that is strength-
ened by deposits of calcium salts. The organic matrix is
greater than 90% collagen fibers, and the remainder is a
homogeneous material called ground substance.
Ground substance is composed of proteoglycans that
include chondroitin sulfate and hyaluronic acid. Salts
deposited in the organic matrix of bone are composed
principally of calcium and phosphate ions in a
combination known as hydroxyapatites.
The initial stage of bone production is the secretion by
osteoclasts of collagen and ground substance. Calcium
salts precipitate on the surfaces of collagen fibers, forming
nidi that grow into hydroxyapatite crystals. Bone is con-
tinually being deposited by osteoblasts and is constantly
being absorbed where osteoclasts are active. The bone-
absorptive activity of osteoclasts is regulated by the para-
thyroid gland. Except in growing bones, the rate of bone
deposition and absorption are equal, so the total mass of
bone remains constant.
Because physical stress stimulates new bone forma-
tion, calcium is deposited by the osteoblasts in proportion to
the compression load that the bone must carry. The de-
position of bone at points of compression may be caused by
small electrical currents induced by stress, called the
piezoelectric effect, stimulating osteoblastic activity at the
negative end of current flow. Osteoblasts are maximally
activated at a bone fracture, the resulting bulge of osteo-
blastic tissue and new bone matrix being known as callus.
Osteoblasts secrete large amounts of alkaline phos-
phatase when they are actively depositing bone matrix. As a
result, the rate of new bone formation is reflected by
elevation of plasma concentration in alkaline phos-phatase.
Alkaline phosphatase concentrations are also in-creased by
any disease process that causes destruction of bone (e.g.,
metastatic cancer, osteomalacia, and rickets).
Calcium salts almost never precipitate in normal tis-
sues other than bone. A notable exception, however, is
atherosclerosis, in which calcium precipitates in the walls
of large arteries. Calcium salts are also frequently
depos-ited in degenerating tissues or in old blood clots.
Bisphosphonates
Bisphosphonates are drugs with a p hosphorus-carbon-
phosphorus (P-C-P) chemical structure that resemble
inorganic pyrophosphate (Fig. 17-3).43 Inorganic pyro-
phosphate is involved in regulation of bone mineralization by
binding hydroxyapatite crystals, inhibiting calcification.
The phosphate groups of bisphosphonates, like inorganic
pyrophosphate, bind hydroxyapatite crystals and become
incorporated into sites of active bone remodeling, thus in-
hibiting calcification. The hydroxyl group attached to the
central carbon further increases bisphosphonate’s ability to
bind calcium, and the final structural grouping is attached to
the central carbon to determine the bisphosphonate’s
potency for inhibition of bone resorption. First-genera-tion
bisphosphonates (etidronate, clodronate, tiludronate),
similar to inorganic pyrophosphate, become incorporated
into adenosine triphosphate (ATP) by class II aminoacyl-
transfer RNA synthetases after osteoclast-mediated uptake
from bone and mineral surface. This abnormal ATP cannot
be hydrolyzed, accumulates, and is believed to be cytotoxic
to osteoclasts. Second- and third-generation bisphospho-
nates (alendronate, risedronate, ibandronate, pamidronate,
and zoledronic acid) contain nitrogen or amino groups in this
position, which increases the antiresorptive potency by
binding and inhibiting farnesyl pyrophosphate syn-thase,
leading to osteoclast apoptosis. Second- and third-
generation bisphosphonate–induced osteoclast apoptosis
can be detected by a r eduction in biochemical markers of
bone resorption; maximum suppression occurs within 3
months of initiation of oral therapy. Suppression is noted to
be more rapid following IV administration. Duration of effect
is a function of potency for mineral matrix binding, with
zolendronic acid suppressing biochemical markers of bone
resorption for up to 1 year in women with post-menopausal
osteoporosis.
Clinical Uses
Bisphosphonates are useful in treating clinical
conditions characterized by increased osteoclast-
mediated bone re-sorption, for example: osteoporosis,
Paget disease of bone, osteogenesis imperfecta,
hypercalcemia, and malignant bony metastasis.
Pharmacokinetics
Oral bioavailability of bisphosphonates is low as they are
hydrophilic with less than 1% absorbed after an oral
dose. About 50% of the absorbed drug is retained in the
skel-eton, depending on renal function, rate of bone
turnover, and binding site availability, and the remainder
of drug is eliminated unchanged in the urine.43,44
Side Effects
Hypocalcemia may follow IV b isphosphonate infusion;
treatment is supportive with calcium and vitamin D sup-
plementation. Ten percent to 42% o f patients receiving
nitrogen-containing bisphosphonates IV may experience an
acute phase reaction44 with fever, myalgias, arthralgias,
headaches, and influenza-like symptoms. The incidence of
this reaction decreases with each subsequent infusion;
pretreatment with antihistamines and antipyretics44 can
reduce the incidence and severity of symptoms. Severe
musculoskeletal pain may occur at any point after initiating
 Chapter 17  • Intravenous Fluids and Electrolytes 443

FIGURE 17-3  Inorganic pyrophosphate (PPi) and bisphosphonates. (Reused from Drake MT, Clarke BL, Khosla S. Bisphos-
phonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008;83:1032–1045, with permission.)

bisphosphonates. Ocular inflammation (conjunctivitis,
uveitis, episcleritis, scleritis) has been associated with both
oral and IV bisphosphonate. Symptoms resolve within a few
weeks of discontinuation. Esophageal irritation and erosion
can occur with oral bisphosphonate therapy, particularly in
the presence of gastroesophageal reflux dis-ease or
esophageal stricture; thus, it is often recommended that
upright posture be maintained for minutes after ingestion
and that oral preparations be taken with a full glass of
water.44 Osteonecrosis of the jaw is associated with high-
dose IV b isphosphonate use, primarily zoledronic acid and
pamidronate, for oncologic conditions with an in-cidence of
1 to 10 per 100 patients. Associated risk factors for this
complication include poor oral hygiene, history of recent
dental procedures, denture use, and prolonged exposure to
high IV bisphosphonate doses. The condition is rare for oral
therapy of osteoporosis (1 in 10,000 to 1 in
100,000).43,44 Bisphosphonate dosing should be adjusted in
patients with renal insufficiency, and its use is cautioned in
patients with creatinine clearance less than 30 mL p er
minute because IV therapy may lead to rapid
deterioration of renal function. Serious atrial fibrillation
(life-threaten-ing or resulting in hospitalization or
disability) occurred more often in patients treated with
zoledronic acid than placebo (1.3% vs. 0.5%, p ,.001) in
the Health Outcomes and Reduced Incidence with
Zoledronic Acid Once Yearly trial; however, there was no
erence in the overall num-ber of atrial fibrillation events
in the two groups, and post hoc analysis of other trials
have not yielded an associa-tion. 44 Hepatotoxicity has
been reported with alendronate and zolendronate. 44
Denosumab
Denosumab is another antiresorptive therapy for meta-bolic
bone diseases. It is a human monoclonal antibody against
RANKL, a r eceptor activator required to differ-entiate and
activate osteoclasts. Denosumab is reversible, administered
biannually via subcutaneous route, and is not eliminated by
the kidneys. Like the bisphosphonates, it is also associated
with osteonecrosis of the jaw.45
444 Part III   • Circulatory System
Potassium
Potassium is the second most common cation in the
body and the principal intracellular cation. Approximately
3,500 mEq of potassium are present in the body of a 70-
kg patient (40 to 50 mE q/kg). With 98% of the body’s
po-tassium being intracellular,46 the concentration in the
extracellular fluid is about 4 mEq/L, and the intracellular
concentration is 150 mEq/L. Because of this huge differ-
ence in concentration, estimation of total body potassium
content from serum potassium values is inaccurate, even
though the vast majority of potassium (.90%) is read-ily
exchangeable between the intra- and extracellular
compartments.
Role of Potassium
Potassium has an important influence on the control of
osmotic pressure and is a catalyst of numerous
enzymatic reactions. It is involved in the function of
excitable cell membranes (nerves, skeletal muscles,
cardiac muscle) and is directly involved in the function of
the kidneys. In car-diac cells, potassium decreases
action potential duration, electrical inhomogeneity, and
risk of digoxin toxicity. Potassium is an endothelial-
dependent vasodilator; it decreases vascular smooth
muscle cell proliferation and inhibits thrombus formation
and platelet activation.46 Disturbances of potassium
homeostasis contribute to car-diac dysrhythmias, skeletal
muscle weakness, and acid– base disturbances.
The kidney is the principal organ involved in body po-
tassium homeostasis, primarily through control of active
potassium secretion in the urine. This is erent from most
other electrolytes, which are regulated by control of
reabsorption in the distal tubule. A number of hormones
influence renal potassium secretion including aldosterone,
glucocorticoids, catecholamines, and arginine vasopressin.
Aldosterone acts at the renal collecting duct to increase
reabsorption of sodium ions, which favors potassium se-
cretion. Arginine vasopressin also increases secretion of
potassium at the distal collecting tubule. Glucocorticoids
influence renal potassium secretion by a direct action in the
renal parenchyma. Catecholamines decrease renal
secretion of potassium by an effect on the distal collect-ing
system. Acidosis opposes and alkalosis favors potas-sium
secretion. When uremia develops, gastrointestinal secretion
of potassium increases, and when creatinine clearance is
less than 20% of normal, gastrointestinal po-tassium loss
can approach 20% of uptake.
Drugs Causing Hypokalemia
Diuretics that induce renal potassium loss are probably the
most common cause of hypokalemia, but there are a num-
ber of other drugs that may result in this condition. Cate-
cholamines shift potassium intracellularly, predominantly
into the liver and skeletal muscle cells, and administration of
b-adrenergic agonists in the treatment of bronchial asthma
or premature labor may cause hypokalemia; in fact,
b agonists may be useful in the treatment of hyperkalemia.
Theophylline also causes potassium to move into cells, and
hypokalemia should be anticipated in the presence of the-
ophylline toxicity. Insulin induces potassium to move into
cells and is used to treat severe hyperkalemia. Hypokale-
mia is caused by gastrointestinal losses of potassium from
chronic laxative abuse or overaggressive bowel prepara-tion
for abdominal surgery. Large doses of penicillin and its
synthetic derivatives increase excretion of potassium in the
urine, and the direct nephrotoxicity of aminoglycoside
antibiotics can also lead to excessive potassium loss.
Drugs Causing Hyperkalemia
Drugs that increase serum potassium concentrations do so
by redistribution, suppression of aldosterone secretion,
inhibition of potassium secretion in the distal collecting duct,
or by direct cell destruction. Extracellular move-ment of
potassium can result in plasma hyperkalemia without an
increase in total body potassium. For example,
succinylcholine causes a release of potassium from skel-
etal muscle cells, resulting in an increase of the serum
potassium concentration by as much as 0.5 mEq/L. Digi-
talis toxicity can cause hyperkalemia by preventing potas-
sium entry into cells. b-Adrenergic antagonists can cause a
modest increase in the serum potassium concentration by
virtue of an extracellular shift. Nonsteroidal antiin-
flammatory drugs may cause hyperkalemia by preventing
aldosterone release. Potassium-sparing diuretics such as
spironolactone inhibit the secretion of potassium in the distal
collecting duct and can cause clinical hyperkalemia. Abrupt
cell lysis from chemotherapy for acute blood cell proliferative
malignancies can cause hyperkalemia through the release
of intracellular potassium.
Hypokalemia
Skeletal muscle weakness and a predisposition to cardiac
dysrhythmias are the most prominent symptoms of clini-cally
significant hypokalemia. At the cellular level, hypo-kalemia
causes hyperpolarity, increases resting potential, hastens
depolarization, and increases automaticity and excitability of
cardiac cells,47 predisposing to tachydys-rhythmias,
including torsade de pointes and atrial fibrilla-tion47, and
48
sudden cardiac death particularly in the setting of acute
myocardial infarction.46 Potassium depletion also produces
diastolic dysfunction of the myocardium.46
Treatment
It is important to determine the cause of hypokalemia before
aggressive potassium replacement is initiated. For example,
if serum potassium concentrations are acutely decreased
due to intracellular redistribution and potas-sium therapy is
initiated, potentially serious hyperkalemia could occur. If
total body depletion is the cause of hypo-kalemia, the
amount of increase in the plasma concentra-tion of
potassium produced by supplementation may be small due
to rapid redistribution into intracellular sites.
 Chapter 17  • Intravenous Fluids and Electrolytes
Life-threatening hypokalemia, presenting as malig-
nant cardiac dysrhythmias, acute digitalis intoxication, or
extreme neuromuscular collapse, requires supplemen-tal
IV potassium administration. The rate of potassium
infusion depends on the urgency of the indication, with a
common recommendation being administration of IV
potassium no greater than 10 mEq per hour peripher-ally
and 20 mEq per hour centrally in adults. Morbidity
associated with supplemental potassium therapy is not
trivial. Patients with diminished internal potassium regu-
lation, especially diabetics and renal failure patients, are
at risk for accidental treatment-induced hyperkalemia.
Hyperkalemia
The earliest sign of hyperkalemia is peaked T w aves on
ECG, which typically occurs when the serum potassium
concentration reaches 6 mEq/L. As the extracellular con-
centration increases further, the transmembrane gradient is
decreased, with prolongation of the P-R interval and QRS
widening on the ECG. At this point, the risk of asystole or
ventricular fibrillation due to cardiac conduction blockade
increases dramatically. Asystole may also occur due to de-
creased automaticity in the sinoatrial node. Occasionally,
hyperkalemia presents with neuromuscular symptoms such
as paresthesias and skeletal muscle weakness.
Treatment
The decision to treat hyperkalemia, in contrast to hypo-
kalemia, is based on the degree of increase in the serum
potassium concentration and the symptoms and signs
that are present. If ECG changes other than peaked T
waves occur, or if the serum potassium concentration is
greater than 6.5 mEq/L, the incidence of serious cardiac
compro-mise is high and rapid intervention is indicated.
Calcium is administered to rapidly offset the adverse
effects of potassium on cardiac conduction and contrac-
tility. Calcium activates calcium ion channels so that ion flux
through these channels generates an action potential and
restores myocardial contractility, eff ctively antago-nizing
the adverse cardiac effects of hyperkalemia. The IV
administration of 10 to 20 mL of a 10% calcium chloride
solution restores myocardial contractility in 1 to 2 min-utes
and lasts for 15 to 20 minutes. Some prefer calcium
gluconate over the chloride form because it induces more
potassium secretion by the renal tubules. The IV adminis-
tration of calcium must be slower in patients on digitalis
preparations because acute hypercalcemia can precipitate
digitalis toxicity. Serum potassium concentrations are not
significantly changed by IV administration of calcium.
Other measures to treat hyperkalemia include IV ad-
ministration of sodium bicarbonate, glucose-insulin mix-
tures, and b agonists to shift extracellular potassium ions
into the cells. Alkalization of the blood with sodium
bicarbonate, 0.5 to 1.0 mEq/kg IV, rapidly moves potas-
sium into cells, decreasing the serum potassium level for
as long as the arterial pH i s increased. Glucose-insulin
445
infusion (50 mL o f 50% glucose plus 10 units of regular
insulin) produces a sustained transfer of extracellular po-
tassium into cells, resulting in a 1.5 to 2.5 mEq/L
decrease in the serum potassium concentration after
approximately 30 minutes. Sodium polystyrene sulfonate
(Kayexalate) is an orally or rectally administered sodium
exchange resin used to remove extracellular potassium
in exchange for sodium in the large intestine. Potassium
removal from the body also may be achieved by loop
diuretics or, most rap-idly and effectively, hemodialysis.
Phosphate
Phosphate is the major intracellular anion. The majority
(85%) of total body phosphate is stored in the bone as
hydroxyapatite crystals within the organic matrix. Most of
the remainder is stored in soft tissue as phosphate, with
only 1% located in the plasma.49 The normal plasma
con-centration of phosphate is 3.0 to 4.5 mg/dL,
accounting for both organic and inorganic forms.
Phosphate is important in energy metabolism, intra-
cellular signaling (cyclic adenosine monophosphate and
cyclic guanosine monophosphate), cell structure (phos-
pholipids), oxygen delivery (2,3-disphosphoglycerate),
regulation of the glycolytic pathway, the immune system, the
coagulation cascade, and buffering to maintain normal acid–
base balance. Phosphorus regulation is a r esult of the
interplay of phosphate and calcium levels, vitamin D, and
parathyroid hormone on gastrointestinal absorption, renal
reabsorption, and bone storage. Phosphorous ab-sorption
from the gastrointestinal tract and reabsorption in the kidney
proximal convoluted tubules is stimulated by Vitamin D, and
renal reabsorption of phosphorous is inhibited by the effects
of parathyroid hormone. Renal disease disrupts this
regulation, and ectopic tissue calcifi-cation as well as
hyperphosphatemia may result.34
A decrease in the plasma concentration of phosphate
permits the presence of a higher plasma concentration of
calcium and inhibits deposition of new bone salts. Hypo-
phosphatemia (phosphorus concentration ,1.5 mg/dL)
causes a decrease in the concentration of ATP and 2,3-di-
phosphoglycerate in erythrocytes. Profound skeletal muscle
weakness sufficient to contribute to hypoventilation may be
caused by hypophosphatemia, as well as central nervous
system dysfunction and peripheral neuropathy. Causes of
hypophosphatemia include alcohol abuse; prolonged par-
enteral nutrition; medications such as acetazolamide, cate-
cholamines, and theophylline; paracetamol overdose; large
burns; recovery from hypothermia; hemodialysis; salicylate
poisoning; and gram-negative bacteremia.49
Iron
Iron present in food is absorbed from the proximal small
intestine, especially the duodenum, into the circu-lation,
where it is bound to transferrin. Transferrin is a
446 Part III   • Circulatory System
glycoprotein that delivers iron to specific receptors on
cell membranes. Approximately 80% of the iron in
plasma en-ters the bone marrow to be incorporated into
new eryth-rocytes. In addition to bone marrow, iron is
incorporated into reticuloendothelial cells of the liver and
spleen. Iron is also an essential component of many
enzymes neces-sary for energy transfer. A normal range
for the plasma iron concentration is 50 to 150 mg/dL.
Iron that is stored in tissues is bound to protein as ferri-
tin or in an aggregated form known as hemosiderin. Hemo-
globin synthesis is the principal determinant of the plasma
iron turnover rate. When blood loss occurs, hemoglobin
concentration is maintained by mobilization of tissue iron
stores. Indeed, hemoglobin concentrations become chron-
ically decreased only after these iron reserves are depleted.
For this reason, the presence of a normal hemoglobin con-
centration is not a sensitive indicator of tissue iron stores.
The infant, parturient, and menstruating female may have
iron requirements exceeding amounts available in the diet
and develop iron-deficiency anemia. Absorption of iron from
the gastrointestinal tract is increased by ascorbic acid
(vitamin C) or in the presence of iron deficiency. Antacids
bind iron and impair its systemic absorption.
Iron Deficiency
Iron deficiency is estimated to be present in 20% to 40%
of menstruating females but only about 5% of adult
males and postmenopausal females. Attempts to prevent
this de-ficiency of iron in large parts of the population
include the addition of iron to flour, use of iron-fortified
formulas for infants, and the prescription of iron-
containing vitamin supplements during pregnancy.
Causes
Causes of iron-defi iency anemia include inadequate dietary
intake of iron, increased iron requirements due to
pregnancy or blood loss, or interference with absorption
from the gastrointestinal tract. Most nutritional iron defi-
ciency in the United States is mild. Severe iron deficiency is
usually the result of blood loss, either from the gastro-
intestinal tract or, in females, from the uterus. Partial gas-
trectomy,50 malabsorptive bariatric surgery,51 and sprue are
causes of inadequate iron absorption.
Diagnosis
Iron deficiency initially results in a decrease in iron stores
and a parallel decrease in the erythrocyte content of iron.
Depleted iron stores are indicated by decreased plasma
concentrations of ferritin and the absence of reticuloen-
dothelial hemosiderin in a bone marrow aspirate. Plasma
ferritin concentrations of less than 12 mg/dL are diagnos-tic
of iron deficiency. Iron-deficiency anemia is defined as
depletion of total body iron associated with a decreased red
cell hemoglobin concentration. The large physi-ologic
variation in hemoglobin concentration, however, makes it
difficult to reliably identify all individuals with
iron-deficiency anemia. Because iron-deficiency anemia
is so common in infants, menstruating females, and re-
cent parturients, mild anemia in these patients is typically
treated empirically with iron supplementation before
pursuing a more exhaustive diagnostic workup. However,
in males and postmenopausal females, iron deficiency is
much less common so it is important to search for a
cause of blood loss whenever anemia is present.
Treatment
Prophylactic use of iron preparations should be
reserved for individuals at high risk for developing iron
deficiency, such as pregnant and lactating females,
low-birth-weight infants, and females with heavy
menses. The inappropri-ate prophylactic use of iron
should be avoided in adults because excessive
accumulation of iron may damage tissues.
In iron-deficiency anemia, administration of medici nal
iron increases the rate of erythrocyte production, resulting in
a r ise in hemoglobin concentration within 72 hours. If the
concentration deficit of hemoglobin before treatment is more
than 3 g/dL, therapeutic doses of oral or parenteral iron
should increase the hemoglo-bin about 0.2 g/dL/day. An
increase of 2 g/dL or more in the plasma concentration of
hemoglobin within 3 weeks is evidence of a positive
response to iron. If this response to iron therapy is not seen,
other causes of anemia should be considered, such as the
chronic blood loss, infectious process, or impaired
gastrointestinal iron absorption.
There is no justification for continuing iron therapy
beyond 3 weeks if a favorable response has not
occurred. If a r esponse to iron therapy is demonstrated,
the iron should be continued until the hemoglobin
concentration is normal and continued for 4 to 6 more
weeks to rees-tablish iron stores. Full replenishment of
tissue iron stores requires several months of therapy.
Oral Iron
Ferrous sulfate administered orally is the most frequent
choice for the treatment of iron-deficiency anemia and is
available as syrup, pills, or tablets. Ferric salts are less
efficiently absorbed than ferrous salts from the gastroin-
testinal tract. Although other salts of the ferrous form of
iron are available, they offer little or no advantage over
sulfate preparations. The usual therapeutic dose of iron
for adults to treat iron-deficiency anemia is 2 to 3 mg/ kg
(200 m g daily) in three divided doses. Prophylaxis and
treatment of mild nutritional iron deficiency can be
achieved with modest dosages of iron, such as 15 to 30
mg daily.
Nausea and upper abdominal pain are the most fre-
quent side effects of oral iron therapy, particularly if the
dosage is greater than 200 mg daily. Hemochromatosis is
unlikely to result from oral iron therapy that is admin-istered
to treat nutritional anemia. Fatal poisoning from overdose of
iron is rare, but children 1 to 2 years of age are
 Chapter 17  • Intravenous Fluids and Electrolytes
most vulnerable. Symptoms of severe iron poisoning may
occur within 30 minutes as vomiting, abdominal pain, and
diarrhea. In addition, there may be sedation, hyperventi-
lation due to acidosis, and cardiovascular collapse. Hem-
orrhagic gastroenteritis and hepatic damage are often
prominent at autopsy in fatal iron toxicity. If iron over-dose is
suspected, a plasma concentration of greater than 0.5
mg/dL confirms the presence of a life-threatening sit-uation,
which should be treated with deferoxamine.
Parenteral Iron
Parenteral iron acts similarly to oral iron but should
be used only if patients cannot tolerate or do not
respond to oral therapy. In addition, tissue iron
stores may be restored more rapidly with parenteral
iron than oral therapy. Th re is no evidence,
however, that the increase in hemoglobin is more
prompt with parenteral iron than with oral iron.
Iron dextran injection contains 50 mg/mL of iron and
is available for IM or IV use. After absorption, the iron
must be split from the glucose molecule of dextran to
become available to tissues. IM injection is painful, and
there is concern about malignant changes at the
injection site. For these reasons, IV administration of iron
is pre-ferred over IM injection. A dose of 500 mg of iron
can be infused over 5 to 10 minutes.
The principal major adverse effect of parenteral iron
therapy is the rare occurrence of a severe allergic reaction,
presumably due to the presence of dextran. Less severe
reactions include headache, fever, generalized lymphade-
nopathy, and arthralgias. Hemosiderosis is more likely to
occur with parenteral iron therapy because it bypasses
gastrointestinal absorptive regulatory mechanisms.
Copper
Copper is present in ceruloplasmin and is a constituent
of other enzymes, including dopamine b-hydroxylase and
cytochrome C oxidase. It is bound to albumin and is an
essential component of several proteins. Copper is
thought to act as a catalyst in the storage and release of
iron from hemoglobin. It is believed to be essential for the
formation of connective tissues, hematopoiesis, and
function of the central nervous system. Copper
deficiency is rare in the presence of an adequate diet.
Supplements of copper should be given during prolonged
hyperalimentation.
Zinc
Zinc is an enzymatic cofactor essential for cell growth and
the synthesis of nucleic acid, carbohydrates, and proteins.
Adequate zinc is provided by a diet containing sufficient
animal protein. Diets in which protein is obtained pri-marily
from vegetable sources may not supply adequate zinc. Zinc
deficiency may occur in elderly or debilitated
447
patients or during periods of increased requirements as
in growing children, pregnancy, lactation, or infection.
Severe zinc deficiency occurs most often in the
presence of malabsorption syndromes. Symptoms of
zinc defi-ciency include disturbances in taste and smell,
suboptimal growth in children, hepatosplenomegaly,
alopecia, cutane-ous rashes, glossitis, and stomatitis.
Chromium
Chromium is important in a cofactor complex with insulin
and thus is involved in normal glucose utilization.
Deficiency has been accompanied by a diabetes-like
syn-drome, peripheral neuropathy, and encephalopathy.
Selenium
Selenium is a constituent of several metabolically impor-
tant enzymes. A selenium-dependent glutathione per-
oxidase is present in human erythrocytes. There seems
to be a close relationship between vitamin E and sele-
nium. Deficiency of selenium has been associated with
cardiomyopathy, suggesting the need to add this trace
element to supplements administered during prolonged
hyperalimentation.
Manganese
Manganese is concentrated in mitochondria, especially in
the liver, pancreas, kidneys, and pituitary. It influences
the synthesis of mucopolysaccharides, stimulates
hepatic synthesis of cholesterol and fatty acids, and is a
c ofac-tor in many enzymes. Deficiency is unknown
clinically, but supplementation is recommended during
prolonged hyperalimentation.
Molybdenum
Molybdenum is an essential constituent of many
enzymes. It is well absorbed from the gastrointestinal
tract and is present in bones, liver, and kidneys.
Deficiency is rare, whereas excessive ingestion has
been associated with a gout-like syndrome.
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