Ebook Oxford textbook of critical care (2/E): Part 2

(BQ) Part 2 book Oxford textbook of critical care has contents: Acute on chronic hepatic failure, the renal system, acute hepatic failure, nutritional failure, nutrition, the neurological system, the metabolic and endocrine systems,.... and other contents.

SECTION 7 Nutrition

Part 7.1 Physiology  950

PART 7.1 Physiology

201 Normal physiology of nutrition  951

Annika Reintam Blaser and Adam M. Deane

202 The metabolic and nutritional response to critical illness  956

Linda-Jayne Mottram and Gavin G. Lavery

Normal physiology of nutrition

Annika Reintam Blaser and Adam M. Deane

Key points

◆ Ingested carbohydrate, glycogenolysis, and gluconeogenesis

are essential for function of brain and anaerobic tissues that depend on glucose as their main energy source

◆ Fat is the most energy-rich nutrient, but most of ingested

lipids will be stored in adipose tissue because the oxidative capacity for lipids is low

◆ During periods of inadequate energy delivery, ingested or

endogenous proteins are diverted into glucose metabolism, and this provides a rationale to deliver more protein during these periods

◆ Basic metabolic rate (BMR) is the largest component of total

daily energy requirements, even in the case of very high cal activity or acute illness

physi-◆ Daily energy requirements range from 1800 to 2800 kcal/

day or 25 to 30 kcal/kg body weight (BW)/day roughly—

carbohydrates should provide 55–60%, lipids 25–30%, and proteins 10–15%

Body composition

Water (approximately 60% in adult males and 50% in females [1] ),

protein, minerals, and fat are the main components of human

body Essential fat is contained in bone marrow, the heart, lungs,

liver, spleen, kidneys, intestines, muscles, and central nervous

system Fat located in adipose tissue is called storage fat The

two-component model distinguishes between fat and fat-free mass

(FFM), while the three-component model further divides FFM

into body cell mass and extracellular mass [2] Lean body mass

is an indirect estimation of the weight of bones, muscles,

liga-ments, and internal organs, which can be calculated using various

equations [3]

Direct methods of assessing body composition, such as skinfolds,

bioelectrical impedance analysis, and hydrostatic weighing are not

routinely used in the critically ill

Estimation of nutritional status

Body mass index (BMI) = weight (kg)/height (m) and provides a

rough estimation of nutritional status [2] A limitation of BMI is

that the calculation does not distinguish between muscle and fat

mass A BMI of 18.5–24.9 kg/m2 is considered ‘normal’ regardless

of age or population [1] BMI has a U-shape relation to

morbid-ity and mortalmorbid-ity [2] In persons >60 years old being slightly

heav-ier (BMI 26–27) is associated with the longer life expectancy [2]

While being underweight is associated with poorer outcomes in the critically ill, obesity does not appear to be harmful (and may be beneficial) [4]

Estimation of the ideal body weight [5] is often inaccurate, but

the range may be useful and can be calculated (Broca’s index):

Clinical examination and laboratory tests

General clinical examination of skin, hair, eyes, gums, tongue,

bones, muscles, and thyroid gland tends only to reveal signs in cases of marked malnutrition or vitamin/mineral deficiencies

Laboratory tests such as blood haemoglobin, total lymphocyte

count, glucose, serum albumin, prealbumin, transferrin, total protein measurements, and calculation of nitrogen balance have limitations, but have been used Nitrogen balance is considered the most dynamic nutritional indicator

Essential nutrients: substrate and energy metabolism

Essential nutrients are substances that are not synthesized (or are synthesized in too small amounts) within the body and must, therefore, be ingested or administered They include essential fatty acids, essential amino acids, vitamins, and dietary minerals

Energy

Energy is derived from three major categories of macronutrient—protein, carbohydrate, and lipids—and is released by breaking down carbon–carbon bonds created in plants via photosynthesis Energy requirements to maintain stable weight can be estimated, using calculations or measured using calorimetry

Oxidative (burning for energy) and non-oxidative (storage,

synthesis) substrate metabolism occur to a different extent ing to the type of macronutrient and state of energy stores [2]

accord-Respiratory quotient (RQ) is used to describe oxidative substrate

metabolism

Carbohydrates

Carbohydrates are compounds comprised of carbon, hydrogen, and oxygen Depending on the composition of these molecules, carbo-hydrates are divided into mono-, di-, oligo-, and polysaccharides While carbohydrates are non-essential nutrients, they comprise a substantial proportion of calories (4.1 kcal/g) in a normal diet [1]

In plants, carbohydrate is stored as starch, whereas in animals it is stored as glycogen

Table 201.1 Nutritional requirements in adults

Nutrient Role Daily needs Deficiency Abnormalities in ICU

Macronutrients Energy, structure, all functions No absolute daily

requirements exist

Carbohydrates Major energy source, energy

storage and transport, structure 55–60% of calories,

max 4 g/kg BW at rest

Hypoglycaemia, ketoacidosis Hyperglycaemia

(insulin resistance, counter-regulatory hormones) Lipids Energy storage, cell membrane

structure, signalling molecules 25–30% of calories Malabsorption of fat-soluble

vitamins

Hyperlipidaemia with excessive parenteral nutrition and propofol Proteins Enzymes, structure, signalling,

immune response 10–15% of calories

0.8 g/kg BW Kwashiorkor, cachexia Protein energy wasting occurs frequently

Vitamin Role RDA Deficiency In ICU

A (retinol) Retinal pigment Male 1000 µg female 800 µg Night blindness, follicular

B1 (thiamine) Coenzyme in decarboxylation of

pyruvate and alpha-keto acids Male 1.5 mg, female 1.1 mg Beriberi, Wernicke’s encephalopathy Threshold for thiamine administration should

be low B2 (riboflavin) Coenzyme for oxidative enzymes Male 1.7 mg, female 1.3 mg Mouth ulcers, normocytic

B3 (niacin) also vitamin

PP or nicotinic acid Coenzyme, precursor for NAD and NADP Male 19 mg, female 15 mg Pellagra, neurological symptoms  

B6 (pyridoxine) Coenzyme in synthesis of amino

acids, haeme, neurotransmitters Male 2.0 mg, female 1.6 mg Muscle weakness, depression, anaemia   B12 (cobalamin) coenzyme (deoxyribonucleotids),

formation of erythrocytes, myelin 2 µg Neurological symptoms With pernicious anaemia (lack of intrinsic factor)

C (ascorbic acid) Cofactor in collagen synthesis 60 mg Scurvy Antioxidant effect, cave

oxalosis

D (1,25-cholecalciferol) Ca 2+ absorption and metabolism 5–10 µg Rickets  

E (alpha-tocopherol) Antioxidant Male 10 mg, female 8 mg Peripheral neuropathy Antioxidant effect

K Clotting, synthesis of

prothrombin, factors VII,IX,X Male 70–80 µg

Biotin (also vitamin B7

or H, or coenzyme R) Cofactor for several carboxylase enzymes; cell growth 30–100 µg Neurological symptoms, alopecia,

conjunctivitis, dermatitis   Folate (vitamin B9) Necessary for synthesis of DNA,

haemopoesis Male 200 µg female 180 µg (pregnancy 400) Megaloblastic anaemia, peripheral neuropathy, neural

Mineral Role RDA Deficiency In ICU

Calcium Bone, intracellular signalling 800–1200 mg Osteoporosis, arrhythmia

peripheral neuropathy

Deficiency reported during long-term parenteral nutrition Copper Cofactor (oxidative

phosphorylation, neurotransmitter synthesis etc.)

1.5–3 mg Myelodysplasia, anaemia,

leucopenia, neurological symptoms

Deficiency after gastric bypass Reduce replacement in liver failure Iron Haemoglobin and cytochromes Male 10 mg, female 15 mg Microcytic anaemia, mucosal

(continued)

CHAPTER 201 normal physiology of nutrition 953

As an energy source, glucose is oxidized to CO2 and water:

At rest, the maximum oxidative capacity is approximately 4 g glucose/

kg BW/day [2] If the glucose intake is greater non-oxidative

metab-olism occurs, resulting in glycogenesis (glycogen store is limited to

200–500 g; storing consumes about 6% of energy stored in glucose)

and, after reaching the limit, in lipogenesis (storing costs 23% of

energy) [6] As an isolated energy source blood glucose covers energy

needs for about 30 minutes, whereas glycogen would last for

approxi-mately one day [2] Glycogen is stored in hydrated form, making it less

energy-efficient, but easily available Hepatic or muscle glycogenolysis

occurs rapidly in response to hypoglycaemia or anaerobic demands

Gluconeogenesis is the synthesis of glucose from non-hexose

pre-cursors (lactate, pyruvate, intermediates of the citric acid cycle, 18 of

20 amino acids and glycerol) [1] Leucin and lysine together with fatty

acids are not gluconeogenic, but ketogenic Their breakdown-product

is acetyl coenzyme A  (CoA), which cannot generate pyruvate or

oxalo-acetate Gluconeogenesis is essential for the brain and

anaero-bic tissues (blood cells, bone marrow, renal medulla) that depend

on glucose as their main energy source [1], but is energy-expensive,

consuming 24% of energy contained in amino acids (AA) [6]

Lipids

Lipids are hydrophobic compounds that are soluble in organic

sol-vents such as acetone

Lipids contain 9.4 kcal/g of energy and can be ingested as

triglyc-erides, sterol esters or phospholipids [1] To generate energy, fatty

acids are oxidized to CO2 and water

C H COOH palmitic acid + 23O+106ADP +106P >16CO +16H O+10

−66ATP + heat RQ =16CO /23O = 0.70( 2 2 ) [eqn 3]

In resting humans the oxidative capacity for lipids is 0.7 g/kg BW/day [2] Greater amounts of ingested lipid will be stored as tri-glycerides in fat tissue Fat constitutes approximately 20% of body weight, and the standard triglyceride store has the capacity to cover the body’s energy requirements for about 2 months

Ketone bodies are produced when accelerated oxidation of fatty acids leads to incomplete breakdown, producing acetyl CoA faster than the citric acid cycle can utilize it [1] Ketone bodies (acetoac-etate, β-hydroxybutyrate, and acetone) may serve as an alternative energy resource, e.g during starvation up to 50% of brain energy demands might be met via ketone bodies [2]

Protein

Nitrogen differentiates protein from carbohydrates and fats The major source of endogenous protein is muscle, which is converted into energy via complex metabolic pathways When AA, either endogenous proteins or ingested, are metabolized to CO2 and water, 4.3 kcal/g of energy can be released [1] Protein metabolism in cells additionally results in the production of energy-containing metabo-lites (urea, ureic acid, and creatinine) The RQ for protein oxidation

is 0.80–0.85 [1] Protein stores are about 14% of body weight, but only half of it is available as an energy source, lasting for 10 days approximately In health, protein catabolism contributes less than 5%

of energy requirements, but this increases to 15% during starvation The body constantly breaks down proteins to AAs and synthesizes other proteins according to the current needs of the body (protein turnover) Nine out of 20 AAs are essential—the body cannot syn-thesize them at sufficient rates for long-term survival and they must

be ingested to replace the proteins oxidized during daily turnover Excess protein is converted to glycogen or triacylglycerols [1]

To maintain nitrogen balance in an average adult individual, ingestion of 0.6–0.8 g/kg BW/day of protein is needed [2] However, during periods of inadequate energy delivery greater amounts

of protein are diverted into glucose metabolism and, in catabolic states, there is a marked increase in endogenous protein break-down Accordingly, more protein either ingested or administered may be beneficial during these periods [7]

Nutrient Role Daily needs Deficiency Abnormalities in ICU

Magnesium Complex with ATP Male 350 mg, female 280 mg Muscle weakness, GI, and cardiac

symptoms Deficiency common and associated with major

adverse outcomes

liver failure

Phosphorus Major component of the

skeleton, nucleic acids, and ATP 800–1000 mg   Potentially catastrophic

reduction during refeeding syndrome

Potassium Membrane potential At least 3510 mg (conditional

recommendation by WHO) Arrhythmias Often life-threatening hyper- or hypo-K, narrow

therapeutic/normal range Selenium Antioxidant Male 70 µg, female 55 µg Cardiomyopathy Antioxidant effect

Zinc Antioxidant, cofactor Male 15 mg, female 12 mg Skin lesions, loss of appetite Antioxidant effect

RDA, Recommended daily allowance.

Adapted from a table published in Medical Physiology, Second Edition, Boron WF and Boulpaep EL, Copyright Elsevier 2012.

Table 201.1 Continued

SECTION 7 nutrition: physiology

954

Nitrogen (N) balance is the sum of protein degradation and

pro-tein synthesis, reflecting the changes in propro-tein stores where:

N Balance N= intake N losses− ,

N intake = protein intake g/day /6.25,( )  and

N losses = urinary urea N UUN , g/day, determined

hour urine collection + 4 gmiscellaneous other N losses

) from skin, mucosa and with faeces

[eqn 4]

N balance is used to estimate current protein requirements

Positive or negative N balances indicate anabolic or catabolic states

respectively

As in patients with renal replacement therapy (RRT)

measure-ment of UUN is not applicable; the total nitrogen appearance

(TNA) is used to express nitrogen losses [8] :

TNA in a patient with RRT = urea nitrogen loss +

AA nitrogen looss during RRT g+ change in interdialytic blood

nitrogen BUN g/L( ) ( ) total body water L( )

Protein energy wasting [9] due to inadequate protein intake and

high catabolism is thought to occur frequently in the critically ill

While preventing or limiting protein deficiency in this group is

often proposed as beneficial, it is not yet established that such an

approach improves outcomes

Other

Other essential nutrients include inorganic elements like calcium,

potassium, iodine, iron, trace elements (dietary minerals that are

needed in very small quantities) and vitamins, which are necessary

for normal functioning of the body The role, recommended daily

allowances and signs of deficiency of these essential vitamins and

minerals are presented in Table 201.1

Vitamins

Vitamins are divided into water-soluble (B,C) and fat-soluble (A,

D, E and K) groups Bonds between fat-soluble vitamins with

proteins are broken by the acidity of gastric juice and proteolysis

Assimilation of fat-soluble vitamins relies on lipid absorption and

their deficiency occurs in various fat malabsorption states

Thiamine (B 1) with its phosphorylated derivatives plays a

fun-damental role in energy metabolism and is used in the biosynthesis

of the neurotransmitters Its best-characterized derivate thiamine

pyrophosphate is a coenzyme in the catabolism of sugars and amino

acids Thiamine derivatives and thiamine-dependent enzymes are

present in all cells of the body, but the nervous system and the heart

are particularly sensitive to its deficiency Thiamine deficiency

may occur because of concomitant chronic disease or alcoholism

and can lead to severe neurological impairment and contribute to

increased mortality [10]

Vitamin K is pivotal for synthesis of coagulation factors VII, IX,

X, protein C and protein S in liver, acting as a co-factor for

carboxy-lation Its deficiency occurs with fat malabsorption, but also during

severe bleeding (disseminated intravascular coagulation) Previous treatment with vitamin K antagonists, blocking carboxylation of prothrombin (factor II), factors VII, IX and X, and making their complexes with Ca2+ and therefore usage for coagulation impos-sible, is common in hospitalized patients

Supplementation of vitamins E and C has been proposed as

hav-ing beneficial antioxidant effects in the critically ill [11] This has yet to be established and particularly in patients with renal failure excessive vitamin C may lead to oxalosis

Minerals

Calcium is necessary for the structure (calcium phosphate in

bones), signalling, and enzymatic processes (co-enzyme for ting factors, pre-synaptic release of acetylcholine) in the body

clot-Magnesium is essential for energy in every cell type in

organ-ism, as ATP, the main source of energy in cells, must be bound to a magnesium ion in order to be biologically active

Supplementation of minerals such as selenium and zinc has been

described in the critically ill and warrants further study [12].Next to the essential nutrients food includes fibres and other bal-last substances, carotinoides, bioflavonoids etc considered impor-tant for health, but their functions are clarified incompletely

Energy consumption

Estimation of energy consumptionBasal metabolic rate (BMR) is an estimation of metabolism,

measured under standardized conditions in the absence of

stim-ulation Resting metabolic rate (RMR) is measured during less

strict conditions and is therefore higher than BMR [1] BMR

and RMR are measured by gas analysis through either direct

(the body is positioned in a chamber to measure the body’s

heat production) or indirect (CO2 production is measured)

simpli-CHAPTER 201 normal physiology of nutrition 955

3 R Hume (1966) Prediction of lean body mass from height and weight

Journal of Clinical Pathology, 19, 389–91.

4 Heyland DK, Dhaliwal R, Jiang X, and Day AG (2011) Identifying

critically ill patients who benefit the most from nutrition therapy: the development and initial validation of a novel risk assessment tool

Critical Care, 15, R268.

5 Pai MP and Paloucek FP (2000) The origin of the ‘ideal’ body weight

equations Annals of Pharmacotherapy, 34, 1066–9.

6 Fontaine E and Müller MJ (2011) Adaptive alterations in

metabolism: prac-tical consequences on energy requirements in the severely ill patient

Current Opinion in Clinical Nutrition and Metabolic Care, 14, 171–5.

7 Shils ME, Shike M, Ross AC, Caballer B, and Cousins RJ (2006)

Modern Nutrition in Health and Disease, 10th edn London: Lippincott

Williams & Wilkins.

8 Chua HR, Baldwin I, Fealy N, Naka T, and Bellomo R (2012) Amino acid balance with extended daily diafiltration in acute kidney injury

Blood Purification, 33, 292–9.

9 Kopple JD (1999) Pathophysiology of protein-energy wasting in

chronic renal failure Journal of Nutrition, 129(1 Suppl.), 247S–51S.

10 Berger MM, Shenkin A, Revelly JP, et al (2004) Copper, selenium, zinc, and thiamine balances during continuous venovenous hemo- diafiltration in critically ill patients American Journal of Clinical

Nutrition, 80, 410–16.

11 Casaer MP, Mesotten D, and Schetz MRC (2008) Bench-to-bedside

review: Metabolism and nutrition Critical Care, 12, 222.

12 Andrews PJ, Avenell A, Noble DW, et al (2011) Randomised trial

of glutamine, selenium, or both, to supplement parenteral tion for critically ill patients; Scottish Intensive care Glutamine or

nutri-selenium Evaluative Trial Trials Group British Medical Journal,

◆ The metabolic response to critical illness is biphasic, the acute

stage being accompanied by increased hypothalamic pituitary

function and peripheral resistance to effector hormones

◆ The acute phase has been considered adaptive, increasing the

availability of glucose, free fatty acids, and amino acids as

sub-strates for vital organs

◆ Prolonged critical illness results in damped hypothalamic

responses that are implicated in the critical illness wasting

syndrome

◆ Cytokines can stimulate the hypothalamic pituitary axis

directly as part of the stress response in critical illness

◆ Gastrointestinal failure may in part be a neuroendocrine

phe-nomenon, with disordered hormonal and enteric nervous

sys-tem responses

Introduction

The metabolic response to critical illness is complex and affects

every body system The response to acute critical illness differs

from the response to more prolonged states These differences or

the dynamic complexity of the neuroendocrine changes

them-selves, may explain the failure of pharmacological manipulation to

date The gut response to critical illness is also an example of

neuro-endocrine derangement The interaction between body systems

becomes apparent when gastrointestinal failure and inadequate

nutrition combine to exacerbate the catabolic state Ultimately, the

consequence is to lengthen the illness, prolong intensive care stay,

and hamper the recovery process

The somatotrophic axis

Normal physiology

Human growth hormone (GH) is produced in the somatotrophic

cells of the anterior pituitary in response to hypoglycaemia,

exer-cise, sleep, high protein intake, and acute stress This process is

regulated by the stimulatory effect of growth hormone

releas-ing hormone (GHRH) from the hypothalamus and also by the

hunger-stimulating hormone, ghrelin Inhibitory effects on GH

release occur via somatostatin secretion from the hypothalamus

GH acts directly on the tissues causing lipolysis, anti-insulin effects,

sodium and water retention, and immunomodulation It also acts

indirectly via hepatic production of insulin-like growth factor

1 (IGF-1) to bring about protein synthesis and thus protect lean body mass

Acute critical illness

Serum GH levels are elevated overall and demonstrate increased pulsatility However, IGF-1 levels are lower and GH receptor expression is reduced, which together produce a state of peripheral

GH resistance Energy-consuming anabolic processes are halted, permitting the release of amino acids for use as an energy substrate The direct effects of lipid breakdown and antagonism of insulin are permitted, which again favourably releases energy reserves in the acute phase of critical illness [1]

Prolonged critical illness

Levels of GH are reduced with a more erratic and less pulsatile pattern of secretion, a process that is compounded by low ghre-lin levels Despite less peripheral resistance to GH, a state of rela-tive deficiency persists and contributes to critical illness wasting [2] The return of peripheral responsiveness to GH was thought

to provide a therapeutic target for exogenous GH administration, but actually results in higher morbidity and mortality These find-ings may be a function of timing of GH administration and remain under investigation Greater abnormalities are seen in the male GH axis, which has been theorized to account for some gender differ-ences in ICU outcome

The thyrotropic axis

Normal physiology

In health, thyrotropin-releasing hormone (TRH) is released from the hypothalamus and in turn the anterior pituitary secretes thyroid-stimulating hormone (TSH), with negative feedback via the thyroid hormones triiodothyronine (T3) and thyroxine (T4)

Acute critical illness

The adaptive response of the thyroid to critical illness is an energy conservation strategy, reducing expenditure on metabolic pro-cesses It is often called ‘non-thyroidal illness syndrome’, but may also be known as ‘low T3 syndrome’ or ‘sick euthyroid syndrome’ Laboratory parameters include low serum T3 levels, increased reverse T, while TSH and free T4 remain largely normal [3] Low T3 levels are partly due to reduced peripheral conversion from T4 The enzyme 5’-monodeiodinase catalyses this peripheral

CHAPTER 202 metabolic and nutritional response 957

conversion and accounts for 80% of free T3 in the circulation This

enzyme is inhibited during the stress response and in particular by

glucocorticoids It contains the novel amino acid selenocysteine

and so may be affected by selenium deficiency

Prolonged critical illness

As the illness progresses, free T4 decreases and is a reflection of

ill-ness severity Those with the lowest T3 and T4 levels in critical care

have the highest mortality [4] There is dampening of the normal

negative feedback loop TSH fails to increase and loses its pulsatile

secretion pattern, only doing so as the patient starts to recover

Non-thyroidal illness syndrome is associated with prolongation

of mechanical ventilation in the ICU population [5] Despite the

biological rationale for treating such a state of continued relative

hypothyroidism, there is little convincing proof of efficacy Others

[6] have argued for treatment with hypothalamic releasing

pep-tides, rather than thyroid hormone per se, but again definitive

evi-dence to support this strategy is lacking

The adrenocortictrophic axis

In health, corticotrophin-releasing hormone (CRH) from the

paraventricular nucleus is carried in the hypophyseal-portal tract

and stimulates release of adrenocorticotrophic hormone (ATCH)

Cortisol is produced in the zona fasiculata of the adrenal cortex and

a negative feedback loop exists to regulate secretion and synthesis

Acute critical illness

Plasma ACTH and cortisol levels increase with loss of the normal

circadian rhythm The hypothalamus is stimulated by a direct effect

of cytokines The typical effects of glucocorticoids are manifest

in order to maintain homeostasis after the stressful insult These

include use of alternative energy strategies, such as mobilization

of amino acids from extrahepatic tissues, lipolysis, and subsequent

utilization of glycerol, and gluconeogenesis in the liver They have

a regulatory role in the acute inflammatory response, by blocking

cytokine gene expression and up-regulating specific

anti-inflam-matory processes The cardiovascular effects of glucocorticoids

include the maintenance of vascular responsiveness to

catecho-lamines, endothelial integrity, and intravascular volume via their

mineralocorticoid actions [7] These anti-inflammatory and

vascu-lar effects explain the biological rationale for the use of low-dose

corticosteroids in septic shock [8]

Prolonged critical illness

When critical illness is protracted, plasma cortisol levels remain

high, but ACTH decreases It is likely that this effect is mediated

via peripheral mechanisms, such as substance P, atrial natriuretic

peptide, endothelin, and cytokines The adverse effects of

sus-tained hypercortisolism, such as muscle wasting, hyperglycaemia,

hypokalaemia, poor wound healing, and psychiatric sequelae

become apparent and can be seen as a maladaptive response [9,10]

Sex hormones and prolactin

In health gonadotrophin-releasing hormone (GNRH) is secreted

in a pulsatile pattern and stimulates the anterior pituitary to release

luteinizing hormone (LH) and follicle-stimulating hormone (FSH)

from the gonadotroph cells In males, LH drives testosterone

pro-duction in the Leydig cells of the testes

In the acute phase of critical illness, serum testosterone levels are low (in spite of elevated LH levels) and prolactin is high Low tes-tosterone switches off the anabolic processes that maintain skeletal muscle mass High oestradiol levels are found—an adaptation that was originally thought to be beneficial as oestrogens inhibit pro-inflammatory cytokine production Recent findings appear to con-tradict this and there is an association with increased mortality [11]

In prolonged critical illness there is a state of hypogonadal onadism and prolactin deficiency T- and B-lymphocytes possess pro-lactin receptors, requiring it for their function Hypoprolactinaemia may play a role in the immune paralysis seen in illnesses of longer duration The use of exogenous dopamine could theoretically sup-press prolactin secretion and negatively impact immune function Despite these concerns and a higher incidence of adverse events in shocked patients treated with dopamine, the evidence falls short of

hypog-it having an adverse impact on mortalhypog-ity [12]

The role of the autonomic nervous system

The classical ‘fight or flight’ response is mediated via adrenaline and noradrenaline A variety of physiological insults, such as pain, hypotension, hypoxia, acidosis, and hypercarbia can stimulate the sympathetic nervous system Pre-ganglionic sympathetic fibres ter-minate in the adrenal medulla and cathecholamines are released rapidly from synaptic vesicles The leukocyte itself can be an addi-tional source of cathecholamines

Cardiovascular responses occur via B1 receptors and include positive inotropy and chronotropy Stimulation of the renin-angiotensoin system at the juxta-glomerular cells acts to maintain intravascular volume and tone B2 receptor activation results in gluconeogensesis and glycongenolysis B2 stimulation dampens the pro-inflammatory cytokine response and in sepsis it alters the balance of T helper cells from THC1 to THC2 Some regulation also occurs via α-receptors Alpha-1-mediated vasconstriction acts

to maintain blood pressure, but reduced gut perfusion and motility are adverse consequences discussed in ‘Loss of Barrier Function’ The parasympathetic response to traumatic and infectious insults

is largely anti-inflammatory and occurs through the activation

of α7 nicotinic acetylcholine receptors This ated reduction in cytokine production occurs, not only from a direct effect on macrophages, but also indirectly via vagal splenic innervation

acetylcholine-medi-Vitamin D metabolism

Vitamin D deficiency is common in critical illness for two reasons:

◆ Vitamin D is lost through lack of serum binding proteins in acute illness

◆ Many chronic conditions predisposing to critical illness will reduce sunlight exposure and thus synthesis of Vitamin D in the skin

The clinical consequences of Vitamin D deficiency are bone tion, hypercalcaemic immune dysfunction, namely reduced innate responses and heightened adaptive responses, such as prolonged hypercytokinaemia [13]

resorp-The role of cytokines

Cytokines are intercellular messenger proteins that act on various cell types to bring about pro- and anti-inflammatory responses

SECTION 7 nutrition: physiology

958

during critical illness They can have local (autocrine or paracrine)

or widespread (endocrine) effects

Cytokines are produced via stimulation of Toll-like receptors

(TLRs), which may be a future pharmacological target At the

cel-lular level, TLRs are activated not only by the presence of

micro-bial proteins as part of the innate immune response, but also by

non-infectious insults, such as tissue injury Here, endogenous

intra-cellular proteins released from dying cells are the trigger, and are

known as ‘alarmins’ The cell surface TLRs initiate the nuclear factor

kappa-beta (NF-κβ) transcription pathway, which ultimately

gen-erates cytokine proteins Note that some cytokines can be released

more readily in response to catecholamines with no requirement for

gene transcription Tumour necrosis factor α (TNFα) has a positive

effect on NF-κβ and is responsible for triggering further cytokine

release, in what is described clinically as the ‘cytokine storm’

There are several cytokine families (Table 202.1) including the

interleukins, interferons, tumour necrosis factors, chemokines,

and colony-stimulating factors Burns, tissue trauma, or infection

results in a cascade of pro-inflammatory cytokines, of which the

key players are TNFα, IL-1, IL-6, and IL-8 Levels of these cytokines

correlate with illness severity and outcome Cytokine gene

poly-morphisms and aberrant responses to TLR ligands are partly

accountable for the individual response to sepsis and other insults

However, despite the wealth of research in this area, modulation of

interleukins and TNFα with recombinant pharmacological agents has not been widely successful

Pathophysiology of the gastrointestinal tract in critical illness

The normal functions of the gastrointestinal (GI) tract extend beyond digestion, absorption, and elimination Important immune and metabolic functions are performed by the gut, and crucially it forms a barrier between bacteria in the intestinal lumen and the sterile internal milieu

The GI dysfunction associated with critical illness has been poorly defined and lacked universal terminology until recently [14] A number of clinical manifestations of GI dysfunction are recognized, including stress ulceration, gastro-oesophageal reflux, intolerance of enteral nutrition, ileus, acalculous cholecystitis, abdominal compartment syndrome, intestinal ischaemia, and gas-trointestinal hypermotility

The pathophysiology of these well recognized clinical ena can be explained by the complex interplay between the epithe-lium, commensal bacteria, and the mucosal immune system [15] The gut has been described as the ‘motor’ of multi-organ dysfunc-tion syndrome and a number of key factors in its response to criti-cal illness reinforce that status as a driver of systemic inflammation

phenom-Loss of barrier function

Although perfusion of the gut is autoregulated, the nal epithelium is predisposed to ischaemia for anatomical rea-sons Macroscopically, endogenous cathecholamines acting on alpha-receptors constrict the splanchic circulation Arginine vasopressin and angiotensin also contribute to this non-occlusive ischaemia The small bowel is particularly prone to this

gastrointesti-Microscopically, the mucosa at the tips of the villi are most at risk of hypoxia A countercurrent blood supply to the metabolically active villus via a central arteriole and network of venules renders

it extremely supply dependent The damaged enterocytes slough off and permit translocation of endotoxins and bacteria In addition, ischaemia-reperfusion injury and oxidant stress are likely to fur-ther exacerbate mucosal injury

Even in the absence of epithelial cell death, the barrier function

of the intestine can be lost through disruption of cellular tight tions This paracellular route is another way in which endotoxin and bacteria may enter the circulation or lymphactics, resulting in sepsis or the systemic inflammatory response syndrome Cytokines are likely to be responsible, with IL-4, interferon-gamma and HMGB-1 being implicated

junc-Alteration of gut microflora in critical illness can also mise intestinal barrier function [16] This shift from commensal bacteria to pathogenic strains can occur as a result of antibiotic use, acid suppression or the illness itself It is likely that commen-sal Gram-negative anaerobes provide protection to the mucosa through promotion of mucosal repair, increased mucus production and the induction of selective bactericidal proteins, which prefer-entially target Gram-positive pathogens

compro-In the stomach, stress ulceration may be regarded as loss of barrier function and classically affects the gastric fundus Reduced mucosal prostaglandin synthesis and lower secretion of bicarbonate-rich

Table 202.1 Effects of cytokines in the inflammatory process

Cytokine Effects

TNFα ◆ Rises early in response to sepsis and trauma

◆ Activates HPA axis

◆ Induces fever and increases insulin resistance

◆ Major trigger for other cytokine release (IL-1 and IL-6)

◆ Promotes phagocytosis and neutrophil chemotaxis

◆ T cell activation and B cell proliferation

◆ Activates HPA axis and suppresses anabolic activity IL-6 ◆ Major activator of acute phase protein synthesis

◆ B and T cell differentiation IL-8 Neutrophil chemotaxis and activation

HMGB1 ◆ Multiple effects including acting as an alarmin and

cytokine

◆ Can be induced via NF-κβ and cell death

◆ Therefore, an initiator and effector of the inflammatory response

◆ Role in vascular endothelium and enterocyte permeability

Macrophage

migration inhibitory

factor (MIF)

◆ Key link between immune and endocrine system

◆ Expressed by leucocytes and stored intracellularly unlike other cytokines

◆ Secreted by HPA axis in response to stress or infection

◆ Antagonizes the immunosuppressive actions of endogenous steroids

CHAPTER 202 metabolic and nutritional response 959

mucus by goblet cells is implicated In fact, gastric acid secretion

may not be increased at all in critical illness [17]

Motility disturbances

Up to 50% of critically-ill patients suffer from gastrointestinal

motil-ity disorders, the adverse consequences of which include inadequate

nutrition and aspiration of gastric contents Common factors

con-tribute to this problem, including electrolyte imbalance, gut oedema

and drugs used in intensive care such as opioids, synthetic

cathecho-lamines and alpha-2 agonists [18] Although, the contribution of

deranged physiology is significant

Gastrointestinal motility in health is regulated via neural and

hormonal mechanisms Cholecystokinin (CCK), a peptide

hor-mone that normally inhibits gastric emptying, is found at higher

levels in critical illness Peptide YY may also have a role in

slow-ing gastric emptyslow-ing and small intestine transit in these patients

Neither of these hormones has been exploited pharmacologically in

clinical settings, although a CCK anatagonist does exist

In contrast, motilin and ghrelin act to accelerate gastric

empty-ing, but ghrelin levels are reduced in early critical illness by up to

50% Erythromycin is a drug with agonist activity at the motilin

receptor, hence the rationale for using it to treat feed intolerance

Ghrelin agonists have potential use in the treatment of

gastro-paresis and appetite stimulation They may also have a wider role

as ghrelin is an endogenous ligand of the GH secretagogue

recep-tor and theoretically could reverse the catabolic state and negative

nitrogen balance described previously In summary, the gut

hor-mone response can be considered like any other endocrine organ

dysfunction in the critically ill [19]

The enteric nervous system of the gut contains the largest

amount of neuronal cells outside the central nervous system The

myenteric plexus regulates motility while the submucous plexus

controls secretory functions and blood flow The migrating

motil-ity complex (MMC) is the collective term for the three phases of

motility seen in the small bowel between meals, also known as the

‘interdigestive’ pattern It has a cleansing effect, sweeping

gastroin-testinal debris into the colon, but is rendered defective during acute

illness and contributes to ileus The usual ‘digestive’ motility pattern

occurs after a meal producing segmentation of the bowel and

peri-stalsis In critical illness it can be abnormally increased and

pro-motes diarrhoea Local and systemic factors essentially produce an

imbalance between sympathetic and parasympathetic motor inputs

as the single common pathway for these clinical manifestations

References

1 Elijah I, Branski L, Finnerty C, and Herndon D (2011) The GH/

IGF-1 system in critical illness Best Practice & Research Clinical

Endocrinology & Metabolism, 25,759–67.

2 Van den Berghe G (2002) Dynamic neuroendocrine responses to

critical illness Frontiers in Neuroendocrinology, 23, 370–91.

3 Economidou F, Douka E, Tzanela M, et al (2011) Thyroid function

during critical illness Hormones, 10, 117–24.

4 Mebis L and Van den Berghe G (2011) Thyroid axis function and

dysfunction in critical illness Best Practice & Research Clinical

Endocrinology & Metabolism, 25, 745–57.

5 Bello G, Pennisi M, Montini L, et al (2009) Nonthyroidal illness syndrome and prolonged mechanical ventilation in patients admitted

to the ICU CHEST Journal, 135, 1448–54.

6 Mebis L and Van den Berghe G (2009) The

hypothalamus-pituitary-thyroid axis in critical illness Netherlands

Journal of Medicine, 67, 332–40.

7 Venkatesh B and Cohen J (2011) Adrenocortical (dys) function in

septic shock-A sick euadrenal state Best Practice & Research Clinical

Endocrinology & Metabolism, 25, 719–33.

8 Annane D (2011) Corticosteroids for severe sepsis: an evidence-based

guide for physicians Annals of Intensive Care, 1, 1–7.

9 Vanhorebeek I and Van den Berghe G (2006) The

neuroendo-crine response to critical illness is a dynamic process Critical Care

Clinics, 22, 1.

10 Gibson S, Hartman D, and Schenck J (2005) The endocrine response

to critical illness: update and implications for emergency medicine

Emergency Medicine Clinics of North America, 23, 909–30.

11 Kauffmann R, Norris P, Jenkins J, et al (2011) Trends in estradiol during critical illness are associated with mortality independent of

admission estradiol Journal of the American College of Surgeons, 212,

703–12.

12 De Backer D, Biston P, Devriendt J, et al (2010) Comparison of

dopamine and norepinephrine in the treatment of shock New England

Journal of Medicine, 362, 779–89.

13 Lee P (2011) Vitamin D metabolism and deficiency in critical illness

Best Practice & Research Clinical Endocrinology & Metabolism, 25,

769–81.

14 Reintam Blaser A, Malbrain MN, Starkopf J, et al (2012)

Gastrointestinal function in intensive care ogy, definitions and management Recommendations of the

patients: terminol-ESICM Working Group on Abdominal Problems Intensive Care

Medicine, 1–11.

15 Clark J and Coopersmith C (2007) Intestinal crosstalk-a new

para-digm for understanding the gut as the ‘motor’ of critical illness Shock,

features British Medical Journal, 296, 155.

18 Fruhwald S, Holzer P, and Metzler H (2007) Intestinal motility turbances in intensive care patients pathogenesis and clinical impact

dis-Intensive Care Medicine, 33, 36–44.

19 Deane A, Chapman M, Fraser R, and Horowitz M (2010)

Bench-to-bedside review: The gut as an endocrine organ in the

criti-cally ill Critical Care, 14, 228.

PART 7.2 Nutritional failure

203 Pathophysiology of nutritional

failure in the critically ill  961

Jan Wernerman

204 Assessing nutritional status in the ICU  964

Pierre-Yves Egreteau and Jean-Michel Boles

205 Indirect calorimetry in the ICU  969

Joseph L Nates and Sharla K Tajchman

206 Enteral nutrition in the ICU  973

Shaul Lev and Pierre Singer

207 Parenteral nutrition in the ICU  977

Jonathan Cohen and Shaul Lev

Pathophysiology of nutritional failure in the critically ill

Jan Wernerman

Key points

◆ There is no evidence supporting nutritional supply of calories

in excess of energy expenditure in critical illness

◆ Early enteral nutrition in critical illness is associated with

more favourable outcomes

◆ In the acute phase of critical illness parenteral nutritional

sup-plementation is not evidence based

◆ The exact time-point when full nutrition should be provided

in critical illness is based on individual factors, and not well defined

◆ The optimal protein nutrition in critical illness remains to be

established

Background

Nutritional failure in critical illness is poorly defined The term

nutritional failure implies there is a definition of correct nutrition

This is not the case At best, we know the energy expenditure of the

patient together with whole body balance of a number of substances

and nutrients Nevertheless, optimal nutrition should be a part of

optimal medical care of the critically-ill patient There is

consider-able evidence that nutritional care and metabolic care makes a

dif-ference [1] This is particularly true for overweight and underweight

patients, while normally-fed patients have a larger safety margin [2]

There is a dogma that critically-ill patients should be in a

posi-tive energy balance In current guidelines this results in

recom-mendations of 20–25–30 kcal/kg/day [3–5] The background is not

survival advantage demonstrated by randomized controlled trials,

but rather studies of nitrogen balances, where whole-body nitrogen

economy is more favourable when patients are in a positive energy

balance [6] This concept has historically led to massive

overfeed-ing, which has repeatedly been demonstrated to be harmful for

critically-ill patients [1,7,8]

Overall, two extrapolations that are not validated to be true, are

commonly used in guidelines for critically-ill patients:

◆ Findings from post-operative patients have been thought to be

valid for all critically-ill patients

◆ Measurements and observations made at times not related to the

admission to the ICU

This is particularly troublesome as most post-operative patients

have quite different characteristics compared with patients with

septic shock, with multi-organ failure, or with mechanical tilation Similarly, the time course for an individual patient may change rather dramatically in terms of energy expenditure during a prolonged period of critical illness

ven-Optimal energy supply

Measurement of energy expenditure by the use of indirect etry has been used for many years The technique is not easy to use and the availability of indirect calorimetry for critically-ill patients

calorim-is often limited Still the most important question calorim-is if actual energy expenditure should be the nutritional target calorie-wise? There

is limited literature indicating that feeding in excess of energy expenditure is not a very good idea during critical illness A pilot study with daily measurements of energy expenditure gave a signal

of better outcomes compared with protocolized energy intake [9]

In the classic study by Krishnan et al., 33–67% of an arbitrary energy target of 27 kcal/kg/day (9–18 kcal/kg/day) was associated with a better outcome than 67–100% [8] Another study demonstrated an advantage in hospital mortality when permissive hypocaloric feed-ing was employed and 58% of an energy target of 20–25 kcal/kg/day was compared with 71% of the energy target among the con-trols [10] None of these studies properly characterized the tempo-ral relation to ICU admission The EPaNIC study suggests delayed parenteral nutritional supplementation shortens ICU stay and prevents infections [1] In another classic study, Sandström et al demonstrated full parenteral nutrition following elective surgery is

a disadvantage, while parenteral nutrition may be an advantage for patients developing post-operative complications [11] Again, in this study, the temporal relationship of extraparenteral nutrition to the course of critical illness was not well defined

Underfeeding

In epidemiology, malnutrition is strongly associated with an vourable outcome This is true also in critical illness, where the highest mortality is seen in the cohort of patients with a BMI <  20 [2,12] The possible benefit of nutritional support in this high risk group of patients is not very strong Observational data indicate an advantage, but again the relation between admission and treatment has been poorly characterized Within the EPaNIC study patients with BMI < 17 were excluded, although patients with BMI > 17, but with a high nutritional risk score [13], did not benefit from early parenteral nutrition supplementation [1] This is clearly an

unfa-SECTION 7 nutrition: nutritional failure

962

area where more evidence is badly needed, as depleted

under-weight patients with limited physiological reserve are very

vulner-able Optimal nutrition is therefore particularly important for these

patients

Overfeeding

A caloric surplus above energy expenditure leads to fat

accumula-tion and is well characterized in healthy individuals, as well as in

critical illness [7] The crucial question is if a marginal surplus of

calories is a disadvantage as compared with hypocaloric feeding?

It is probably important to differentiate between the acute phase

of critical illness and the chronic phase Indirect evidence suggests

marginal overfeeding is harmful, particularly in the early phase of

critical illness [1,8,10] The positive results obtained when

employ-ing early enteral nutrition [14] may be interpreted as a beneficial

effect, directly related to nutrition in the gut at an early time-point

An alternative interpretation of the results is that tolerance of early

enteral nutrition selects patients with sufficient reserve to

toler-ate feeding in the early phase of critical illness As success rtoler-ate of

enteral feeding will always have a large scatter, these questions of

interpretation will always remain

A mechanistic hypothesis concerning the harmful effects of full

feeding in the early phase of critical illness is the inhibited autophagy

as a result of feeding Autophagy represents the necessary turnover

of cellular structures and body proteins Insufficient autophagy is

frequently seen in muscle and liver tissue of critically-ill patients

and proteins that are normally eliminated by autophagy are

accu-mulated [15] Early feeding and insulin therapy are potent

inhibi-tors of autophagy [16], while blood sugar control offers a possibility

to eliminate the inhibition More research to clarify the

mecha-nisms behind the negative effects of marginal overfeeding during

the early phase of critical illness is needed

Optimal protein supply

Available evidence concerning the protein or amino acid

require-ments of ICU patients is sparse and not very recent [6,17] In

sum-mary, an amino acid supply of more than 0.2 g nitrogen/kg/day

does not improve nitrogen balance if the energy provided is on the

level of energy expenditure Techniques to estimate whole-body

protein content have insufficient precision and proxy measures,

such as nitrogen balance or protein turnover, are not always easy

to interpret [18] The obvious increased losses associated with

con-tinuous renal replacement therapy have attained special interest

[19] This group of patients in the ICU are at particular risk to be

under-fed in terms of proteins and/or amino acids

Several authors who have reviewed this area recently

recom-mend not less than 1.5 g of protein/kg/day for critically-ill patients

[20], which is more than what is usually given today However, the

shortage of solid evidence and the poorly-understood

underly-ing mechanisms regulatunderly-ing protein economy in critical illness are

underlined

Conclusion

Nutritional failure implies there may be a concept of correct or

opti-mal nutrition Today sufficient knowledge is not at hand to define

such optimal nutrition in critical illness Over time in longstanding

critical illness malnutrition develops, which may be attenuated or delayed by nutrition therapy On the other hand, overfeeding in the very early phase of critical illness may be detrimental for the patient Knowledge is particularly sparse concerning the optimal protein intake during critical illness

References

1 Casaer MP, Mesotten D, Hermans G, et al (2011) Early versus late

parenteral nutrition in critically ill adults New England Journal of

3 Kreymann KG, Berger MM, Deutz NE, et al (2006) ESPEN Guidelines

on Enteral Nutrition: Intensive care Clinical Nutrition, 25(2), 210–23.

4 McClave SA, Martindale RG, Vanek VW, et al (2009) Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition

(A.S.P.E.N.) Journal of Parenteral and Enteral Nutrition, 33(3),

277–316.

5 Singer P, Berger MM, Van den Berghe G, et al (2009) ESPEN

Guidelines on Parenteral Nutrition: intensive care Clinical Nutrition,

28(4), 387–400.

6 Larsson J, Lennmarken C, Martensson J, Sandstedt S, and Vinnars

E (1990) Nitrogen requirements in severely injured patients British

Journal of Surgery, 77(4), 413–16.

7 (1991) Perioperative total parenteral nutrition in surgical patients The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group

New England Journal of Medicine, 325(8), 525–32.

8 Krishnan JA, Parce PB, Martinez A, Diette GB, and Brower RG (2003) Caloric intake in medical ICU patients: consistency of care with guide-

lines and relationship to clinical outcomes Chest, 124(1), 297–305.

9 Singer P, Anbar R, Cohen J, et al (2011) The tight calorie control study (TICACOS): a prospective, randomized, controlled pilot study

of nutritional support in critically ill patients Intensive Care Medicine,

37(4), 601–9.

10 Arabi YM, Tamim HM, Dhar GS, et al (2011) Permissive ing and intensive insulin therapy in critically ill patients: a randomized

underfeed-controlled trial American Journal of Clinical Nutrition, 93(3), 569–77.

11 Sandstrom R, Drott C, Hyltander A, et al (1993) The effect of erative intravenous feeding (TPN) on outcome following major surgery

postop-evaluated in a randomized study Annals of Surgery, 217(2), 185–95.

12 Gupta R, Knobel D, Gunabushanam V, et al (2011) The effect of low

body mass index on outcome in critically ill surgical patients Nutrition

in Clinical Practice, 26(5), 593–97.

13 Kondrup J, Allison SP, Elia M, Vellas B, and Plauth M (2003) ESPEN

guidelines for nutrition screening 2002 Clinical Nutrition, 22(4),

415–21.

14 Doig GS, Heighes PT, Simpson F, Sweetman EA, and Davies AR (2009) Early enteral nutrition, provided within 24 h of injury or inten- sive care unit admission, significantly reduces mortality in critically ill

patients: a meta-analysis of randomised controlled trials Intensive Care

16 Klionsky DJ (2007) Autophagy: from phenomenology to molecular

understanding in less than a decade Nature Reviews Molecular Cell

CHAPTER 203 pathophysiology of nutritional failure 963

18 Ishibashi N, Plank LD, Sando K, and Hill GL (1998) Optimal protein

requirements during the first 2 weeks after the onset of critical illness

Critical Care Medicine, 26(9), 1529–35.

19 Bellomo R, Seacombe J, Daskalakis M, et al (1997) A

prospec-tive comparaprospec-tive study of moderate versus high protein intake for

critically ill patients with acute renal failure Renal Failure, 19(1),

111–20.

20 Sauerwein HP and Serlie MJ (2010) Optimal nutrition and its

poten-tial effect on survival in critically ill patients Netherlands Journal of

Medicine, 68(3), 119–22.

Assessing nutritional status in the ICU

Pierre-Yves Egreteau and Jean-Michel Boles

Key points

◆ All the traditional markers of malnutrition lose their

specific-ity in the sick adult as each may be affected by a number of

non-nutritional factors

◆ Nutritional assessment is required for patients presenting with

clinical evidence of malnutrition, patients with chronic

dis-eases, patients with acute conditions accompanied by a high

catabolic rate, and elderly patients

◆ The initial nutritional status and the extent of the

disease-related catabolism are the main risk factors for

nutri-tion related complicanutri-tions

◆ Muscle function evaluated by hand-grip strength and serum

albumin provide an objective risk assessment Calculating a

nutritional index is helpful in subsets of patients to determine

complication risk and the need for nutritional support

◆ A strong suspicion remains the best way of uncovering

poten-tially harmful nutritional deficiencies

Introduction

Normal nutritional status is a key element in the ability to

over-come critical illness Normal body composition and function are

maintained in adults by a daily diet providing nutrients meeting the

needs of the individual

Why assess nutritional status?

Nutrition and disease interact in several ways Decreased nutrient

intake, increased body requirements, and/or altered nutrient

uti-lization are frequently combined in critically-ill patients The

fre-quency of malnutrition in hospital in-patients has been estimated

to be between 30 and 50% of both medical and surgical patients

There is an established relationship between initial nutritional

status and in-hospital morbidity and mortality [1] Many

complica-tions are related to protein energy malnutrition (PEM): increased

nosocomial infection rates due to diminished immune competence,

delayed wound healing due to decreased ability to repair tissue,

delayed weaning from mechanical ventilation due to altered vital

functions, and frequent depression and psychological disturbances

Assessing nutritional status pursues several goals—determination

of nutritional deficiencies and evaluation of risk factors of

nutrition-related complications that could affect patient outcome,

evaluation of the need and potential value of nutritional support, and monitoring the efficacy of and therapeutic response to nutri-tional support, including tolerance

An international committee proposed a nomenclature based on recognition of acute systemic inflammatory response [2] The aetiology-based malnutrition definitions include

‘starvation-associated malnutrition’:

◆ When there is chronic starvation without inflammation

◆ ‘Chronic disease-associated malnutrition’, when inflammation is chronic and of mild to moderate degree

◆ ‘Acute disease or injury-related malnutrition’, when tion is acute and of severe degree [3,4]

inflamma-Which patients should be assessed?

Obviously, patients with apparently normal physical build, mal diet intake, and no reason for significant increased nutrient requirements need no further investigation Several subsets of patients require a more precise assessment:

nor-◆ Patients presenting with clinical evidence of malnutrition asmus or the hypoalbuminaemic form of protein energy malnu-trition or a mixed form)

(mar-◆ Patients with chronic disease, such as malignancy, alcoholism, organ dysfunction, particularly those undergoing treatment, which impairs nutrient absorption and/or utilization

◆ Patients with acute conditions accompanied by a high catabolic rate, such as severe sepsis, trauma, or burns, and emergency surgery

◆ Elderly patients: ageing is associated with a physiological

ano-rexia, and poor dentition, economic problems, and chronic ness affect nutritional status

ill-How can nutritional status be assessed?

Nutritional assessment should include assessment of body position, the presence and duration of inadequate nutrient intake, and the degree and duration of metabolic stress The main mark-ers of nutritional assessment in healthy adults are shown in Table 204.1 All the current criteria for objective evidence of malnutrition are non-specifically affected by many diseases and are subject to wide errors; also, disease and inactivity alone can result in the same effects as malnutrition

com-CHAPTER 204 assessing nutritional status in the icu 965

In current practice, a comprehensive assessment of nutritional

status relies on a step-by-step clinically based approach and

cau-tious interpretation of measurements and results

Clinical assessment

Recording the patient’s history and physical examination is the first

stage of nutritional assessment

History

The history includes dietary habits, nutrient intake, and

interfer-ence between nutrition and the disease process itself The latter may

be responsible for either inadequate intake or excessive losses

Physical examination

Signs of nutritional deficiency, such as muscle wasting, loss of

sub-cutaneous fat, skin rashes, hair thinning, oedema, ascites,

finger-nail abnormalities, such as koilonychia, glossitis, and other mucosal

lesions, should be sought Particular signs of specific nutrient

defi-ciencies may also be observed

Estimation of weight loss

A loss of 10% of the usual body weight over a 6-month period or 5%

over a 1-month period are indicative of a compromised nutritional

status Weight and weight variations do not reflect nutritional

sta-tus or nutritional support efficacy when oedema or dehydration are

or have been present

Other anthropometric measurements

Anthropometric measurements must be interpreted with care

as they may be affected by non-nutritional factors Bed-ridden

patients will lose muscle mass without malnutrition

Measurements include weight, height, and body mass index (BMI) and mid-arm circumference (mid-AC) and triceps skinfold thickness (TSF) of the non-dominant side measured with a skin caliper Mid-arm muscle circumference (MAMC), which is cal-culated from the preceding two measures, reflects skeletal muscle TSF reflects fat stores Mid-AC < 15th percentile defines serious malnutrition and predicts a high mortality and complication rate in critical patients [5] High coefficients of variation between observ-ers suggest that measurements should always be recorded by the same observer These measurements are of no value in cases of sub-cutaneous emphysema or generalized oedema Because of slow var-iations, they cannot be used to evaluate nutritional support efficacy

Functional tests

Functional changes, such as a reduction in muscle power due to reduced nutrient intake, occur long before demonstrable anthro-pometric changes and are better predictors of complications than other anthropometric measurements (6,7) Muscle function can be considered as a specific measure of the effect of nutrient inadequate intake and refeeding Two methods can be used in critically-ill patients

◆ Assessment of hand-grip strength (of the non-dominant side)

with a hand-grip dynamometer is reserved for co-operative patients: it has been shown to correlate with MAMC and to be the most sensitive test for predicting postoperative complications [6]

◆ Measurement of the contraction of the adductor pollicis

mus-cle in response to an electrical ulnar nerve stimulation at the wrist

can be performed in unconscious patients The combination of an abnormal force–frequency curve and a slow relaxation rate is the

Table 204.1 Markers of nutritional assessment

Anthropometric

measurements Body mass (usual, actual, ideal)BMI = BM/H2 (kg/m 2 )

Mid-arm circumference (mid-AC) (cm) Triceps skinfold thickness (TSF) (mm) Mid-arm muscle circumference (MAMC) MAMC = mid-AC – (0.314 × TSF)

Female 16.5 28.5 23.2

12.5 29.3 25.3

Biological tests Plasma proteins

Albumin (g/L) Transferrin (g/L) Prealbumin (TTr) (mg/L) Retinol-binding protein (mg/L) IGF1

Urinary index Creatinine height index (mg/kg ideal body weight) Urinary 3 methyl histidine/urinary creatinine

Normal values

40 ± 5 2.8 ± 0.3

307 ± 36

62 ± 7 Female 18

23 ± 7.10 –3 Half-life (days)

21 10 2 0.5 0.08–0.16 Male 23

Muscle function testing ◆ Hand-grip strength

◆ Force-frequency curve and relaxation rate of the adductor pollicis muscle History ◆ Usual nutritional intake

◆ Impossibility of oral intake

◆ Physical and mental capacities Body composition ◆ Bioelectrical impedance analysis

◆ Ultrasound, CT, MRI, X-Ray absorptiometry, isotopic evaluation

SECTION 7 nutrition: nutritional failure

966

most specific and sensitive predictor of nutritionally-associated

complications in surgical patients [7]

Plasma proteins

Plasma proteins reflect the visceral protein mass They include

albu-min, transferrin, thyroxin-binding pre-albualbu-min, and in patients

with normal kidney function, retinol-binding protein

Serum albumin level is the most widely used measure of plasma

proteins in nutritional assessment A fall in albumin level reflects

more the severity and duration of the metabolic stress than the

nutritional status itself Sensitivity to predicting complications is

better when measurements of serum albumin and transferrin are

combined Although dependent on the iron status, transferrin has

a better response than albumin to nutritional repletion

Transthyretin (TTr, called prealbumin or thyroxin-binding

pre-albumin), retinol-binding protein or insulin-like growth factor

1 (IGF1), are particularly useful for following the efficacy of

nutri-tional support [8]

Creatinine height index

The daily urinary creatinine excretion is correlated with the lean

body mass Averaged over three consecutive days, it is matched

with normal controls for sex and height Creatinine Height Index

(CHI) is a reliable index of muscle mass in patients without renal

failure or rhabdomyolysis

Urinary 3 methyl-histidine also reflects muscular

catabo-lism Repeated measurements allow an evaluation of therapeutic

response

Immune competence

Cellular immunity is the most sensitive component of

tion, but reduced immune competence is not specific of

malnutri-tion, thus making it a poor predictor of such a state in sick patients

Subjective global assessment

Subjective global assessment (SGA) is based on history and

physi-cal examination of the patient

◆ Weight change: loss in past 6 months, and change in past 2 weeks

(in the case of recent weight gain, previous loss is not considered)

◆ Dietary intake: no change or suboptimal intake, liquid diet, or

hypocaloric fluids or starvation

◆ Gastrointestinal symptoms for more than 2 weeks (none,

ano-rexia and nausea, vomiting, diarrhoea)

◆ Functional capacity: normal, suboptimal work, ambulatory, or

bedridden

◆ Stress: none, minimal, or high.

◆ Physical signs: loss of subcutaneous fat, muscle wasting, fluid

retention, or mucosal lesions suggestive of deficiency

The patient is classified into one of three classes

◆ Well nourished: no or minimal restriction of food intake and/or

absorption with minimal change in function and body weight

◆ Moderate malnutrition: clear evidence of food restriction with

functional changes but little evidence of any changes in body mass

◆ Severe malnutrition: changes in both food intake and body mass

with poor function

In a critically-ill population, SGA is a reliable, easy to handle and reproducible method of nutrition assessment [9]

Nutritional indices

Several nutritional indices have been developed using ematical and statistical methods to identify patients at risk of nutritionally-mediated complications These indices were designed and generally validated in specific groups of patients, usually cancer

pre-The Nutritional Risk Index (NRI), using serum albumin and weight variation [11], allows identification of patients who can profit from nutrition therapy

NRI = [1.519 × albumin g / L ]+ 0.417 × % usual body weight

The Pronostic Inflammatory Nutritional Index (PINI) reflects inflammation influence on plasma nutritional protein levels in critically-ill patients and discriminates risk of complications [12]

PINI = [CRP (mg / L) × orosomucoid (mg / L)]

/ [albumin (g / L) × TTr (mg // L)] [eqn 2]where CRP is C-reactive protein Two scores associate clinical assessment and severity of disease:  the Malnutrition Universal Screening Tool (MUST) [13] and the Nutritional Risk Screening tool 2002 (NRS-2002) [14] In a study comparing NRS-2002, MUST, and the NRI to SGA, NRS-2002 was the most reliable [15].The NUTRIC scores age, severity of disease (APACHE II, SOFA), comorbidities, days from hospital to ICU admission and serum interleukin-6 As the score increases, so does the mortality and the duration of mechanical ventilation [16]

Assessment methods of human body composition

Bioelectric impedence provides a reliable estimate of total body water, fat-free mass, and body fat in healthy individuals and in critically-injured patients Disturbance of water distribution is fre-quent in critically-ill patients, making this technique irrelevant in the ICU setting [17]

Sophisticated methods measuring body composition have been developed, such as multiple isotope dilution methods, dual-photon absorption, and g-neutron activation Because of their techni-cal complexity, scientific limitations, and high cost, none of these methods is of clinical utility in routine critical care [17]

Computed tomography and MRI also allow for estimation of pose tissue, skeletal muscle

adi-Guidelines for the assessment of nutritional status

Before initiation of nutrition, assessment of nutritional status should include evaluation of weight loss and nutrient intake before admission, level of disease severity, comorbid conditions, and func-tion of the gastrointestinal tract [4,18,19]

CHAPTER 204 assessing nutritional status in the icu 967

Obese patients should be assessed similarly Guidelines require

body weight (usual, actual, and ideal) and BMI as ‘vital signs’

Biomarkers of the metabolic syndrome (serum levels of

triglycer-ide, cholesterol, and glucose) and the degree of systemic

inflamma-tory reaction should also be assessed [20]

An algorithm to screen for malnutrition using BMI, weight loss,

TTr, CRP, NRI, and critical illness severity should be performed

upon admission and during the ICU stay (Fig 204.1)

References

1 Hiesmayr M (2012) Nutrition risk assessment in the ICU Current

Opinion in Clinical Nutrition and Metabolic Care, 15(2), 174–80.

2 Jensen GL and Wheeler D (2012) A new approach to defining and

diagnosing malnutrition in adult critical illness Current Opinion in

Critical Care, 18(2), 206–11.

3 Jensen GL, Mirtallo J, Compher C, et al (2010) Adult starvation and

disease-related malnutrition: a proposal for etiology-based sis in the clinical practice setting from the International Consensus

diagno-Guideline Committee Clinical Nutrition, 29(2), 151–3.

4 White JV, Guenter P, Jensen G, Malone A, and Schofield M (2012)

Consensus statement: Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition: characteristics recommended for the identification and documentation of adult mal-

nutrition (undernutrition) Journal of Parenteral and Enteral Nutrition,

36(3), 275–83.

5 Ravasco P, Camilo ME, Gouveia-Oliveira A, Adam S, and Brum G

(2002) A critical approach to nutritional assessment in critically ill

patients Clinical Nutrition, 21(1), 73–7.

6 Klidjian AM, Foster KJ, Kammerling RM, Cooper A, and Karran

SJ (1980) Relation of anthropometric and dynamometric variables

to serious postoperative complications British Medical Journal,

Current Opinion in Clinical Nutrition and Metabolic Care, 6(2), 211–16.

9 Sheean PM, Peterson SJ, Gurka DP, and Braunschweig CA (2010)

Nutrition assessment: the reproducibility of subjective global

assess-ment in patients requiring mechanical ventilation European Journal of

Clinical Nutrition, 64(11), 1358–64.

10 Buzby GP, Mullen JL, Matthews DC, Hobbs CL, and Rosato EF (1980)

Prognostic nutritional index in gastrointestinal surgery American

Journal of Surgery, 139(1), 160–7.

11 Buzby GP, Knox LS, Crosby LO, et al (1988) Study protocol: a omized clinical trial of total parenteral nutrition in malnourished surgi-

rand-cal patients American Journal of Clinirand-cal Nutrition, 47(2 Suppl.), 366–81.

12 Ingenbleek Y and Carpentier YA (1985) A prognostic inflammatory

and nutritional index scoring critically ill patients International Journal

for Vitamin and Nutrition Research, 55(1), 91–101.

13 Malnutition Advisory Group (2000) In: Elia M (ed.) Guidelines for the Detection and Management of Malnutrition A report by the Malnutrition Advisory Group, a standing committee of the British Association for Parenteral and Enteral Nutrition, Proceedings of a Consensus Conference, organized by BAPEN.

14 Kondrup J, Allison SP, Elia M, Vellas B, and Plauth M (2003) ESPEN

guidelines for nutrition screening 2002 Clinical Nutrition, 22(4),

415–21.

15 Kyle UG, Kossovsky MP, Karsegard VL, and Pichard C (2006)

Comparison of tools for nutritional assessment and screening at

hospi-tal admission: a population study Clinical Nutrition, 25(3), 409–17.

N.R.I.

TTr mg/l

< 83.5 Severely malnourished

83.5–97.5 Moderately malnourished

97.5

No malnutrition

< 50

Sepsis Trauma Intake < 35 kcal/kg/day Impossibility of oral intake No

Yes

Surveillance Dietary

± Artificial nutrition

Artificial nutrition

± Pharmaco nutrients 50–110

BMI ≤ 18.5

and/or Weight loss 2% 1 week

5% 1 month 10% 6 months and/or TTr < 110 mg/l

and/or CRP > 50 mg/l

Stop

TTr twice a week

Level 1 Day 1

Level 2 Day 2

Level 3

Fig. 204.1 Algorithm to screen for malnutrition.

SECTION 7 nutrition: nutritional failure

968

16 Heyland DK, Dhaliwal R, Jiang X, and Day AG (2011) Identifying

critically ill patients who benefit the most from nutrition therapy: the

development and initial validation of a novel risk assessment tool

Critical Care, 15(6), R268.

17 Lee SY and Gallagher D (2008) Assessment methods in human body

composition Current Opinion in Clinical Nutrition and Metabolic Care,

11(5), 566–72.

18 Kreymann KG, Berger MM, Deutz NE, et al (2006) ESPEN Guidelines

on Enteral Nutrition: Intensive care Clinical Nutrition, 25(2), 210–23.

19 Martindale RG, McClave SA, Vanek VW, et al (2009) Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: Executive Summary

Critical Care Medicine, 37(5), 1757–61.

20 McClave SA, Kushner R, Van Way CW, et al (2011) Nutrition therapy

of the severely obese, critically ill patient: summation of conclusions

and recommendations Journal of Parenteral and Enteral Nutrition,

35(5 Suppl.), 88S–96S.

Indirect calorimetry in the ICU

Joseph L Nates and Sharla K Tajchman

Key points

◆ Oxygen consumption can be used to determine a patient’s

energy expenditure

◆ Indirect calorimetry is the gold standard for determining

nutrition requirements in critically-ill patients

◆ Interpretation of indirect calorimetry results should be

per-formed in conjunction with the patient’s clinical condition and should take into consideration any factors that may potentially alter energy expenditure

◆ Despite the potential benefits of indirect calorimetry to

pre-vent adverse effects associated with over- and underfeeding, widespread utilization is limited due to its cost and the need for trained personnel to perform gas exchange measurements

◆ Aside from nutrition purposes, indirect calorimetry can assist

clinicians in weaning mechanical ventilation in patients with limited respiratory reserve and increased work of breathing

Introduction

Despite the advancement in nutrition and medicine since Antoine

Lavoisier conducted the first indirect calorimetry study over

200  years ago, the assessment of energy expenditure (EE) in

critically-ill patients remains a clinical challenge The metabolic

stress response, acuity of illness, and underlying comorbidities

com-monly present in ICU patients yield a wide variation of

unpredict-able metabolic derangements that are difficult, if not impossible, to

quantify Unmet metabolic demand has deleterious consequences

in critically-ill patients and accurately assessing energy expenditure

throughout a patient’s ICU stay is vital to optimizing care and

pre-venting adverse outcomes

Indirect calorimetry methodology

Calorimetry is a direct measurement of heat production and

usu-ally requires 24-hour patient isolation in a hermeticusu-ally-sealed

room to assess temperature change Indirect calorimetry (ICal)

quantifies the amount of heat generated by the body (or resting

energy expenditure (REE)) in relation to the amount of substrate

used and by-product generation Fuel substrates (carbohydrates,

protein, and lipids) are oxidized to CO2, water, and heat in the

presence of O2 By measuring the amount of O2 consumed (VO2)

and CO2 produced (VCO2), ICal can be used to calculate EE ICal

was validated using direct calorimetry and is considered to be the

gold standard for determining EE in the intensive care unit (ICU)

O2+substrate→CO + H O heat2 2 + [eqn 1]Circulatory ICal (CICal) is based on a thermodilution technique that requires the insertion of a pulmonary artery catheter to meas-ure cardiac output and mixed venous O2 saturation EE is calcu-lated using measurements taken from an arterial blood gas via the Fick method (eqn 2) Catheter and arterial cannula measurements are both instantaneous and do not allow for continuous assessment

of values While CICal can provide useful results, it is an invasive technique that requires placement of a pulmonary artery catheter that may contribute to complications This method of calorimetry

is reserved for patients who already have a catheter inserted and who are not eligible for respiratory ICal due to major air leaks or other contraindications

Fick method for determining EE

EE kcal/day = CO Hb SaO( ) × ( 2×SvO2)×95.18 [eqn 2]

where CO is cardiac output in L/min, Hb is haemoglobin tration in mg/L, SaO2 is the oxygen saturation of arterial blood, and SvO2 is the oxygen saturation of mixed venous blood

concen-Respiratory ICal is what most clinicians refer to as ‘indirect calorimetry’ By measuring VO2 and VCO2 via pulmonary gas exchange, EE can be calculated using the Weir equation (eqn 3) The urinary nitrogen component (uN2) is often omitted from EE calculations (eqn 4) as it accounts for <4% of true EE in critically-ill patients and results in <2% error in the final EE calculation The

VO2 accounts for 70–80% and the VCO2 for 20–30% of the tion [1,2] The Weir equation can also facilitate the identification

equa-of the substrate that is predominantly being metabolized for fuel, although it is not commonly used in this capacity

Simplified Weir equation

EE kcal/day( )=(VO2×3.941) (+ VCO 1.112× )×1440 [eqn 4]where VO2 and VCO2 are both measured in L/min, uN2 is the uri-nary nitrogen component measured in g/day and 1440 accounts for the number of minutes in a day

SECTION 7 nutrition: nutritional failure

970

ICal can be performed on mechanically-ventilated or

sponta-neously breathing patients Canopies, face masks, mouthpieces,

or nose pieces used to trap all gas exchange can be utilized to

perform ICal in spontaneously breathing patients Mechanical

ventilators may be equipped with ICal modules to measure VO2

and VCO2 continuously in ventilated patients In order to achieve

the most accurate results, all patients should be screened for ICal

study eligibility and only trained personnel should perform the

test Technical factors that can affect the accuracy of ICal results

and are thus considered exclusion criteria for ICal are listed in

Box 205.1 [3] Many of the exclusion criteria listed can be linked

to the addition or elimination of O2 or CO2 from the ICal study

circuit, which will alter VO2 and VCO2 measurements The

dura-tion of an ICal study will depend on the achievement of steady

state conditions, defined as stable VO2 and VCO2 that vary by

<10% for 5 consecutive minutes or the coefficient of variation for

the two values is <5% for 5 minutes [4] Steady state represents a

period of metabolic equilibrium and ensures the reliability of the

measurements obtained from the ICal study When performed

under appropriate conditions, respiratory ICal is non-invasive,

reliably reproducible, and accurate Although the use of ICal has

expanded significantly over the past 25 years, its use remains

lim-ited by availability, cost, and the need for trained personnel for its

correct use

Determining energy expenditure

A patient’s total daily energy expenditure is the summation of basal

energy expenditure (BEE) or basal metabolic rate, diet-induced

thermogenesis, and activity-related thermogenesis The BEE is

the energy required to maintain the body’s basic cellular

meta-bolic activity and organ function Many factors may affect or alter

the body’s BEE and are listed in Table 205.1 [5,6] BEE can only

be measured when a person is in a deep sleep ICal measures ing EE (REE), which has traditionally been described as the energy expended when a patient is lying in bed, awake, and aware of his

rest-or her surroundings To measure REE, ICal should be perfrest-ormed under strict testing conditions including a minimum of 5 hours

of fasting, at least 30 minutes to an hour of resting with no cal activity, and in the absence of any stimulants or depressants Critically-ill patients rarely meet the previously mentioned condi-tions, thus the term measured energy expenditure (MEE) is more commonly used to describe EE in critically-ill patients

physi-Clinical measurement of REE

At least four different organizations have published guidelines for the provision of nutrition support in critically-ill patients, although none of them provide specific recommendations on the use of ICal

in the ICU [7–10] Ideally, all critically-ill patients should receive ICal if their ICU length of stay is estimated to be >72 hours, espe-cially if they are mechanically-ventilated (Fig 205.1) However, due to cost considerations, and the availability of equipment and trained personnel, obtaining ICal may not be possible for all patients or at every institution All factors considered, it is strongly recommended that ICU patients with any of the following condi-tions have an ICal study performed:

◆ Any clinical condition that significantly alters EE (e.g acute or chronic respiratory distress syndrome, acute pancreatitis, burns, multiple trauma, multisystem organ failure, sepsis, systemic inflammatory response syndrome)

◆ Failure to respond to presumed adequate nutritional support (wound dehiscence, loss of lean body mass)

◆ Long-term ICU patients with multiple insults for the provision

of individualized nutrition support (baseline and serial ICal measurements)

Box 205.1 Common contraindications for performing ICal

◆ Mechanical ventilation with FIO2 ≥ 0.6

◆ Mechanical ventilation with positive end expiratory

pressure >12 cmH2O

◆ Hyper- or hypoventilation

◆ Leak in the sampling system

◆ Moisture in the system, which can affect the oxygen analyser

◆ Continuous flow through the system >0 L/min during exhalation

◆ Inability to collect all expiratory flow

◆ Unstable inspiratory FiO2 (>± 0.01)

◆ Chest tube with air leak

◆ Bronchopleural fistula

◆ Supplemental oxygen in spontaneously breathing patients

◆ Haemodialysis in progress

◆ Indirect calorimeter calibration error

Data from Branson RD and Johannigman JA, ‘The measurement of energy

expenditure’, Nutrition in clinical practice: official publication of the American

Society for Parenteral and Enteral Nutrition, 2004, 19, 6, pp 622–636 Epub

2005/10/11.

Table 205.1 Factors affecting energy expenditure

Non-modifiable Modifiable

Age Body composition (e.g obesity, ascites, oedema) Disease processes

(e.g. malignancy) Gender Genetics Hormonal status Limb amputation Post-operative organ transplantation

Acute or chronic respiratory distress syndrome

Burn Diet Fever/Infection Large or multiple open wounds Nutrition status

Medications (e.g sedatives, paralytics) Multisystem organ failure

Sepsis Systemic inflammatory response syndrome Trauma

Use of paralytic agents or sedation

Data from Brandi LS et al., ‘Indirect calorimetry in critically ill patients: clinical applications and practical advice’, Nutrition, 1997, 13, 4, pp 349–358 Epub 1997/04/01; McClave SA

and Snider HL, ‘Use of indirect calorimetry in clinical nutrition’, Nutrition in clinical practice:

official publication of the American Society for Parenteral and Enteral Nutrition, 1992, 7, 5,

pp 207–221 Epub 1992/10/01.

CHAPTER 205 indirect calorimetry in the icu 971

Interpretation of ICal results

It is important to note the ICal study results are a MEE and may

not accurately represent the BEE or REE depending on patient

conditions during the study Ideally, ICal should be measured

under resting conditions Many patient, environmental, and

equipment-related factors can affect the accuracy of ICal

measure-ments (Box 205.2) [3,6,11,12] Keeping this in mind, ICal results

give an accurate measure of the EE for the patient under the

spe-cific testing conditions If patient conditions drastically change

(discontinuation of paralytic agents, sedatives, initiation of

nutri-tion, etc.) a follow-up ICal should be considered to evaluate the

change in EE

The MEE should serve as the daily caloric target for the

provi-sion of nutrition support in critically-ill patients The addition

of stress or activity factors to the MEE is not necessary and can

increase the risk of overfeeding as the MEE has been shown

to closely approximate 24-hour EE [6] Also, since most ICU

patients are receiving continuous feeding, diet-induced

ther-mogenesis is accounted for in the MEE However, if nutrition

is intermittent, MEE should be increased by 5% to account for

thermogenesis

Another value derived from ICal is the respiratory quotient

(RQ), which is defined as the ratio between VO2 and VCO2 The

RQ value is a reflection of substrate utilization Complete oxidation

of glucose in a closed system yields an RQ value of 1. The use of

protein and lipids as substrates for fuel yield different values within

the physiological range of RQ values (see Fig 205.2) It is

impor-tant to remember the RQ value is a summation of whole body

sub-strate utilization Also, since many factors can influence the RQ,

and result in false or inaccurate RQ values, the RQ value is mainly

used as a measure of ICal study quality An RQ value around 0.7

suggests underfeeding and a shift toward lipolysis for fuel substrate;

alternatively, an RQ > 1 suggests overfeeding due to lipogenesis as

substrate is stored as fat

Mechanical ventilation for > 24 h?

Expected extubation within 24–48 h?

Reassess after

24 h of mechanical ventilation

Reassess in 24 h

Reassess ICal eligibility in 24 h

Is the patient eligible for ICal?

(see Table 205.1)

Perform ICal study

Fig. 205.1 Algorithm for performing indirect calorimetry.

Box 205.2 Recommendations to improve the accuracy of ICal

Resting conditions

◆ Supine position at least 30 minutes prior to the study

◆ Quiet, thermoneutral environment

◆ Normal voluntary muscle movement is present during the study

◆ No/minimum involuntary muscle movement is present during the study

◆ Adequate pain control

◆ No/minimal agitation

◆ All sedatives and/or analgesics should be administered at least

30 minutes prior to the study when clinically feasible

Nutrition considerations

◆ Intermittent nutrition:

• If thermogenesis is to be included in the REE—perform study 1 hour after feeding

• If thermogenesis is not to be included in the REE—perform

study 4 hours after feeding

◆ Continuous nutrition: no changes to the rate and/or

composi-tion of continuous nutricomposi-tion for at least 12 hours prior to the study

• Continuous—cannot perform study until continuous renal

replacement therapy is discontinued

◆ No general anaesthesia within 6–8 hours prior to the study

◆ Painful procedures: wait at least 1 hour and ensure pain is

adequately controlled prior to study

◆ Avoid routine nursing care or procedures during the study

Measurement considerations

◆ Data used to calculate EE and RQ are taken from steady state conditions

Data from Branson RD and Johannigman JA, ‘The measurement of energy

expenditure’, Nutrition in clinical practice: official publication of the American

Society for Parenteral and Enteral Nutrition, 2004, 19, 6, pp 622–636 Epub

2005/10/11; McClave SA and Snider HL, ‘Use of indirect calorimetry in

clinical nutrition’, Nutrition in clinical practice: official publication of the

American Society for Parenteral and Enteral Nutrition, 1992, 7, 5, pp 207–221

Epub 1992/10/01; Matamis D et al., ‘Influence of continuous related hypothermia on haemodynamic variables and gas exchange in septic

haemofiltration-patients’, Intensive care medicine, 1994, 20, 6, pp 431–436 Epub 1994/07/01; Matarese LE, ‘Indirect calorimetry: technical aspects’, Journal of the American

Dietetic Association, 1997, 97, 10, Suppl 2, pp S154–160 Epub 1997/10/23.

SECTION 7 nutrition: nutritional failure

972

Clinical benefits of ICal

Malnutrition occurs in approximately 43–88% of ICU patients and

accurate determination of energy requirements is essential to avoid

feeding-associated adverse effects [13] Underfeeding may result in

the development of malnutrition and associated adverse outcomes,

such as decreased wound healing, increased infectious

complica-tions, increased duration of mechanical ventilation, and increased

ICU length of stay [14,15] Recent literature has suggested that a

negative caloric balance in the ICU may lead to injurious

conse-quences, including an increased ICU length of stay, duration of

mechanical ventilation, overall rate of complications (pressure

ulcers, acute kidney insufficiency, acute respiratory distress

syn-drome, and sepsis), and death [15–17] Conversely, overfeeding

critically-ill patients can lead to hyperglycaemia, hepatic

dysfunc-tion, prolonged mechanical ventiladysfunc-tion, fluid overload

includ-ing pulmonary oedema, and congestive heart failure [18] More

recently, the concept of tight caloric control has been advocated

that critically-ill patients should avoid the deleterious effects of

under- and overfeeding, although the studies have had conflicting

results [19,20]

Weaning from mechanical ventilation

Determination of accurate daily caloric needs with ICal can also

assist in the facilitation of weaning from mechanical ventilation

Overfeeding results in excessive production of CO2 and results in

increased work of breathing, which can be detrimental to weaning

efforts, especially in patients with limited respiratory reserves such

as those with chronic obstructive pulmonary disease and acute

respiratory distress syndrome Performing ICal allows clinicians

to determine whether overfeeding is contributing to

unsuccess-ful ventilator weaning attempts Subsequently, decreasing caloric

intake can help reduce excessive CO2 production and decrease

respiratory efforts required to successfully wean a patient from

mechanical ventilation Due to the dynamic metabolic profile of

critically-ill patients, it is difficult to estimate daily caloric needs

accurately

References

1 Bursztein S, Saphar P, Singer P, and Elwyn DH (1989) A mathematical analysis of indirect calorimetry measurements in acutely ill patients

American Journal of Clinical Nutrition, 50(2), 227–30.

2 Ferrannini E (1988) The theoretical bases of indirect calorimetry: a

review Metabolism, 37(3), 287–301.

3 Branson RD and Johannigman JA (2004) The measurement of energy

expenditure Nutrition in Clinical Practice, 19(6), 622–36.

4 McClave SA, Spain DA, Skolnick JL, et al (2003) Achievement of steady state optimizes results when performing indirect calorimetry

Journal of Parenteral and Enteral Nutrition, 27(1), 16–20.

5 Brandi LS, Bertolini R, and Calafa M (1997) Indirect calorimetry

in critically ill patients: clinical applications and practical advice

Nutrition, 13(4), 349–58.

6 McClave SA and Snider HL (1992) Use of indirect calorimetry in

clinical nutrition Nutrition in Clinical Practice, 7(5), 207–21.

7 Heyland DK, Dhaliwal R, Drover JW, Gramlich L, and Dodek P (2003) Canadian clinical practice guidelines for nutrition support in mechani-

cally ventilated, critically ill adult patients Journal of Parenteral and

Enteral Nutrition, 27(5), 355–73.

8 Kattelmann KK, Hise M, Russell M, Charney P, Stokes M, and Compher C (2006) Preliminary evidence for a medical nutrition

therapy protocol: enteral feedings for critically ill patients Journal of

the American Dietetic Association, 106(8), 1226–41.

9 Kreymann KG, Berger MM, Deutz NE, et al (2006) ESPEN Guidelines

on enteral nutrition: intensive care Clinical Nutrition, 25(2), 210–23.

10 McClave SA, Martindale RG, Vanek VW, et al (2009) Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.)

Journal of Parenteral and Enteral Nutrition, 33(3), 277–316.

11 Matamis D, Tsagourias M, Koletsos K, et al (1994) Influence of continuous haemofiltration-related hypothermia on haemodynamic

variables and gas exchange in septic patients Intensive Care Medicine,

20(6), 431–6.

12 Matarese LE (1997) Indirect calorimetry: technical aspects Journal of

the American Dietetic Association, 97(10 Suppl 2), S154–60.

13 Giner M, Laviano A, Meguid MM, and Gleason JR (1996) In 1995

a correlation between malnutrition and poor outcome in critically ill

patients still exists Nutrition, 12(1), 23–9.

14 Singer P, Pichard C, Heidegger CP, and Wernerman J (2010)

Considering energy deficit in the intensive care unit Current Opinion

in Clinical Nutrition and Metabolic Care, 13(2), 170–6.

15 Villet S, Chiolero RL, Bollmann MD, et al (2005) Negative impact of hypocaloric feeding and energy balance on clinical outcome in ICU

patients Clinical Nutrition, 24(4), 502–9.

16 Dvir D, Cohen J, and Singer P (2006) Computerized energy balance and complications in critically ill patients: an observational study

18 Port AM and Apovian C (2010) Metabolic support of the obese

inten-sive care unit patient: a current perspective Current Opinion in Clinical

Nutrition and Metabolic Care, 13(2), 184–91.

19 Singer P, Anbar R, Cohen J, et al (2011) The tight calorie control study (TICACOS): a prospective, randomized, controlled pilot study

of nutritional support in critically ill patients Intensive Care Medicine,

37(4), 601–9.

20 Strack van Schijndel RJ, Weijs PJ, et al (2009) Optimal nutrition ing the period of mechanical ventilation decreases mortality in criti- cally ill, long-term acute female patients: a prospective observational

dur-cohort study Critical Care, 13(4), R132.

Acidosis Hyperventilation

Overfeeding

Alkalosis Hyperventilation

ketosis Underfeeding

1.3

P H Y S I O L O G I C A L R A N G E

1.0 Carbohydrate

RQ = VCO2/VO2

Protein Fat

0.8 0.7 0.67

Fig. 205.2 Interpretation of the RQ value.

Enteral nutrition in the ICU

Shaul Lev and Pierre Singer

Key points

◆ Enteral feeding is an integral part of patient care and should

be started early as soon as the patient is stabilized

◆ Nasogastric or nasojejunal tubes are the main routes of enteral

nutrition (EN) administration

◆ Monitor gastric residual volume and follow protocols to start

enteral feeding

◆ Choice of feed composition should depend on the main

disease—acute lung injury, diabetes, trauma, or others

◆ The main complications are aspiration and diarrhoea

Introduction

Artificial nutritional support is considered an integral part of

criti-cal care Artificial feeding can be in the form of enteral nutrition

(EN), parenteral nutrition (PN) or as a combination The primary

goal of nutrition support in the critically ill is to supply patients with

macro- and micronutrients that are needed for new protein

synthe-sis, energy production, and to sustain enzymatic function

A sec-ondary goal is to modulate immune function in order to improve

infection rates, wound healing, and to avoid non-adaptive

proteoly-sis of vital proteins and hyper-inflammatory reactions This field of

nutrition is called immunonutrition The intensive care unit (ICU)

population is very heterogenic and the appropriate nutritional

intervention should be chosen with care First the calorie–protein

targets should be defined followed by the timing for commencing

EN and choice of route of feeding EN is currently viewed as the first

line of feeding for critically-ill patients who cannot be fed by mouth

and has many benefits in maintaining the functionality of the

intes-tine The timing for starting feeding is a matter of controversy, but

it is usually started in the early stages of ICU hospitalization, during

the first 2 days, in order to avoid major caloric and protein deficits

The concept of commencing early nutrition for critically-ill patients

is based on observation that feeding started within short time frame

is associated with less gut permeability, diminished activation, and

release of inflammatory cytokines and reduced systemic

endotox-aemia A meta-analysis by Heyland et al [1] showed a trend toward

reduced mortality and infectious morbidity A systematic review by

Marik and Zaloga [2] showed significant reduction in infectious

morbidity and hospital stay with early EN compared with delayed

feedings While most experts agree that patients who can tolerate

feeding should be nourished as soon as they are stabilized,

contro-versy exists regarding the best management of patients who cannot

tolerate EN matched to their estimated needs

a functioning digestive system, will begin enteral nutrition 24–48 hours after admission to the ICU Bowel sounds are a poor indica-tor of small bowel activity, particularly in patients subject to tra-cheal intubation and mechanical ventilation Their absence should not delay a trial of enteral nutrition

Methods of administration

Enteral feeds are usually given continuously by gravity feed or pump-assisted infusion Intermittent bolus feeds may also be given every 6 hours and may have a more positive effect on protein syn-thesis than the same quantity of continuous feeds The adminis-tration set must be sterile and have connectors incompatible with intravenous infusions to minimize the risk of confusion with fluids intended for intravenous use Enteral feeds should not be left hang-ing at the bedside for more than 24 hours at room temperature, since bacterial colonization of enteral feeds have been found in up

to 24% of enteral feed reservoirs at 24 hours

Routes of feeding: stomach versus small bowel

Routes of feeding include nasogastric (NG), nasoduodenal, junal (NJ), gastrostomy, and jejunostomy Nasal tube feeding should

nasoje-be performed via a soft, fine-bore tunasoje-be in order to avoid tion of the nose or oesophagus Patients tolerate nasal tubes better than oral tubes, but the nasal route is associated with increased fre-quency of bleeding during insertion and with sinusitis Nasal intu-bation is relatively contraindicated in patients with a fractured base

ulcera-of skull Nasogastric feeding usually starts using a 12–14-French tube to allow aspiration of gastric contents to check feed absorp-tion, and administration of viscous elixirs or crushed tablets.The placement of nasoduodenal tubes should be considered

if gastric residues are large (250–500 mL) This kind of feeding, directly to the small bowel, bypasses the stomach, enables nutri-tional goals to be reached faster and eliminates the need for par-enteral feeding Direct feeding to the small bowel does not cause special complications The main disadvantage relates to the diffi-culty in tube placement Fewer than 50% of fine-bore tubes pass through the pylorus spontaneously within 24 hours of insertion

SECTION 7 nutrition: nutritional failure

974

Tubes can be guided through the pylorus using fluoroscopy or

endoscopy The position of the tip of a feeding tube should be

con-firmed by radiography before feeding starts in order to avoid

acci-dental tracheal intubation

In selected patients creation of a feeding jejunostomy is

consid-ered, especially when there is a laparotomy This procedure allows

the administration of early enteral nutrition in most patients, but

may be complicated by leaks, peritonitis, wound infection, and

bowel obstruction

Monitoring tolerance of enteral feeding

Up to 47% of patients in the ICU suffer from GI motility problems

Gastric residual volume (GRV) is viewed as the most common

indi-cator of tolerance for enteral feeding, although many studies found

no correlation between GRV and pneumonia rate [4] Serial GRV

measurements may decrease the amount of nutrition that is

actu-ally given According to the American Society for Parenteral and

Enteral Nutrition (ASPEN) [4], when GRV levels are 200–500 mL,

and with the absence of other indicators for intolerance of feeding,

enteral feeding should not be stopped [4] One of the recommended

approaches to tackle motility problems is the use of prokinetic

medication If the nasogastric aspirates are significant (i.e more

than 150 mL), prokinetic drugs such as metoclopramide (10–20 mg

intravenously (iv) every 6 hours), or erythromycin (80–300 mg iv)

are used to decrease gastric paresis and to assist transpyloric

place-ment of transpyloric tube [4] Several studies and meta-analyses

have questioned the advantages of post-pyloric feeding in the ICU

A small number of studies demonstrated that post-pyloric feeding

benefits by reducing gastro-oesophaegeal reflux and rate of

aspira-tions, especially if the tip of tube is located distally in the

duode-num A meta-analysis that covered 11 studies of 637 ICU patients,

did not demonstrate any advantage in the clinical outcome of

patients fed directly into the small bowel, with respect to

mortal-ity, duration of hospitalization, rate of pneumonia, and aspirations

[5] A recent meta-analysis of 15 randomized clinical trials

enroll-ing 966 participants found that post-pyloric feedenroll-ing was associated

with a reduction in pneumonia compared with gastric feeding

(rel-ative risk (RR) 0.63, 95% CI 0.48–0.83, p = 0.001; I² = 0%) [6] The

risk of aspiration (RR, 1.11; 95% CI, 0.80–1.53, p = 0.55; I² = 0%)

and vomiting (RR, 0.80; 95% CI, 0.38–1.67, p = 0.56; I² = 65.3%)

were not significantly different between patients treated with

gas-tric and post-pyloric feeding [6] A recent multicentre Australian

study did not find an increase in the amount of energy delivered in

181 ventilated patients with medium GRV when an early NJ tube

was introduced as compared to NG tube [7]

EN composition

Many formulas are commercially available, and may differ in their

caloric density, amount of proteins, and their enrichment with

cific components, such as fibres, specific amino acids, fish oil,

spe-cific fatty acids, nucleotides, and other nutrients and antioxidants

Most standard formulations contain 1 kcal/mL ‘Energy dense’

formulation with high fat content may contain up to 2 kcal/mL

Formulations also vary in osmolality, electrolyte, mineral, and

vita-min content All the feeds are lactose and gluten free Carbohydrates

are provided as sucrose, fructose, or glucose polymers Proteins are

provided as whole proteins New formulations with high protein

content have recently been introduced into the market The value

of a very high protein-to-energy ratio is still unproven, but allows delivery of higher amounts of proteins without fluid overload Elemental or semi-elemental feeds contain a mix of oligopeptides and free amino acids They are used in patients with short bowel syndrome, severe diarrhoea, radiation enteritis and pancreatic insufficiency Fats may be provided as medium-chain fatty acids or long-chain triglycerides Special feeds are constantly being devel-oped, including feeds with nucleotides and arginine, and formu-lations enriched with fish oils Electrolyte content varies and may affect the choice of feed when sodium or potassium restriction is important; these electrolytes can always be added to a feed when supplementation is needed Most of the commercial formulations meet the daily recommended intake of healthy adults if given in

an amount higher than 1000–1500 mL/day The daily needs might

be higher for some vitamins in settings of increased losses, such as continuous haemodiafiltration

Specific nutrients

Some nutrients have been intensively research both in animal els and humans due to their specific biological effects, rather than their use as energy sources or substrates for protein synthesis

mod-Glutamine

Glutamine is a conditionally essential amino acid and is the most abundant amino acid in plasma Glutamine is involved in many biochemical reactions in the cells The glutamine stores in muscle tissue are depleted and low plasma glutamine concentrations are an independent prognostic factor for an unfavourable outcome in the critically-ill patient Under catabolic conditions, such as sepsis and shock, release of glutamine from muscle tissue serves as a ‘stress signal’ to the organism that leads to gene activation in order to pro-mote cellular protection and immune regulation Glutamine serves

as a precursor of nucleotides and glutathione, and is the major metabolic fuel for the enterocytes of the gut mucosa, lymphocytes, and macrophages Several other properties are associated with glu-tamine, including antioxidant activity, promotion of production of heat shock proteins and protection of gut barrier functionality In most enteral formulations glutamine is present in low concentra-tions and glutamine supplementation is given intravenously for burns, trauma and ICU patients

‘Immune-enhancing’ enteral formulas (arginine,

omega-3 fatty acids, probiotics, nucleotides)

Specific formulas designed with the aim of improving immune function and reducing the risk of infections, are called immune-enhancing enteral feeds

These formulas are usually enhanced with omega-3, γ-linolenic acid (GLA), arginine, and/or nucleotides (low molecular weight intracellular compounds that are composed of a purine and pyri-dimine backbone) The effect of these feeds is controversial and might be related to a specific formula Well-designed large clinical trials did not show improved outcome in critically-ill patients

Arginine

Arginine-enriched formulas reduced the risk of infections and shortened the duration of hospitalization in elective surgical patients Heyland et  al [8] suggest in a systematic review that

CHAPTER 206 enteral nutrition in the icu 975

immune modulating formulas decrease rate of infections in elective

surgical patients, but may increase mortality rates in general ICU

patients, although the data to support such conclusion was weak

[8] Arginine enriched formulas might be beneficial to patients

before and after major surgery and trauma, but in the meantime

should not be provided to patients suffering from severe sepsis

Omega-3 fatty acids and γ-linolenic acid

Omega-3 fatty acids help down-regulate the inflammatory response

and improve overall immune function Both eicosapentaenoic acid

(EPA) and docosahexaenoic acid (DHA) show benefits in membrane

structure and function and gene transcription Animal models have

established the ability of fish oil solutions to reduce lung

permeabil-ity in acute lung injury (ALI) compared with solutions with omega-6

or saturated fat Preclinical data supported the concept that EPA and

DHA may be beneficial in ALI/acute respiratory distress syndrome

(ARDS) by reducing inflammation Most of the animal studies have

involved a pre-injury supplementation protocol and have delivered

the fish oil supplementation before or soon after the insult to the lungs

Patients with ALI/ARDS have been found to have very low omega-3

levels compared with normal individuals, suggesting a potential role

for omega-3 dietary supplementation in these patients [9]

Clinical data regarding the use of formulas enhanced with EPA

and GLA in ALI/ARDS patients come from five randomized

con-trolled studies Three studies demonstrated an association between

the administrations of an enteral formula enriched in EPA, GLA,

and antioxidants and improved clinical outcome as compared

with high-fat formula A meta-analysis done on these three trials

showed a significant reduction in the risk of mortality as well as

rel-evant improvements in oxygenation and clinical outcomes of

ven-tilated patients with ALI/ARDS [10] Nevertheless, there are two

recent studies that addressed the same question in patients with

ALI or ARDS with mixed results In a Spanish multicentre study

[11], the EPA-GLA diet group showed a trend toward a decreased

SOFA score, but it was not significant In this study, no

improve-ment in the gas exchange measured by the PaO2/FiO2 ratio was

measured in the omega-3-treated group [11] Liver function tests,

glycaemia, cholesterol and triglycerides were similar in both groups

[11] The control group stayed longer in the ICU than the EPA-GLA

diet group [11] In a recent study [12], the authors used a

differ-ent approach of twice-daily bolus administration of omega-3 fatty

acids instead of continuous enteral infusions to deliver the

sup-plements In contrast to the previous studies in this study enteral

supplementation of omega-3 fatty acids, GLA, and antioxidants

did not improve the rate of nosocomial infections, non-pulmonary

organ function, lung physiology, or clinical outcomes in patients

with ALI compared with supplementation of an isocaloric control

[12] Furthermore, the study was stopped early for futility despite

an 8-fold increase in plasma eicosapentaenoic acid levels [12] The

use of the omega-3 supplement resulted in increased duration of

diarrhoea [12] The study had sustained heavy criticism since the

control formula contained five times more protein and the omega-3

supplements were given up to 5 days after the respiratory

deteriora-tion Moreover, half the patients were underfed and the omega-3

fatty acids might have been catabolized as an energy source

Fibres

Fibres are non-digestible, sugar-based, long molecules that are

subject to bacterial breakdown to short-carbon molecules, such

as acetate, propionate, and butyrate These serve as important strates for the cells of the colonic mucosa, and their uptake enhances absorption of water and electrolytes from the bowel lumen Fibres also bind bile salts, which would otherwise be irritants to the colonic mucosa, promotes glucose absorption, and provides sub-strate for the normal bowel flora The main importance of fibres is their ability to improve stool consistency Despite concern being raised about their utility in patients who suffer from gut ischae-mia, no adverse effects have been reported from including fibre in enteral feeds, and most new formulations contain a fibre source

sub-Probiotics

Probiotic therapy can be defined as any supplemental micro-organisms that are safe and stable and, when adminis-tered in adequate amounts, confer a health benefit to the patient Looking at patients’ microbiota profile over time in hospital reveals profound changes These changes are due to broad spectrum anti-biotics, ulcer prophylaxis, vasoactive-pressor agents, alterations in motility, and decreases in luminal nutrient delivery These agents act by competitively inhibiting pathogenic bacterial growth, blocking epithelial attachment of invasive pathogens, eliminating pathogenic toxins, enhancing the mucosal barrier function, and favourably modulating the host inflammatory response There is

an inverse correlation between the changes in patients’ microbiota and clinical outcome [13] Unfortunately, despite the fact that the administration of probiotics agents has been shown to decrease infection rate in specific critically-ill patient populations involving transplantation, major abdominal surgery, and severe trauma [13],

no recommendation has currently been made for use of probiotics

in the general ICU population due to a lack of consistent outcome effect

Many experts believe that as the ease and reliability of taxonomic classification will improve, stronger recommendations could be made for the use of specific probiotics in specific populations of critically-ill patients

Complications

The most severe complication of EN is aspiration and is a main cause of pneumonia Some patients have increased risk factors for aspiration, such as mechanical ventilation, old age, decreased consciousness, supine position, poor oral health, etc In order to reduce the risk of aspiration, it is important to maintain a posture where the upper body is raised to 30–45° and to assess the toler-ance for feeding Gastrointestinal complications, especially diar-rhoea, affecting up to 60%, are commonly encountered, as well as regurgitation, nausea, vomiting, constipation, abdominal pain, and bloating Soluble fibre-enriched solutions can be used in cases of diarrhoea and in severe cases a use of a polypeptide-based formula may be tried Metabolic complications, such as hyperglycaemia, electrolyte disturbance, especially hypokalaemia, are mainly linked

to the medical condition of the patient and the content of the mula Special attention should be given to the possible develop-ment of refeeding syndrome, a group of symptoms that appear after sudden feeding of a patient who was in a starved state The sudden change affects insulin secretion that, in turn, causes changes in elec-trolytes and fluids These changes could cause cardiac, respiratory, haematological, metabolic, and neurological disturbances and, in severe cases, a multi-organ failure and death [14] The electrolytic

for-SECTION 7 nutrition: nutritional failure

976

disturbances include hypophosphataemia, hypokalaemia, and

hypomagnesaemia

References

1 Heyland DK, Dhaliwal R, and Drover JW (2003) Canadian clinical

practice guidelines for nutrition support in mechanically ventilated,

critically ill adult patients Journal of Parenteral and Enteral Nutrition,

27, 355–73.

2 Marik PE and Zaloga GP (2001) Early enteral nutrition in acutely ill

patients: a systematic review Critical Care Medicine, 29, 2264–70.

3 Kreymann KG, Berger MM, and Deutz NEP (2006) ESPEN

guide-lines on enteral nutrition: intensive care Clinical Nutrition, 25,

210–23.

4 Stephen A, McClave MD, and Robert G (2009) Guidelines for the

Provision and Assessment of Nutrition Support Therapy in the Adult

Critically Ill Patient Journal of Parenteral and Enteral Nutrition,

33, 277.

5 Ho KM, Dobb GJ, and Webb SA (2006) A comparison of early gastric

and post-pyloric feeding in critically ill patients: a meta-analysis

Intensive Care Medicine, 32, 639–49.

6 Jiyong J, Tiancha H, Huiqin W, and Jingfen J (2013) Effect of gastric

versus post-pyloric feeding on the incidence of pneumonia in critically

ill patients: observations from traditional and Bayesian random-effects

meta-analysis Clinical Nutrition, 32, 8–15.

7 Davies AR, Morrison SS, Bailey MJ, et al (2012) ENTERIC Study

Investigators; ANZICS Clinical Trials Group A multicenter,

randomized controlled trial comparing early nasojejunal with

nasogas-tric nutrition in critical illness Critical Care Medicine, 40, 2342–8.

8 Heyland DK, Novak F, Drover JW, Jain M, Su X, and Suchner U (2001) Should immunonutrition become routine in critically ill

patients? A systematic review of the evidence Journal of the American

Medical Association, 286, 944–53.

9 Singer P, Theilla M, and Fisher H (2006) Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in venti-

lated patients with acute lung injury Critical Care Medicine, 34, 1033–8.

10 Pontes-Arruda A, Demichele S, Seth A, and Singer P (2008) The use of

an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data

Journal of Parenteral and Enteral Nutrition, 32, 596–605.

11 Grau-Carmona T, Moran-Garcia V, Garcia-de-Lorenzo A, et al (2011) Effect of an enteral diet enriched with eicosapentaenoic acid, gamma-linolenic acid and anti-oxidants on the outcome of mechanically

ventilated, critically ill, septic patients Clinical Nutrition, 30, 578–84.

12 Rice TW, Wheeler AP, Thompson BT, et al (2011) Acute Respiratory

Distress Syndrome Network of Investigators Journal of the American

Medical Association, 306, 1574–81.

13 Shimizu K, Ogura H, Asahara T, et al (2013) Probiotic/synbiotic therapy for treating critically ill patients from a gut microbiota perspec-

tive Digestive Diseases and Sciences, 58, 23–32.

14 Byrnes MC and Stangenes J (2011) Refeeding in the ICU: an adult and

pediatric problem Current Opinion in Clinical Nutrition and Metabolic

Care, 14, 186–92.

Parenteral nutrition in the ICU

Jonathan Cohen and Shaul Lev

Key points

◆ The parenteral nutrition formula should be designed to meet

nutritional needs

◆ Daily writing of parenteral nutrition orders needs to include

laboratory evaluation, fluid, caloric, and protein requirements

◆ Calorie and protein requirements should be calculated daily

◆ Laboratory assessment should be performed daily

◆ Monitor drug and nutrient interactions, and their effects on

laboratory variables

Introduction

Parenteral nutrition (PN) is a technique of artificial nutrition

sup-port, which consists of the intravenous administration of

macro-nutrients (glucose, amino acids, and triglycerides), micromacro-nutrients

(vitamins and trace elements) and water While enteral nutrition

(EN) is recognized as the optimal method for providing energy and

protein needs, it is not always an option in many patients and may

fail to meet patient requirements For this reason, PN has become

integrated into ICU patient management with the aim of

prevent-ing energy deficits and preservprevent-ing lean body mass The addition of

PN to enteral nutrition is known as supplemental PN

Indications and modes of administration

Indications for parenteral feeding

Parenteral feeding should be considered in the following

circumstances:

◆ Enteral nutritional support is contraindicated: e.g in the

pres-ence of gut obstruction, high output fistulae, severe gut

ischae-mia or gut failure

◆ Enteral nutrition alone is unable to meet energy and nutrient

requirements and PN is given as supplemental nutrition: this

approach may be especially relevant in high risk patients who are

chronically malnourished

Approach and clinical evidence for supplemental PN

International guidelines differ considerably regarding the

indica-tions for PN [1–3] Thus, the European Society of Parenteral and

Enteral Nutrition (ESPEN) guidelines [3] recommend initiating

PN in critically-ill patients who do not meet caloric goals within

2–3 days of commencing EN The Canadian guidelines [2]

recom-mend PN only after extensive attempts to feed with EN have failed,

while the American Society of Parenteral and Enteral Nutrition

(ASPEN) guidelines [1] advocate administering PN after 8 days of attempting EN unsuccessfully

Five randomized prospective trials have been published ing the early use of supplemental PN [4–8] The first trial was pub-lished in 2000, by a French group [4] and randomized 120 patients

regard-to receive either EN plus PN from day one or conventional EN given as early as possible Despite a significant energy delivery difference between the two groups and better biochemical param-eters, the only clinical improvement noted in the PN group was a decrease in the length of hospital stay Due to these disappointing results and to a strong negative sentiment in the medical commu-nity, the use of PN was largely neglected for many years Recently, however, there has been renewed interest in the use of PN and four randomized controlled trials (RCTs) have been published in the last 3 years [5–8] The TICACOS study [5] was performed on 130 patients randomized to receive either EN or PN where required according to indirect calorimetry measurements and a control group targeted to 25 kcal/kg/day The study did not find a dif-ference in ICU mortality, but reported a significantly better hos-pital survival for the study group when analysing the results per protocol The very recent bicentre Swiss trial (SPN) [6] allocated

301 patients to receive PN on the fourth day of admission if it was shown that energy delivery was less than 60% of measured EE The study reported significantly better outcomes regarding infection rates, days of antibiotic administration and length of ventilation when analysing the results after 9 days of admission The largest study on very early PN administration, the EPANIC study [7], recruited more than 4000 patients to receive either PN on the first

2 days of admission versus adding PN on the 8th day of admission The study group received a low protein formulation, severely mal-nourished patients were excluded and most of the population com-prised non-high risk patients The study did not find any positive outcome and even suggested harm However, the results should

be interpreted with caution and the main conclusion that can be drawn is that patients who are not high risk, who are not chroni-cally malnourished should not receive early supplemental PN A sub-analysis of the trial also did not find any benefit in any sub-group analysed, including the patients with higher illness sever-ity scores or patients with high malnutrition scores A very recent multicentre Australian study prospectively randomized patients

to receive complimentary PN as soon as possible if they were not expected to be orally fed for at least for 24 hours The study did not find any significant clinical improvement except for length of ventilation, which was reduced by 1 day and a slightly improved quality of life after 1 month, which was not considered to be clini-cally meaningful Interestingly, the infection rate, including blood stream infections, was not increased in the PN group [8]

SECTION 7 nutrition: nutritional failure

978

Methods of administration

PN is usually delivered by programmable pumps and requires

reli-able vascular access A dedicated catheter or lumen is needed

PN should be prescribed by trained health care professionals

applying validated protocols Energy delivery should be matched

to the energy target, preferably defined by indirect calorimetry

or calculated by a trained dietitian Meticulous glucose control is

important, with a therapeutic goal targeting levels between 140 mg/

dL to 180 mg/dL

Choice of parenteral feeding route

Central venous

The central venous route is preferred for administration of

hyper-osmolar solutions (>850 mOsmol/kg) in cases where high energy

intake (> 1500 kcal) is to be infused The femoral route should not

be used if possible due to a higher risk of catheter-related infections

Peripheral venous

Parenteral nutrition via the peripheral route is possible when the

prescribed solution is of low osmolality In order to achieve this,

the volume of the solution can be increased or the energy content

(particularly from carbohydrate) reduced Peripheral cannula sites

should be changed every 72–96 hours

PN composition

Carbohydrate is normally provided as concentrated glucose while

30–40% of total calories are usually given as lipids (e.g soya bean

emulsion) The nitrogen source is synthetic, crystalline L-amino

acids, which should contain appropriate quantities of all

essen-tial and most non-essenessen-tial amino acids Carbohydrate, lipid, and

nitrogen sources are typically mixed into a large bag in a sterile

pharmacy unit Vitamins, trace elements, and appropriate

electro-lyte concentrations can then be added to the infusion, thus

avoid-ing multiple connections Volume, protein, and calorie content of

the feed should be determined on a daily basis in conjunction with

the appropriate health care professional

Stability

Commercial solutions are highly stable after preparation and can

be stored for months in cool storage conditions After opening the

bag, the solution should be given within 24–48 hours depending on

manufacturer’s recommendations The vitamin solutions are

usu-ally stable for up to 24 hours

Immunonutrition

The concept of immunomodulating formulae has been extensively

studied in relation to EN, but not substantiated regarding PN In this

regard, glutamine and omega-3 fatty acids have received the most

attention Glutamine is an important metabolic fuel for the cells of

the gut and the immune system It is also involved in the

regula-tion of muscle and liver protein balance, probably mediated by an

increase in cellular hydration, a triggering signal or protein

anabo-lism Several studies have demonstrated that parenteral glutamine

supplementation may improve outcome, and the ESPEN

guide-lines give a grade A recommendation to the use of glutamine in

critically-ill patients who receive PN Three large multicentre trials

have been published since the release of the ESPEN guidelines The

Scandinavian multicentre, double-blind, RCT of intravenous (iv)

glutamine supplementation for ICU patients was recently published [9] In this trial, patients were given supplemental iv glutamine (0.283 g/kg body weight/24 hours) for their entire ICU stay They demonstrated a lower ICU mortality in the treatment arm compared with controls, which was not significant at 6 months No change in the SOFA (Sequential Organ Failure Assessment) scores were noted The SIGNET trial [10] recruited 502 patients to receive glutamine via PN, which was given as a supplement to EN This study did not find any benefit from iv glutamine administration to unselected crit-ically-ill patients A trial conducted on 1223 mechanically ventilated critically-ill patients reported disappointing results and concluded that glutamine administration in this critically-ill population might

in fact cause harm [11] The harm was noted mainly in patients with multi-organ failure, haemodynamic instability, and renal failure The doses used in this trial were higher than those recommended and glutamine was given very early in the course of hospitalization.Studies on IV omega-3 fatty acids have yielded promising results

in animal models of acute respiratory distress syndrome and proved superior to solutions with omega-6 composition The clinical expe-rience with the use of these solutions in critically-ill patients is not

as yet proven The discrepancy between animal models and clinical practice could be related to different time frames Thus, while in the animal studies the fish oil solutions were given in proximity

to the insults, the administration in clinical trials was much later after the primary insults

Complications

The use or misuse of PN may be associated with many potential complications [12], which may be divided into mechanical, infec-tious, and metabolic complications Most of the complication can

be avoided by optimum hand hygiene, maximal barrier tions, and close medical care by specialized total parenteral nutri-tion (TPN) team

◆ Fatty liver and liver failure

◆ Hyperosmolar, hyperglycaemic, and hypoglycaemic states

◆ Hypophosphataemia and hyperphosphataemia

◆ Hypercalcaemia

CHAPTER 207 parenteral nutrition in the icu 979

◆ Metabolic acidosis with hyperchloraemia

◆ High endogenous insulin levels

◆ Vitamin deficiencies—folate, thiamine, vitamin K

Timely and adequate parenteral nutritional support administered

according to guidelines recommendations, may help to achieve

balanced nutritional support Both under- and overfeeding

should be avoided In addition to energy balance, careful

atten-tion should be devoted to the adequacy of protein and

micro-nutrient administration Avoiding infectious complications by

applying meticulous sterile techniques in catheter insertion and

avoiding metabolic complications by close metabolic follow-up

can be achieved as shown by studies reporting low rates of PN

complications

References

1 Stephen A, McClave MD, and Robert G (2009) Guidelines for the

provision and assessment of nutrition support therapy in the adult

critically ill patient Journal of Parenteral and Enteral Nutrition, 33, 277.

2 Heyland DK, Dhaliwal R, and Drover JW (2003) Canadian clinical

prac-tice guidelines for nutrition support in mechanically ventilated, critically

ill adult patients Journal of Parenteral and Enteral Nutrition, 27, 355–73.

3 Singer P, Berger MM, and Van den Berghe G (2009) ESPEN

Guidelines on parenteral nutrition: intensive care Clinical Nutrition,

28, 387–400.

4 Bauer P, Charpentier C, Bouchet C, Nace L, Raffy F, and Gaconnet N

(2000) Parenteral with enteral nutrition in the critically ill Intensive

ill patients: a randomised controlled clinical trial Lancet, 2, 354–5.

7 Casaer MP, Mesotten D, Hermans G, et al (2011) Early versus late

parenteral nutrition in critically ill adults New England Journal of

sive care unit patients Acta Anaesthesiologica Scandinavica, 55,

812–18.

10 Andrews PJ, Avenell A, Noble DW, et al (2011) Scottish Intensive Care Glutamine or Selenium Evaluation Trial (SIGNET) Trials Group Randomised trial of glutamine, selenium, or both, to supplement

parenteral nutrition for critically ill patients British Medical Journal,

342, d1542.

11 Heyland D, Muscedere J, Wischmeyer PE, et al (2013) A Randomized

Trial of Glutamine and Antioxidants in Critically Ill Patients New

England Journal of Medicine, 368,1489–97.

12 Jeejeebhoy KN (2012) Parenteral nutrition in the intensive care unit

Nutrition Reviews, 70, 623–30.

SECTION 8 The renal system

Part 8.1 Physiology  982

PART 8.1 Physiology

208 Normal physiology of the renal system  983

Bruce Andrew Cooper

◆ The impact of kidney disease is often predictable.

◆ The kidney plays a critical role in fluid and electrolyte balance

via many specialized trans-membrane pathways

◆ The kidney is also involved in the production and

modifica-tion of two key hormones and one enzyme

◆ Understanding normal renal physiology can help determine

clinical management

Renal structure

General anatomy

Standard renal anatomy consists of two kidneys situated either side

of the L2–5 lumbar vertebrae in a retroperitoneal position each

with a single feeding artery, a single draining vein and a single

ure-ter each connecting to the urinary bladder, which acts as a reservoir

to be emptied on demand through a single urethra Some

anatomi-cal variants include a fused or single kidney (1 in 750–1000 people),

multiple renal arteries (32%) and veins (30%; usually right-sided)

and duplication of the collecting system (<1%) which can be at the

level of the renal pelvis, ureter, or down to the level of the bladder

Vascular duplication is usually functionally unimportant although

can result in complexity at times of surgery or other invasive

proce-dures Ureteric duplication if often associated with obstruction or

reflux Sympathetic nerves travel within the renal artery adventitia

to supply the kidney

Internal structure

The macroscopic internal structure of the kidney can be divided

into several key areas: renal cortex, renal medulla, renal pyramids,

and the calyceal system including the renal pelvis The microscopic

structure of the renal parenchyma consists of between 900,000

to 1 million nephron units [1] and the renal interstitium which

includes arcuate arteries, peritubular capillaries, and interstitial

fibroblasts The nephron unit begins with the renal glomerulus, a

delicate tuft of capillaries supported by specialized epithelial cells

(podocytes and mesangial cells) that is supplied and drained by

an afferent and efferent arteriole respectively Each glomerulus sits

within a capsule (Bowman’s) that is drained by a single renal tubule

Each tubule consists of a single layer of epithelial cells that have a luminal membrane (urine side) and basolateral membrane (inter-stitial side) The sections of the renal tubule include the proximal convoluted tubule (PxCT), the loop of Henle (LOH: consisting of the thin descending limb, thin ascending limb, and thick ascending limb), and distal convoluted tubule (DCT) several of which join together to form a collecting duct (CD) The renal cortex consists

of mostly glomeruli and the PxCT and DCT, the renal medulla sists of mostly the LOH and the renal pyramids contain the CD that drain the final urine into the calyceal system The calyceal sys-tem acts to funnel the urine via the renal pelvis into the muscular ureter that then propels the urine towards the bladder The most metabolically active cells within the nephron unit include the PxCT and DCT, the thick ascending limb of the LOH and the glomerular podocyte Therefore, these are the areas of the kidney that are most susceptible to toxic or ischaemic injury

con-Renal function

The combined blood flow to both kidneys is in the order of 1 L/min, i.e 20% of the entire cardiac output The blood flow to each glomerulus is controlled by the afferent (feeder) arteriolar tone, i.e vasodilatation will result in an increase in pressure and flow into the glomerulus and vasoconstriction will result in a decrease

in pressure and flow into the glomerulus This mechanism is under the control of prostaglandins which when present results in vasodilatation and when absent or inhibited (e.g by non-steroidal anti-inflammatory drugs) results in vasoconstriction The glo-merular tuft is therefore subject to variable pressure loads (glo-merular filtration pressure) that are not only determined by the afferent arteriolar inflow, but also the efferent arteriolar outflow The efferent arteriolar tone is under the control of angiotensin II and vasoconstricts when present, causing an increase in the glo-merular pressure and vasodilates when absent or inhibited (e.g by angiotensin converting enzyme (ACE) inhibitors or angiotensin

II receptor blockers (ARB)) resulting in a decrease in glomerular pressure The glomerular tuft acts as a semi-permeable membrane consisting of a basement membrane that is only 330 ± 50 (SD)

nm thick in the males and 305 ± 45 nm thick in the females ported on the blood side by a single layer of endothelial cells and

sup-on the urine side by a single layer of podocytes Therefore, changes

in the glomerular pressure will result in an increased or decrease

in the filtration rate when the pressure is increased or decreased respectively This filtration rate is described as the glomerular

SECTION 8 renal system: physiology

984

filtration rate (GFR) and in a normal adult male is approximately

120 mL/min or 170 L/day

GFR is often used synonymously with ‘renal function’ although

as described later in this chapter there are many other aspects of

kidney function beyond GFR GFR can be defined as the rate of

clearance of a substance from the blood into the urine by

glomeru-lar filtration assuming that it passes through the nephron unit

with-out undergoing any metabolism, tubular secretion, or reabsorption

As GFR can be difficult to measure accurately in a clinical setting

(laboratory based settings use inulin infusions) surrogate estimates

of GFR are often used As creatinine is a continuously produced

endogenous substance (muscle derived) that undergoes

glomeru-lar filtration without any subsequent reabsorption and only

mini-mal tubular secretion it can be used as a simple measure of GFR

Creatinine clearance (CrCl) can be calculated using a timed urine

collection by measuring the urinary flow rate (V) (mL/min) and

urinary creatinine concentration (U) (µmol/L) with a

simultane-ously drawn plasma creatinine concentration (P) (µmol/L) using

the simple equation: CrCl = UV/P (Note: plasma creatinine should

now universally be measured by the standardized isotope dilution

mass spectrometry (IDMS) method, which is considered the best

reference standard measure [2] ) However, as creatinine

produc-tion is significantly influenced by age, gender, and muscle mass and

as there is often the need to compare renal function between

differ-ent patidiffer-ent groups, various estimating equations for GFR (eGFR)

have been derived (Cockcroft and Gault [3], modification of diet

in renal disease (MDRD) [4], CKD Epidemiology Collaboration CKD-EPI [5]) It is important to remember that these are estimat-ing equations derived in specific patient populations (e.g MDRD equation was derived from patients with GFRs between 15 and 60 mL/min/1.73 m2); they are inaccurate in patients not at steady state (i.e during acute renal failure or its recovery) and in patients on dialysis The units of GFR are usually millilitres per minute (mL/min) corrected for body size to an average body surface area of 1.73

m2, i.e mL/min/1.73 m2 This enables the comparison of renal tion in two or more individuals of different body size Creatinine concentration can be used as a simple measure of renal function Again assuming that creatinine production remains unchanged an increase in creatinine in a given individual reflects worsening renal function whereas a decrease reflects improving renal function It

func-is important to remember that the relationship between GFR and serum creatinine is inverse and non-linear (see Fig 208.1).From Fig 208.1, it can also be seen that up to 50% of GFR can be lost before the serum creatinine rises outside of the normal range, and at lower levels of GFR further small reductions in GFR can result in a significant rise in the blood concentration of creatinine and other important solutes (urea and potassium)

Due to the semi-permeable nature of the glomerulus, the sition of the glomerular filtrate is effectively identical to that of the blood plasma minus the proteins which under normal circumstances are too large to cross Given that the daily GFR is 170 L a significant recovery mechanism is needed to prevent major solute and fluid loss This is achieved by the subsequent luminal fluid manipulation, both active and passive, that occurs in various segments of the renal tubule The final urine produced is therefore a highly modified version of the glomerular filtrate and is so well balanced that subtle adjustments in various elements and fluid balance can be achieved

compo-Tubular reabsorption

The majority of the filtered solute (sodium, potassium, chloride, calcium, phosphate, and bicarbonate) is recovered in the PxCT [6] (see Table 208.1) via specific pathways driven by a sodium/potas-sium adenosine 5’-triphosphatase (Na+/K+ ATPase) found on the basolateral membrane ATPase generates an electrochemical gra-dient by removing sodium from the cell and moving potassium

0 Normal range Serum Cr

50 GFR %

100

Fig. 208.1 Association between GFR and creatinine.

Table 208.1 Summary of renal handling

Element PxCT DL of the LOH AL of the LOH DCT CD Urine content as

% indicates the percentage of filtered elements reabsorbed in different part of the nephron.

PxCT, proximal convoluted tubule; DL, descending limb; AL, ascending limb; LOH, Loop of Henle; DCT, distal convoluted tubule; CD, collecting duct.

Data from Maddox DA and Gennari FJ, ‘The early proximal tubule: a high-capacity delivery-responsive reabsorptive site’, American Journal of

Physiology, 1987, 252(4 Pt 2), pp F573–84.

CHAPTER 208 normal physiology of the renal system 985

into the cell Amino acids and glucose, when at normal levels, are

completely recovered by the PxCT via luminal sodium-amino acid

and sodium–glucose cotransporters Significant water recovery

also occurs in parallel to this active solute uptake in the proximal

tubules The thick ascending limb of the loop of Henle selectively

recovers another 20–25% sodium and chloride via a luminal sodium

potassium chloride co-transporter, without any passage of water

This mechanism is blocked by frusemide The distal convoluted

tubule absorbs small amounts of sodium and chloride again

uti-lizing a basolateral Na+/K- ATPase and a luminal sodium-chloride

co-transporter (the latter is blocked by thiazide diuretics [7])

Water balance

As mentioned earlier, a large volume of fluid is filtered by the

glo-merulus and so several mechanisms exist to prevent significant fluid

losses The majority of filtered water (65–70%) returns to the

circula-tion along with the filtered solute in the PxCT The second locacircula-tion

for water reabsorption is in the thin descending limb of the LOH

This part of the LOH is permeable only to water and as it travels

deeper into the renal medulla it is exposed to increasing osmotic

forces, from the iso-osmolar (300 mOsm/kg) cortex through to the

hyperosmolar (up to 1200 mOsm/kg) medulla This osmotic

concen-tration gradient is generated by the active solute exchange (counter

current exchange [8] ) that occurs in the LOH Aquaporin channels

selectively allow the movement of water across the cell membrane

under the influence of the osmotic gradient The solute reabsorption

in the DCT also results in water reabsorption (approximately 5%)

The final location for water reabsorption is in the CD The CD again

utilizes the increasing osmotic gradient as it traverses from the cortex

to the medulla and water is reabsorbed via aquaporin channels under

the control of anti-diuretic hormone (ADH) ADH is produced by

osmoreceptors (neurosecretory neurons) in the hypothalamus under

circumstances of dehydration and secreted by the posterior pituitary

into the blood ADH then travels via the blood to the kidney where it

binds to a basolateral membrane receptor that initiates a cyclic AMP

dependent protein kinase pathway that results in insertion of

pre-formed aquaporin channels onto the luminal membrane of the CD

[9] allowing water reabsorption The action of ADH is to produce a

reduced volume of more concentrated urine ADH secretion is

inhib-ited by over hydration and in the absence of ADH the CD aquaporin

channels are removed from the luminal surface rendering the CD

impervious to water This absence of ADH results in the passage of a

larger urine volume with a low osmolality Through these processes

serum osmolality is maintained between 285 and 295 mOsm/kg by

the kidney’s ability to produce urine with a concentration varying

between 50 and 1200 mOsm/kg [10]

Acid balance

Normal metabolic function results in the production of acid Some

of these acids can be removed in the form of carbon dioxide via

res-piration Other acids can only be removed by passage in the urine

Two areas of the nephron are critical in managing acid base balance

via proximal tubular bicarbonate recovery and acid secretion in the

late distal tubule/cortical collecting duct [11]

Proximal tubule

As bicarbonate is freely filtered by the glomerulus a recovery

mech-anism is required to prevent massive bicarbonate loss that would

result in acidosis (i.e proximal renal tubular acidosis (RTA), also known as type II RTA); the PxCT is a site of major bicarbonate recovery The mechanism used to recover bicarbonate relies on a luminal sodium-hydrogen exchange carrier molecule (NHE-3) and luminal carbonic anhydrase (CA) Freely filtered HCO3– combines with actively secreted hydrogen to form H2CO3 In the presence of

CA, H2CO3 dissociates to H2O and CO2, the latter can then diffuse into the PxCT Within this cell and again in the presence of CA the

CO2 combines with H2O to form H2CO3 This can then dissociate into H+ and HCO3- of which the former can move via the NHE-3 into the luminal fluid and the latter into the blood via a basolat-eral Na+/HCO3- co-transporter Any defect in this system results in bicarbonate remaining within the tubule (although the distal tubule can compensate for some of these losses) resulting in a metabolic acidosis The most common cause of this in adults is the use of a carbonic anhydrase inhibitor (acetazolamide) and in children due

to a congenital tubular defect (Fanconi’s syndrome which is also associated with increase urinary losses of amino acids, glucose, phosphate, and uric acid)

Insulin and gluconeogenesis

The kidney has an important role in the control of blood glucose through several mechanisms Under normal physiological condi-tions freely filtered glucose is completely reabsorbed by the prox-imal tubule leaving the resultant urine free of glucose However,

as the maximal re-absorptive capacity of filtered glucose is only

11 mM, filtered glucose loads above this level (i.e during tes induced hyperglycaemia) will result in glycosuria The pro-cess of glucose reabsorption is achieved by luminal membrane based sodium-glucose linked transporters (SGLT1/2) [13], again driven by a basolateral based Na+/K+ ATPase, and the passive removal of intracellular glucose via basolateral glucose transport-ers (GLUT1/2) [14] The kidney is now also considered to be an important site of glucose production (up to 40%) [15], after that

diabe-of the liver, through the process diabe-of gluconeogenesis This results in

SECTION 8 renal system: physiology

986

the generation of glucose from non-carbohydrate carbon substrates

(principally lactate) A final factor that impacts on blood glucose

control is the kidneys role in insulin clearance Insulin is freely

fil-tered by the glomerulus and then reabsorbed by the PxCT where

it undergoes proteolytic degradation into small peptide fragments

that are then returned to the circulation

Hormonal function

Erythropoietin

Erythropoietin is a critical glycoprotein hormone that controls

erythropoiesis If the oxygen concentration of the blood passing

through the kidney is low, specialized fibroblasts within the

peri-tubular interstitium are stimulated to produce erythropoietin [16]

This erythropoietin then travels through the blood to the bone

mar-row where it stimulates the proliferation of erythrocyte precursors

into mature red blood cells In kidney disease erythropoietin levels

can be inappropriately low or absent causing significant anaemia

This can easily be corrected by administration of synthetic

eryth-ropoietic agent [17]

Vitamin D and parathyroid hormone

Vitamin D is a critical hormone for calcium homeostasis and bone

metabolism The kidney converts 25-hydroxycholecalciferol into

its activated form 1,25-dihydroxycholecalciferol [18] In the

pres-ence of kidney disease activated vitamin D levels fall resulting in

a decrease in serum calcium concentration Decreasing calcium

concentration are countered by increasing parathyroid hormone

(PTH) concentration, which stimulates the release of calcium from

bones in an attempt to return the serum calcium concentration to

normal PTH concentration also increases in kidney disease due

to reduced phosphate clearance resulting in elevated serum

phos-phate concentration PTH increases renal phosphos-phate clearance in

the attempt to return the serum phosphate to normal This

stim-ulation of the parathyroid gland to produce PTH is termed

sec-ondary hyperparathyroidism although if prolonged can result in

the production of uncontrolled parathyroid adenomas (tertiary

hyperparathyroidism) [19]

Renin

Renin is an enzyme produced by specialized cells within the

affer-ent arteriole adjacaffer-ent to the DCT (juxtaglomerular apparatus)

Factors that stimulate renin production include a decrease in blood

pressure, reduced sodium delivered to the DCT and increased

sympathetic activity [20], i.e situations suggesting dehydration or

hypotension Once in the blood, renin hydrolyses angiotensinogen

(produced by the liver) into angiotensin I, which in turn is

con-verted to angiotensin II by ACE within the lungs Angiotensin

II increases blood pressure through arteriolar vasoconstriction,

aldosterone production, sympathetic nervous system activation,

increased thirst, and direct stimulation of proximal tubular sodium

reabsorption Important factors that result in inappropriate renin

production and resulting systemic hypertension include renal

artery stenosis and kidney disease

Influencing hormones

Aldosterone is an important steroid hormone that is produced in

the adrenal gland (zona glomerulosa) in the presence of angiotensin

II or high potassium concentration Aldosterone acts to stimulate

sodium reabsorption (via luminal epithelial sodium channels ENaC which is blocked by amiloride) and potassium secretion (via

K+ channels in the luminal membrane) in the cortical collecting duct (principal cell), again driven by a basolateral Na+/K- ATPase, resulting in salt and water retention

3 Cockcroft DW and Gault MH (1976) Prediction of creatinine

clear-ance from serum creatinine Nephron, 16(1), 31–41.

4 Levey AS, Coresh J, Greene T, et al (2006) Using standardized serum creatinine values in the modification of diet in renal disease study

equation for estimating glomerular filtration rate Annuals of Internal

Medicine, 145(4), 247–54.

5 Levey AS, Stevens LA, Schmid CH, et al (2009) A new equation to

estimate glomerular filtration rate Annals of Internal Medicine, 150(9),

604–12.

6 Maddox DA and Gennari FJ (1987) The early proximal tubule: a

high-capacity delivery-responsive reabsorptive site American Journal

of Physiology, 252(4 Pt 2), F573–84.

7 Beaumont K, Vaughn DA, and Fanestil DD (1988) Thiazide diuretic drug receptors in rat kidney: identification with [3H]metolazone

Proceedings of the National Academy of Sciences USA, 85(7), 2311–14.

8 Barrett KE and Ganong WF (2012) Ganong’s Review of Medical

Physiology, 24th edn New York, London: McGraw-Hill Medical.

9 Katsura T, Gustafson CE, Ausiello DA, and Brown D (1997) Protein kinase A phosphorylation is involved in regulated exocytosis of

aquaporin-2 in transfected LLC-PK1 cells American Journal of

Physiology, 272(6 Pt 2), F817–22.

10 Halperin ML, Kamel KS, and Oh MS (2008) Mechanisms to

con-centrate the urine: an opinion Current Opinion in Nephrology and

Hypertension, 17(4), 416–22.

11 Unwin RJ and Capasso G (2001) The renal tubular acidoses Journal of

the Royal Society Medicine, 94(5), 221–5.

12 Adeva MM, Souto G, Blanco N, and Donapetry C (2012) Ammonium

metabolism in humans Metabolism, 61(11), 1495–511.

13 Lee WS, Kanai Y, Wells RG, and Hediger MA (1994) The high affinity Na+/glucose cotransporter Re-evaluation of function and distribution

of expression Journal of Biological Chemistry, 269(16), 12032–9.

14 Sacktor B (1989) Sodium-coupled hexose transport Kidney

International, 36(3), 342–50.

15 Meyer C, Stumvoll M, Dostou J, Welle S, Haymond M, and Gerich

J (2002) Renal substrate exchange and gluconeogenesis in normal

postabsorptive humans American Journal of Physiology: Endocrinology

Metabolism, 282(2), 428–34.

16 Bachmann S, Le Hir M, and Eckardt KU (1993) Co-localization of erythropoietin mRNA and ecto-5’-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce

erythropoietin Journal of Histochemicals and Cytochemicals, 41(3),

335–41.

17 Macdougall IC and Ashenden M (2009) Current and upcoming erythropoiesis-stimulating agents, iron products, and other novel

anemia medications Advanced Chronic Kidney Disease, 16(2), 117–30.

18 Perwad F and Portale AA (2011) Vitamin D metabolism in the kidney: regulation by phosphorus and fibroblast growth factor 23

Molecular Cell Endocrinology, 347(1–2), 17–24.

19 Jamal SA and Miller PD (2013) Secondary and tertiary

hyperparathy-roidism Journal of Clinical Densitom, 16(1), 64–8.

20 Kurtz A (2012) Control of renin synthesis and secretion American

Journal of Hypertension, 25(8), 839–47.

Renal monitoring and risk prediction

209 Monitoring renal function in the critically ill  988

Paul M. Palevsky

210 Imaging the urinary tract in the critically ill  992

Andrew Lewington and Michael Weston

CHAPTER 209

Monitoring renal function

in the critically ill

Paul M. Palevsky

Key points

◆ Renal function needs to be closely monitored in patients at

high risk for acute kidney injury (AKI)

◆ Urine output should be monitored continuously in all patients

◆ Serum creatinine should be measured at least daily, with more

frequent measurement in patients at increased risk for AKI as

the result of underlying susceptibilities and acute exposures

◆ Calculated estimates of glomerular filtration rate (eGFR)

are unreliable in critically-ill patients with unstable kidney

function

◆ Biomarkers of tubular injury may be helpful in the

differen-tial diagnosis of AKI and for assessment of prognosis,

how-ever, they do not have a role in routine monitoring of kidney

function

Introduction

The manifestations of kidney dysfunction in critically-ill patients

range from asymptomatic laboratory abnormalities associated with

early or mild disease to a constellation of symptoms including

oligu-ria, volume overload and overt uremic manifestations accompanied

by acidaemia and electrolyte derangements in patients with severe

acute kidney injury (AKI) A fundamental difficulty in the

assess-ment of kidney function is the absence of reliable bedside methods to

measure glomerular filtration rate (GFR) and rapidly detect changes

in kidney function In the critical care setting, kidney function is

commonly monitored based on changes in the concentration of urea

and/or creatinine in the blood or as the result of sustained reduction

in urine output and these are the parameters that are used for the

consensus definitions and staging of AKI Tables 209.1 and 209.2 [1]

Urine volume

Although reductions in urine volume may be a manifestation of

both AKI and advanced chronic kidney disease (CKD), urine

vol-ume is neither a sensitive nor specific index of kidney function

Sustained acute oliguria, which is defined as a urine output of <20

mL per hour or <400–500 mL per day, in the absence of effective

intravascular volume depletion almost always indicates the presence

of AKI While oliguria is often considered to be a cardinal feature of

AKI, the majority of critically-ill patients with AKI are non-oliguric

Thus, although the acute onset of sustained oliguria should prompt

the evaluation for AKI, the presence of a well-maintained urine

output should not be equated with the absence of impaired kidney function Anuria (the absence of urine output) always demands prompt attention True anuria is most often caused by complete uri-nary obstruction, but may also be seen with vascular catastrophes resulting in bilateral renal infarction and less commonly with severe forms of rapidly progressive glomerulonephritis Rarely, severe intrinsic AKI due to acute tubular necrosis may result in transient anuria In patients with CKD, urine output is generally preserved until kidney function is severely impaired and may even be sus-tained in occasional patients requiring chronic dialysis

Markers of glomerular filtration rate

GFR is the primary index used to assess kidney function While most rigorously measured from the clearance of exogenous markers

Table 209.1 Kidney Disease: Improving Global Outcomes (KDIGO)

definition and staging of acute kidney injury

Serum creatinine Urine output

Definition Increase by ≥26.5 µmol/L (≥0.3

mg/dL) within 48 hours;

or

Increase to ≥1.5 times baseline, which is known or presumed to have occurred within the previous 7 days

<0.5 mL/kg per hour for 6 hours

Stage 1 1.5–1.9 times baseline

or

≥26.5 µmol/L (≥0.3 mg/dL) increase

< 0.5 mL/kg per hour for 6–12 hours

Stage 2 2.0–2.9 times baseline <0.5 mL/kg/hour for

≥12 hours Stage 3 ≥3.0 times baseline

Anuria for ≥12 hours

Either serum creatinine or urine output criteria satisfied.

Reprinted by permission from Macmillan Publishers Ltd: ‘KDIGO Clinical Practice Guideline

for Acute Kidney Injury’, Kidney International Supplements, 2012, 2(1), pp. 1–138, copyright

KDIGO 2012.