Role of biochemical nutritional parameters as predictor of post

operative morbidity in major spine surgeries

Dissertation submitted in Partial Fulfillment of the requirements for

the award of degree of
POST DOCTORAL FELLOWSHIP IN
SPINAL DISORDERS SURGERY
CHRISTIAN MEDICAL COLLEGE AND HOSPITAL
VELLORE, TAMIL NADU, INDIA

JULY 2019
 DECLARATION

I hereby declare that this dissertation titled “Role of biochemical

nutritional parameters as predictor of post operative morbidity in major spine
surgeries”, was carried out by me during my Post Doctoral Fellowship period,
in Spinal Disorders Surgery Unit, Department Of Orthopaedics, CMC Vellore
from July 2018 to June 2019. This work was done under the guidance of
Associate Prof. Dr.Justin Arockiaraj S.V,, Spinal Disorders Surgery Unit. This
dissertation is submitted in partial fulfilment of the requirements for the
award of the degree of “Post Doctoral Fellowship in Spinal Disorders
Surgery”, the examination for which is to be held in July 2019.

Place: Vellore

Date: 30.06.2019

Signature of the Candidate

 CERTIFICATE

This is to certify that this dissertation titled, " Role of biochenical nutritional
parameters as predictor of post operative morbidity in majq splne surgeries" is a
bonafide work carried out by Dr. S. Deepak, in Spinat Disorders Surgery Unit,
Department Of Orthopaedics, CMC Veltore, under my direct supervision and
guidance during his period of Post Doctorat Fetlowship program from July
2017 to June 2019.

Place: Vetlore

Date:30.06.2019

r$.* "A.-$*
Prof . Dr.lustin Arockiaraj SV., D.Ortho, M5, DNB Ortho,
Associate Professor,
SpinaI disorders Surgery Unit,
Department of Orthopaedics,
Christian Medicat Cotlege,
Vettore- 632004.
 CERTIFICATE

This is to certify that this dissertation titled, “Role of biochemical

nutritional parameters as predictor of post operative morbidity in major
spine surgeries” is a bonafide work carried out by Dr.S.Deepak, in Spinal
Disorders Surgery Unit, Department Of Orthopaedics, CMC Vellore, during
his period of Post Doctoral Fellowship program from July 2017 to July 2019.

Place: Vellore

Date : 01.07.2019

Prof. Dr.K.Venkatesh D.Ortho,DNB (Ortho),

Head of the Unit, Principal,
Spinal disorders Surgery Unit, Christian Medical College,
Department of Orthopaedics, Vellore 632004.
Christian Medical College,
Vellore- 632004.
 ACKNOWLEDGEMENT

First and foremost I thank all my family members who encouraged me throughout the course .

I express my wholehearted gratitude to Dr. Justin Arockiaraj SV Associate Professor, Department of

Spinal Disorders Surgery, for always being supportive and encouraging. He being my guide
provided me the essence of this research and through his continuous support and prompt
suggestions helped me attain an in-depth knowledge about this research. His guidance helped me in
all the work and writing of this thesis.

Besides my guide, I would like to specially thank Dr. K. Venkatesh, Professor and Head of Spinal
Disorders Surgery Unit, for his valuable support and guidance throughout this course in every
aspect . In addition, I would like to thank other esteemed professors Dr. Kenny S David and
Dr .Rohit Amritanand who helped me in finishing my thesis and took great effort to guide me
through this fellowship programme. I also would like to thank the Mrs. Reka department of
Biostatistics and Mrs. Vaidehi Dinesh for her guidance in analysing the data.

Also, I would like to thank my senior colleagues Dr Arul Parthasarathy, Dr. Ashok Kumar and my
fellow colleague Dr. Ram Kumar and junior colleagues Dr Srinivas Balagani, Dr Paulson Mathew
and Dr Emmanuel Bhore for their support and encouragement. I also would like to thank our
secretary Mrs. Rajakumari and Ortho-1 secretary Mr. Murali for their help.

Finally I would like to thank my parents and my brother Dr Dinesh and my wife, Dr.Saranya for her
sacrifices and looking after my baby without much support from me in all these days. Her constant
support and encouraging words at the needed times, helped me to complete my fellowship period.

5
TABLE OF CONTENTS

S.NO. CONTENT PAGE NO.

1. Introduction 8

2 Aims and objectives 11

3 Review of literature 13

4 Methodology 43

5 Results 46

6 Discussion 54

7 Conclusion 59

8 Bibliography 61

10 Master chart 73

Role of biochemical nutritional

parameters as predictor of post
operative morbidity in major
spine surgeries

 INTRODUCTION

!8
The importance of nutrition on surgery was first recognised in 1930s, when surgical outcomes were
noted to be adversely affected by malnutrition. In 1936, Cuthbertson’s descriptions of the adverse
effect of malnutrition on his patients made orthopaedic surgeons aware of this relationship. As
many as 40% of hospitalised patients were malnourished and an estimated 4.3% of community
population were undernourished.1 Preoperative malnutrition has been associated with a number of
poor post surgical outcomes (infection, acute kidney injury, increased hospital/ICU stay,Revision
surgeries and mortality).2 Malnutrition is thought to predispose patients to Surgical site infections
by impairing wound healing and prolonging inflammation by impaired fibroblast proliferation and
collagen synthesis3-5. Klein et al. found that patients who were malnourished preoperatively were at
a significantly higher risk for infection and postoperative complications.6 Jevsevar and Karlin7
found that malnourished patients had a significantly higher rate of infection and longer length of
hospital stay. Both these above mentioned studies defined preoperative malnutrition as - serum
albumin less than 3.5 g/dL or total lymphocyte count less than 1500/mm 3. Decreased lymphocyte
count impairs the ability of the immune system to eradicate or prevent infection predisposing to
infections.8
However ,not all studies have consistently found this association. In a systematic review of the
literature, Schuster et al. noted that only 2 of the 4 published studies have found an association
between preoperative malnutrition and surgical site infection.9 In case-control studies, both
Apisarnthanarak et al. and Klekamp et al. did not find an increased incidence of malnourishment in
patients who developed postoperative infection.10-11 A retrospective multicenter case-control study
by Hungerford et al. at Aarhus university hospital, Denmark, studied and found that there was no
statistically significant association between undernutrition and increased risk of infection. With this
mixed evidence and the fact that there is paucity of literature on outcome of major spine surgery
with respect to nutrition this study is aimed to address the issue.12
While it is well established that malnutrition increases susceptibility to complications, the exact
relationship between preoperative malnutrition and postoperative infection rates in orthopaedic
patients has remained clouded. Numerous hypotheses have been proposed. Smith13 elegantly
postulated the possible relationship between malnutrition and postoperative infections. His
reasoning were, a decrease in angiogenesis due to lack of protein substrate and therefore poor
wound healing; third-space fluid losses due to lack of blood protein causing pulmonary edema, poor
pulmonary perfusion and resultant poor blood oxygenation; a decrease in lymphocytes, cell
mediated immunity, phagocytic leukocytes, complement proteins and granulocyte function all
contributing to a lack of host defence mechanisms; and a lack of essential vitamins and minerals
which causes, among other things, a decrease in the functioning of T lymphocytes and natural killer
cells. All of these consequences of malnutrition combine to create a welcoming environment for
invading bacteria.
Jensen and colleagues14 studied complications related to orthopaedic surgeries performed on
malnourished patients. They measured triceps skin folds, arm-muscle circumference, creatinine
height index, transferrin concentration, albumin concentration, total lymphocyte count (TLC) and
skin-antigen testing in 129 patients, who underwent elective and trauma surgery, at regular intervals
pre- and postoperatively when applicable. Of the patients who developed complications
postoperatively, 59% had at least one severely abnormal visceral protein measurement — albumin
less than 3.0 g/dL; transferrin less than 150 mg/dL; TLC less than 1,000 cells/mm³; and anergy to
skin-antigen testing equal to 0 mm of induration.
Of 31 postoperative wound complications in the study, 27 were in nutritionally depleted patients.
For patients undergoing elective hip surgery, they found that arm-circumference was the best single
predictor of complications; however, skin-antigen testing, TLC, albumin and transferrin
concentrations indicated a tendency towards increased complications as well.

"10
AIM OF THE STUDY

"11
AIM OF THE STUDY

1) To assess the association of nutritional parameters on post operative surgical site infections and
ICU and duration of hospital stay in patients undergoing major spinal surgery.
2) To assess the biochemical marker useful to assess the immediate change in nutritional status.

"12
 REVIEW OF LITERATURE

!13
Nutrition in surgical patient

The goal of nutritional support in the surgical patient is to prevent the catabolic effects of disease or
surgery. Although several important biological parameters have been used to measure the efficacy
of nutritional regimens in surgical patients , the ultimate validation for nutritional support in
surgical patients should be improvement in clinical outcome and restoration of function.15

Bistrian et al.16 reported a 50 per cent prevalence of malnutrition in patients who had been admitted
to medical and operative services and increased rates of medical and operative morbidity and
mortality have been correlated with poor nutritional status.17 Research has confirmed the
association of malnutrition with poor healing of wounds and a reduced immune response.18

The incidence of post operative morbidities may be decreased by the use of preoperative nutritional
support. Preoperative nutritional support for patients with only mild to moderate malnutrition may
not be routinely indicated.19 But severe protein depletion results in delayed wound healing.

Malnutrition leads to significant increase in death in the preoperative period and three fold increase
in the post operative infection rate. Literature evidence reveals that indication for nutritional support
before elective surgery when there is a history of weight loss in excess of 10% of body weight or an
anticipated prolonged post operative recovery period during which the patient would not be fed
orally.20

Protein calorie malnutrition produces reduction in lean muscle mass, alteration in respiratory
mechanics, impairment in immune function and intestinal atrophy. These changes result in
diminished wound healing, predisposition to infection and increased postoperative morbidity.21

NUTRITIONAL ASSESSMENT:

A comprehensive nutritional assessment incorporates history, physical examination and laboratory

testing to provide a overview of the patients nutritional health.

1) History :

The possibility of malnutrition is suggested by the underlying disease or by a history of recent

weight loss. Anorexia, nausea, vomiting, dysphagia, gastroesophageal reflux or a history of
generalised muscle weakness should prompt further evaluation. Recent weight loss (5% in the last
month or 10% over 6 months) or a current body weight of 80 to 85% (or less) of ideal bodyweight
suggests significant malnutrition. 22

2) Physical Examination:

May identify muscle wasting (thenar and temporal muscles), loose or flabby skin (loss of
subcutaneous fat), and peripheral edema and/or ascites (hypoproteinemia). Subtle findings of
nutritional deficiency include skin rash, pallor, glossitis, gingival lesions, hair changes, neuropathy
and dementia. 22

3) Anthropometric measurements:23-24

Anthropometry is the science of assessing body size, weight and proportions. Measurements like
MHMC ( mid humeral muscle circumference) <22mm25 and calf muscle circumference <21 cm
reflect low body muscle mass and fat reserve . Although the triceps skinfold test is a poorly
described tool for assessing nutrition, it continues to be used widely in the orthopaedic literature.26

These are indirect indicators of undernutrition via body composition measurement.27 These are
cheaply and easily performed but cannot detect marginal or acute undernutrition. They better reflect
long-term changes in nutritional status than do serologic laboratory values.28 Measurement that can
be easily performed in the clinic or at the bedside include determination of height and weight with
calculation of Body Mass Index (BMI), which is the most reliable indicators. These values assess
the patients visceral and somatic protein mass and fat reserve.29

4) Laboratory tests30 that suggest malnutrition are

ALBUMIN

• Serum albumin of less than 3.5 g% in a stable, hydrated patient suggests malnutrition. In
dehydrated patients, serum albumin levels are normal despite malnutrition. Two thirds of the body
albumin stores are located in the extravascular compartment with remainder in the circulation.
Trauma, sepsis and malignant diseases (catabolic states) lower plasma levels of albumin. Serum
albumin has a half life of 14 -20 days.

The most common definitions of malnutrition are a serum total lymphocyte count <1500 cells per
cubic millimetre and a serum albumin concentration of <3.5 g/dL.31
It is a major protein of human plasma and makes up approximately 60% of the total plasma
proteins. The normal serum value is between 3.5-5.5 gm/dl. Molecular weight is 69kda. 40% of
total albumin is present in the plasma and the other 60% is present in the extracellular space. The
liver produces about 12gm of albumin per day, representing about 25% of total hepatic synthesis
and half its secreted protein.32

The total exchangeable pool of albumin is 4-5gm/kg body wt; between 6-10% of the exchangeable
pool is degraded per day.33

Mature human albumin consists of one polypeptide chain of 585 amino acids and consists 17
disulfide bonds. It has ellipsoidal shape which meaning that it does not increase the viscosity of
plasma. It is responsible for 75-80% of the osmotic pressure of the human plasma. To maintain
adequate colloidal oncotic pressure, serum albumin of >2.5gm/dl and total protein >5gm/dl is
required.34

Albumin synthesis is decreased during fasting and in condition of protein malnutrition. (16)
Albumin is a acute phase protein. The concentration of which is decreased by at least 25%
following injury.35

Serum albumin is an index of visceral protein mass and decreased levels is statistically associated
with poor wound healing, post operative infectious complications, mortality and
immunosuppression.36

EXTENT OF MALNUTRITION

• Normal- 3.5-5.5gm/dl

• Mild – 2.8-3.5gm/dl

• Moderate - 2.1-2.7gm/dl

• Severe *- <2.1gm/dl

* - Require nutritional supplement.37

CAUSES OF HYPERALBUMINEMIA (>5.5g/dl)

There are no known pathological causes for a raised plasma albumin.

Causes include:

a. Dehydration: this is also reflected in an increase in plasma total protein, a raised hematocrit and
appropriate clinical features.

b. Venous stasis

c. Albumin infusion

CAUSES OF HYPOALBUMINEMIA (<3.5g/dl)

a. Increase in plasma H2O: This occurs as a part of physiological response in pregnancy. Other
causes include, excessive infusion of IV fluids, H2O retention in SIADH, glucocorticoid deficiency.

b. Diminished synthesis- any cause of generalised protein malnutrition will ultimately be reflected
in low plasma albumin. Causes for this include: diet deficient in protein nitrogen; protein
malabsorption such as coeliac disease, tropical sprue, crohn’s disease, cystic fibrosis; decreased
synthesis in chronic liver disease; in hereditary analbuminemia there is a marked impairment of
albumin biosynthesis with plasma levels which are typically low.

c. Increased catabolism- This is a feature of hypercatabolic state. The important feature of

hypercatabolic state is the stress related stimulation of glucocorticoid production. These hormones
are known to stimulate protein catabolism. Condition such as fever, trauma, major surgery, severe
sepsis, malignant disease may all be associated with varying degrees of hypoalbuminemia.

d. Losses of albumin from body- sites of excessive loss are GI tract , kidneys and skin.38

Hypoalbuminemia is associated with poor tissue healing, decreased collagen synthesis in surgical
wounds , and impairment of immune response such as macrophage activation. Therefore in
hypoalbuminemic patients wound infection and remote infection such as pneumonia are commonly
found.39

PREALBUMIN

• Serum prealbumin also known as Transthyretin, is a more useful indicator of acute change in
nutritional status. It is predominantly produced by liver. It has a half life is 2-3 days which is
 shorter than the half life of albumin which is 14- 20 days. Prealbumin, however, has not been
used as extensively to assess perioperative nutrition, perhaps because this parameter is too
sensitive to accurately reflect changes in protein-caloric nutrition.40 No established definition of
malnutrition using prealbumin exists in the orthopaedic literature.The normal range of prealbumin
is approximately 16 to 35 mg/dL.41 It has one of the highest proportions of essential-to
nonessential amino acids of any protein in the body, making it a distinct marker of visceral
protein synthesis.42-43 Furthermore, prealbumin has a short half-life of 1.9 days, making it an early
indicator of changes in nutritional status and thus a preferred marker for studies linking
malnutrition to outcome after surgery.

Prealbumin is degraded by the kidneys, and consequently any renal dysfunction causes an increase
in its serum levels. Furthermore, one of the functions of Prealbumin is to act as a transport protein
for thyroxine. In hyperthyroid states, the molecules of prealbumin are saturated with thyroxine, and
hence the measured serum levels of Prealbumin are low. Similarly, Prealbumin levels are high in
hypothyroid states.44

• 10-17 mg% pre albumin - mild depletion

5-10 mg% pre albumin - moderate depletion

<5mg% pre albumin - severe depletion

TRANSFERRIN

• Serum transferrin of less than 200 mg% suggests malnutrition. It has a half life of 8 -10 days .
Table 1

• Transferrin is a serum protein and a negative phase reactant that has been used to determine
nutritional well-being.45 Inaccuracies can result from this method because of transferrin’s role in
iron transport. In iron-deficiency states (including chronic blood loss anaemia), the levels of
transferrin are elevated due to increased amount of iron absorption. Consequently, the levels are
decreased in iron-overload states.46 One study, which compared 44 underweight patients with 69
normal or overweight elderly subjects, reported that there was no correlation between fat-free
mass and transferrin levels, making it a poor serum marker for assessing malnutrition.47 Like

Prealbumin, transferrin levels also increase with renal failure. Oral contraceptives or oestrogen
formulas also alter serum transferrin levels.48

• The Rainey-MacDonald nutritional index (RMNI) has been used in several studies. It is
calculated from serum albumin and serum transferrin:

• RMNI= (1.2 x serum albumin) + (0.013 x serum transferrin) - 6.4349

• A zero or negative score indicates nutritional depletion. The RMNI has not been validated.

TOTAL LYMPHOCYTE COUNT

Total lymphocyte count (TLC) is calculated by the formula

TLC = %lymphocyte x WBC /100

1500 – 1800 cells/mm 3 –mild depletion

900 – 1500 cells/mm 3 – moderate depletion

<900 cells/mm 3 – severe depletion

Low total lymphocyte counts lowers the immunity which is reflected by the delayed type
hypersensitivity.

Techniques such as triceps skin-fold and arm-muscle circumference are indirect indicators of body
fat and skeletal muscle mass. Because these energy stores are depleted slowly and late in the course
of malnutrition, they are unsatisfactory for detecting marginal nutritional depletion or acute changes
in nutritional status. Visceral proteins, such as albumin, prealbumin and transferrin, are much more
sensitive indicators of marginal depletion and, because of their relatively short half-life, are able to
detect acute nutritional changes more reliably.50-51

In 1979, Seltzer et al. described a method of nutritional assessment utilising the parameters of a
total lymphocyte count of at least 1,500 cells/cumm and an albumin level of at least 3.5 g/dL to
indicate adequate nutritional status.52-53 These two tests are usually obtained wi!h a routine
preoperative screen and were shown in their study to have a strong correlation with morbidity and
mortality rates in intensive care patients.

OTHER NUTRITIONAL INDICES.

BODY MASS INDEX: (Quetelet’s Index)

It was invented between 1830 and 1850 by the Belgian Adolphe Quetelet during the course of
developing “ Social Physics”.

It is a statistical measure of the weight of a person scaled according to height. BMI is defined as an
individual’s body weight divided by the square of their height.
A frequent use of the BMI is to assess how much an Individual body weight departs from what is
normal or desirable for a person of his or her height. The weight excess or deficiency may, in part,
be accounted for by body fat or muscle

BMI = weight(Kg) / height 2 (m)

BMI correlates with body fat. It is a better estimate of body fat than body weight and has
advantages over the ideal body weight estimation. Unlike the ideal body weight tables that were
based on mortality data alone, BMI correlates with morbidity. It is used for both men and women.54

Both low and high BMI correlate with morbidity and mortality. Low levels of BMI are also
associated with lethargy and diminished work productivity. The lowest survivable levels of BMI, as
suggested by observation in starvation, famine and anorexia nervosa, or by theoretical models, have
been estimated to be 12-13kg/m2 . Recent studies have indicated that independently living older
individuals with a BMI less than 22 kg/m2 are at a much higher risk for all causes of mortality.55 It
has been demonstrated that low BMI and inadequate dietary intake are associated with diminished
functional status among older adults in the community.

There are few limitations of BMI. It may overestimate total body fat in persons who are very
muscular (athletes) and may underestimate body fat in persons who have lost muscle mass(elderly).
It will also inaccurately reflect body fat in edematous states or in individuals who are less than 5
feet tall.

Adogwa56 et al showed in their study that average BMI of more than 27 was found for both cohorts
of malnourished patients, serving as a reminder that a patient can be overweight and malnourished
at the same time.

Body mass index57

BMI (kg/m2)

Underweight Grade III <16

Grade II 16 – 16.99

Grade I 17 - 18.49

Normal 18.5 -24.9

 Overweight 25-29.9

Obesity Grade I 30 – 34.9

Grade II 35 – 39.9

Grade III >40

BMI is used differently in children. It is calculated the same way as for adults, but then compared to
typical values for other children of the same age. Instead of set thresholds for underweight and
overweight, the BMI percentile allows comparison with children of the same age and sex. A BMI
that is less than the 5 th percentile is considered underweight, between 85 th and 95 th percentile at
risk of being overweight and above the 95 th percentile is considered overweight.58

PROGNOSTIC NUTRITIONAL INDEX (PNI):

It has been validated in patients undergoing either major cancer or gastrointestinal surgery and
found to accurately identify a subset of patients at increased risk of complications. Furthermore,
preoperative nutritional repletion has been shown to reduce post operative morbidity in this patient
group.

PNI =158 – [16.6 x Alb] – [0.78 x TSF] – [0.2 x TFN] – [5.8 x DH]

Alb - Albumin

TSF – Triceps skin fold thickness (mm)

TFN – Transferrin (mg/dl)

DH – Delayed cutaneous hypersensitivity;

Induration > 5mm =2

1 -5 mm =1

Anergy =0

PNI indicates the risk of developing complication -

Low <40%
Intermediate 40 -49%

High >50 %

NUTRITION RISK INDEX (NRI):

The index successfully stratifies perioperative morbidity and mortality using serum albumin and
weight loss as prediction of malnutrition. Of note, the NRI is not a tool for tracking the adequacy of
nutritional support, since supplemental nutrition often fails to improve serum albumin levels.

NRI = [15.19 x Alb] +41.7 x [actual wt (kg)/ Ideal wt (kg)]

NRI = Well nourished >100

Mild malnutrition 97.5 -100

Moderate malnutrition 83.5 -97.5

Severe Malnutrition <83.5

CATABOLIC INDEX (CI)

CI = [24 hr urine urea nitrogen excretion in g] – [0.5 x (dietary nitrogen intake in g)]

No physiologic stress - 0

Mild stress - 0 to 5

Moderate to severe stress - more than 5

ESTIMATION OF CALORIC REQUIREMENTS:

It is necessary to provide adequate substrates for healing and tissue repair. Failure to provide
adequate amounts of both calorie and protein leads to further depletion of lean body mass.59

Basal Energy Expenditure (BEE) is calculated using a modification of the Harris Benedict equation:
BEE in kcal/day in,

Males: 16.4+ [13.7 x weight (kg)] + [5.0 x height(cm)] – [6.8 x age(yr)]

Females: 655 + [9.6 x weight(kg)]+[1.7 x height(cm)] – [4.7 x age(yr)]

The actual caloric requirement is obtained by multiplying BEE by a specific stress factor. Most
stressed patients require 25 -30 kcal/kg/day

Total energy expenditure(TEE) in kcal/day=TEE = BEE x stress factor

Selective stress factors Stress factor

Starvation 0.8 - 1.0

Elective surgery 1.0- 1.1

Peritonitis/other infection 1.05 to 1.25

ARDS or sepsis 1.3 to 1.35

Cardiopulmonary disease 1.3 to 1.55

With major surgery like Pancreatitis or major burns 1.3-1.8

ESTIMATION OF PROTEIN REQUIREMENT:

The protein requirement varies with age and the clinical condition of the patient. The appropriate
ratio of caloric: nitrogen is 150:1 (for a caloric: protein ratio of 24:1)

Clinical condition Protein requirement

(g/dl ideal body Wt/day)

Normal person 0.8

Elective hospitalisation 1.00 to 1.10

Complicated post operative case, infection 1.20 to 1.40

Major trauma, sepsis, pancreatitis 1.50 – 2.50

Protein needs can also be assessed in Serum Albumin levels.60

Albumin (g/dl) Protein requirement(g/kg/day)

Normal nutritional status >3.5 0.8

Mild depletion 2.8 to 3.5 1.0 to 1.2

Moderate depletion 2.1 to 2.7 1.2 to 1.5

Severe depletion <2.1 1.5 to 2.0

STRESS METABOLISM:

Physiologic process, immunocompetence, wound healing and recovery from critical illness all
depend upon adequate nutrient intake.

Starvation: After an overnight fast, liver glycogen is rapidly depleted due to decreased plasma
insulin and a rise in glucagon levels. Carbohydrate stores are exhausted after a 24 hr fast. Liver
glycogen is used first, followed by muscle glycogen. Hepatic glucose metabolism must satisfy the
energy demands of the hematopoietic and the central nervous system particularly the brain, which is
dependant on glucose oxidation during acute starvation. Within approximately 10 days of
starvation, the brain adapts to use fat as its fuel source. Thereafter brain relies on ketoacids
produced by the liver. This has a protein sparing effect.

The adaptive changes to starvation are a decrease in basal energy expenditure (up to 30%), a change
in the type of fuel consumed, and a relative preservation of protein.

Physiologic stress:

The interaction of metabolic and endocrine responses that result from major operation, trauma or
sepsis can be divided into three phases

1) Catabolic phase: After major surgery, the metabolic demand is dramatically increased, as
reflected in a significant rise in the urinary excretion of nitrogen. Following a major surgical
procedure, protein depletion initially occurs because patients are commonly prevented from eating
in addition to having an elevated basal metabolic rate. The hormonal response of physiologic stress
includes elevation in the serum levels of glucagon, glucocorticoids and catecholamines and
reduction of insulin.

2) Early Anabolic phase: (cortical withdrawal phase) since it marks the shift from catabolism to
anabolism, it ranges from several weeks to few months. This phase is marked by a positive nitrogen
balance, and there is a rapid and progressive gain in weight and muscle strength. The total amount
of nitrogen gained is equivalent to the amount lost in the catabolic phase.

3) Late Anabolic phase: It is the final period of recovery and may last from several weeks to
months. Adipose stores are replenished gradually, and nitrogen balance equilibrates. Weight gain is
much slower than in early anabolic phase due to higher caloric content of fat – the primary energy
stores deposited during the early anabolic phase – as compared to protein.

Following elective operation, neural impulses carried via spinothalamic pathways activate the brain
stem, thalamic and cortical centres which stimulate the hypothalamus. Hypothalamic stimulation
triggers combined neural and endocrine discharges. Nor epinephrine is released from sympathetic
nerve endings. Epinepheine from the adrenal medulla, Aldosterone from adrenal cortex, ADH from
posterior pituitary, insulin and glucagon from the pancreas and ACTH, TSH and GH from the
anterior pituitary. These hormones produce secondary elevations of cortisol, thyroid hormone and
stomatomedins. The effects of the heightened neuroendocrine secretion include a) peripheral
lipolysis from the synergistic activation of hormone sensitive lipase by glucagon, epinephrine,
cortisol and thyroid hormone b) accelerated catabolism, arise in proteolysis stimulated by cortisol
and c) decreased peripheral glucose uptake due to insulin antagonism by GH and epinephrine. The
consequences are a marked rise in plasma concentration of free fatty acids, glycerol, glucose, lactate
and amino acids. The liver responds with an increase in substrate uptake and glucose production, as
a result of glucagon stimulated glycogenolysis and enhanced gluconeogenesis induced by cortisol
and glucagon.

Operation and trauma are neuroendocrine driven processes. The BEE rises by 10% in post operative
patients.

The metabolic response to trauma is a result of neuroendocrine stimulation, which

accelerates protein breakdown, stimulates gluconeogenesis, and produce glucose

intolerance.

"26
WOUND HEALING:

Healing is a fibroproliferative response that patches rather than restores a tissue. It is a complex but
orderly phenomenon involving a number of processes.61

1. Induction of an inflammatory process in response to the initial injury with removal of damaged
and dead tissue.

2. Proliferation and migration of parenchymal and connective tissue cells.

3. Formation of new blood vessels (angiogenesis) and granulation tissue.

4. Synthesis of ECM proteins and collagen deposition.

5. Tissue remodelling.

6. Wound contraction.

7. Acquisition of wound strength.

The earliest account of wound healing date back to about 2000B.C.when the sumarius employed
two modes of treatment: a spiritual method consisting of incantations and a physical method of
applying poultice-like materials to the wound. The Egyptians were the first to differentiate between
infected and diseased wounds compared to noninfectious wounds. The Greeks, equipped with the
knowledge by the Egyptians, went even further and classified wounds as acute or chronic in
nature62

Acute wound healing is the normal orderly process that occurs after a typical injury and requires
minimal practitioner intervention.

Chronic wound healing often necessitates a variety of interventions to correct and shift the healing
process towards a more normal state of wound healing.

Acute wounds are typically traumatic or surgical in origin. These wounds occur suddenly, moves
rapidly and predictably through the repair process and result in durable closure.

Chronic wounds in contrast, are wounds that fail to proceed normally through the repair process.
Chronic wounds are frequently caused by vascular compromise, chronic inflammation or repetitive
insults to tissues and either fail to close in a timely manner or fail to result in durable closure.63
WOUND HEALING PHASES:

a. Hemostasis and Inflammation

b. Proliferation

c. Maturation and Remodelling

HEMOSTASIS AND INFLAMMATION

During the immediate reaction of the tissue to injury, hemostasis and inflammation occur. This
phase represents an attempt to limit damage by stopping the bleeding, sealing the surface of the
wound and removing any necrotic tissue, foreign debris or bacteria present. The inflammatory
phase is characterised by increased vascular permeability, migration of cells into wound by
chemotaxis, secretion of cytokines and growth factors into the wound and activation of the
migratory cells.64

During an acute tissue injury blood vessels damage results in exposure of subendothelial collagen to
platelets, which leads to platelet aggregation and activation of coagulation pathway. Initial intense
local vasoconstriction of arterioles and capillaries is followed by vasodilation and increased
vascular permeability. Cessation of haemorrhage is aided by plugging of capillaries with
erythrocytes and platelets which adhere to the damaged capillary endothelium.65

PROLIFERATIVE PHASE

As the acute responses of hemostasis and inflammation begin to resolve the scaffolding is laid for
repair of wound through angiogenesis, fibroplasia and epithelialisation.66 This stage is characterised
by formation of granulation tissue which consists of capillary bed, fibroblasts, macrophages and a
loose arrangement of collagen, fibronectin and hyaluronic acid.67

Angiogenesis

It is a process of new blood vessel formation and is necessary to support a healing wound
environment after injury, activated endothelial cells degrade the basement membrane of post
capillary venules there by allowing the migration of cells through this gap.
Fibroplasia

Fibroblasts are specialised cells that differentiate from resting mesenchymal cells in connective
tissue. After injury the normal quiescent and sparse fibroblasts are chemo attracted to the
inflammatory site, where they divide and produce the components of extracellular matrix. The
primary function of fibroblasts is to synthesise collagen. The time required for undifferentiated
mesencymal cells to differentiate into highly specialised fibroblasts accounts for the delay between
injury and the appearance of collagen in a healing wound. This period, generally 3 to 5 days,
depending on the type of tissue injured is called the lag phase of wound healing.68

Epithelialisation

Re-epithelialisation of wound begins within hours after injury and is completed within 48 hours in
case of approximated incised wounds. Initially wound is rapidly sealed by clot formation and than
by epithelial cell migration across the defect. If the basement membrane zone is intact,
epithelialisation proceeds more rapidly.

MATURATION AND REMODELLING

Extracellular matrix(ECM)

The ECM exists as a scaffold to stabilise the physical structure of tissues. Cells within it produces
the macromolecular constituents, including the following:

• Glycosaminoglycans, or polysaccharide chains, are usually found covalently linked to protein in

the form of proteoglycans.

• Fibrous proteins such as collagen, elastin, fibronectin and laminin.

The wound matrix accumulates and changes in composition as healing progress, balanced between
new deposition and degradation. The provisional matrix is scaffold for acellular migration and
composed of fibrin, fibrinogen, fibrinonectin, and vitronectin.69 Glycosaminoglycans and
proteoglycans are synthesised next and support further matrix deposition and remodelling. Collagen
which are the predominant scar proteins are the end results.70

"29
Wound contraction:

The wounds undergo some degree of contraction. The major cell responsible in this process is the
myofibroblast. These cells start appearing from day 6. The wound contraction starts almost
immediately after injury. The movement of cells with concomitant reorganisation of the
cytoskeleton is responsible for contraction.71

Wound strength:

At the end of 1 st week, the wound strength is approximately 10% that of a unwounded skin, which
increases rapidly over the next 4 weeks. At the end of 3 rd month it reaches a plateau at about 70%
to 80% of the tensile strength of unwounded skin, a condition that may persist for life. The recovery
of tensile strength results from the excess of collagen synthesis over collagen degradation during
the 1 st 2 months of healing and at later times from structural modification of collagen fibres (cross
linking, increased fibre size) after collagen synthesis ceases.72

FACTORS THAT AFFECT WOUND HEALING:

• AGE

The older the patient, the slower the healing.73 Studies suggest that the defect in age-related wound
healing is related to abnormal initiation of healing as a result of insufficient presence of growth
factors.74

• MALNUTRITION

Septic, surgical, and trauma patients in hyper-metabolic states associated with the release of
endogenous cytokines from activated leukocytes experience excessive protein loss in an effort to
maintain normoglycemia; these patients require additional caloric input to counter a negative
nitrogen balance. Such patients consume body stores of fat and protein, particularly skeletal muscle,
more rapidly than patients with normal metabolism. This, together with depletion of micronutrients
and immunonutrients, has implications in immune system function and healing.75 Elevated steroid
levels because of stress are intimately involved in muscle catabolism. Insulin administration may
help modulate muscle protein losses in patients with severe burns.76 Growth hormone stimulates
wound healing, but its effects in critical illness need further study.77
Glucose is the main fuel for wound repair. Protein malnutrition and particularly deficiencies in the
amino acids, arginine and methionine are associated with compromised wound healing because of
prolonged inflammation and disruption of matrix deposition, cellular proliferation, and
angiogenesis.78 Malnutrition is associated with decreased deposition of collagen in skin wounds.79

Glutamine has been reported to enhance the actions of lymphocytes, macrophages, and, in
particular, neutrophils, and may be of particular benefit in severe infection and trauma.80 Glycine
has inhibitory effects on leukocytes and may have an important role in reducing inflammation-
related tissue injury.81 Micronutrients such as vitamins and minerals are critically important in
immune function and wound healing. Many trace metals, including manganese, magnesium, copper,
calcium, and iron, are cofactors in collagen production, and deficiencies influence collagen
synthesis.82 Zinc influences reepithelialization and collagen deposition.83 Zinc has also been
demonstrated to greatly influence B and T lymphocyte activity, but many other nutrients, including
copper, selenium, several other metals, and several vitamins, including A, B, C, and E, have been
implicated in immune dysfunction.84 Vitamin C is the main vitamin associated with poor healing,
because of its influence on collagen modification. L-Arginine is required in a variety of metabolic
functions, wound healing, and endothelial function. It is important in the synthesis of nitric oxide,
and deficiency is linked to immune dysfunction and failure of wound repair. Maintenance of plasma
oncotic pressure is dependent on adequate production of plasma proteins and is important in
maintaining body water distribution and preventing soft-tissue edema. Vitamins and minerals,
particularly ascorbic acid, zinc, and selenium, are essential for wound repair. Copper recently has
been linked to the production of vascular endothelial growth factor.85

Adequate nutrition is also essential to a competent immune system and prevention of infection.
Proteins, calories, vitamin-C, vitamin-A, zinc, magnesium, and iron are all critical to collagen
synthesis and development of normal tensile strength. Protein catabolism can result in a delay of
wound healing.

Several studies have found that a low levels of serum albumin is associated with a high risk of
pulmonary complications and a higher overall mortality.86

Adogwa et al.87 in their study found that preoperative malnutrition (defined as serum albumin level
<3.5 g/dL) was an independent risk factor for post-surgical complications for patients with elective
spine surgery (Deformity or degenerative causes). Conversely, in patients undergoing spine
decompression and fusion surgery for neoplastic and traumatic causes, baseline nutritional status
was not independently predictive of postoperative surgical complications. This study demonstrates
that optimisation of patient’s nutritional status is an important part of preparing patients for elective
degenerative and deformity spinal surgery and as such, baseline serum albumin level can be a
valuable prognostic tool for detecting malnutrition and assessing subsequent risk for adverse
surgical outcomes.

Jevsevar et al.88 studied two groups of patients who underwent surgery for scoliosis following
cerebral palsy and found that patients who had serum albumin at least 3.5mg percent and total
lymphocyte count of at least 1500 cells per cubic millimetre had shorter period of hospital stay,
lower rates of infection and shorter period of endotracheal intubation after the operation.

However, there was no increased SSI risk in underweight malnourished patients in a level III
study89 and the same proportion of patients with and without SSIs had low albumin in a level IV
study.90

Gibbs et al.91 studied the precision and reliability of estimates of the association between
preoperative serum albumin concentration and surgical outcome. A total of 54,215 major non
cardiac cases were studied. A decrease in serum albumin from concentration > 46gm/dl to < 21gm/
dl was associated with an exponential increase in mortality rates from <1% to 29% and in morbidity
rates from 10% to 65%. Albumin levels was a better predictor of some type of morbidity,
particularly sepsis and major infection than other types. Serum albumin is a better predictor of
surgical outcome than many other preoperative patient characteristics. It is relatively low cost test
that should be used more frequently as a prognostic tool to detect malnutrition and risk of adverse
surgical outcomes.

Jeffrey d Klein et al.92 showed that 25 % of the patients who underwent elective spine fusion
surgeries in their set up were malnourished preoperatively . This was even higher in elderly
patients(42%). They recommended that close attention must be paid to pre op nutritional status and
patients with suboptimal nutritional status should be supplemented and replenished before elective
surgery.

A retrospective study by Kudsk et al.93 of 526 surgical patients who had preoperative serum
albumin levels measured and were undergoing elective oesophageal, gastric, pancreaticoduodenal,
or colon surgery a serum albumin levels below 3.25gm/dl correlated immensely with complications,
length of stay, postoperative stay, and mortality.

Palma et al.94 in his prospective study, reported cholesterol and serum albumin as a risk factor for
death in patients undergoing general surgery, multivariate analysis revealed significant negative
trends for serum albumin, total cholesterol and HDL-C ; for each variable a lower level was
associated with a higher risk of death. Total cholesterol and its fraction were similar in patients with
a serum albumin levels below 3.4gm/dl and in those with a higher level. The results indicate that
low levels of serum albumin, total cholesterol and HDL-C are associated with risk of death up to
2years after general surgery.

J Guan et al.95 showed that patients in their cohort with lower perioperative prealbumin levels had a
significantly higher rate of developing non wound related infections postoperatively compared with
those with higher prealbumin levels. The mean prealbumin level in their cohort was quite low, 12.2
mg/dL, which falls into the“increased risk” range defined by the Prealbumin in Nutritional Care
Consensus Group.96-97 This is likely due, at least in part, to the effects of the surgery itself.98

In a study done by M.B. Badia et al.99 of 158 patients on multivariate analysis , preoperative
hypoalbuminemia was significantly associated with higher morbidity and lengthier hospital stay
regardless of the type of surgery.

In a study done by Detsky et al.100 on 202 patients who were planned for gastrointestinal surgery ,
several techniques of nutritional assessments were adapted to predict major post operative
complications. Subjective global assessment(SGA) and albumin were both of predictive value , and
combination of these variables were useful in differentiating low risk from high risk patients. It was
concluded in study that SGA and albumin are useful “nutritional assessment techniques” for
patients undergoing major gastrointestinal surgeries if the purpose of such an assessment is to
predict postoperative nutrition associated complications.

A meta-analysis of cohort studies and controlled studies of hypoalbuminemia in acute illness; is

there a rationale for intervention by Vincent et al.101 shows that hypoalbuminemia was a potent dose
dependant , independent predictor of poor outcome. Each 10gm/dl decline in serum albumin
concentration significantly raised the odds of mortality by 137%, morbidity by 89%, prolongs ICU
and hospital stay by 28% and 71% respectively. A serum albumin level of <2gm/dl in critically ill
patients has been shown to be associated with a mortality of nearly 100%. The association between
hypoalbuminemia and poor outcome appeared to be independent of both nutritional status and
inflammation. The complication rates may be reduced when serum albumin level attained during
albumin administration exceeds 30gm/dl. Complications were higher when serum albumin level
was lower than <2.5gm/dl in critically ill adult patients in a study by Foley et al.102

In a prospective randomised clinical study by Woods et al.103 done to identify the role of serum
albumin concentration on length of postoperative illness , the hypothesis was that patients whose
albumin levels dropped below 3.5gm/dl would have a more prolonged postoperative hospital course
as a result of delay in return of bowel function.

Increased incidence of pneumonia, wound infection, septicaemia postoperatively was reported by

Brown et al.104 in their study in patients with serum albumin levels < 3g/dl.

Golub et al.105 studied the effect of hypoalbuminemia (serum albumin levels <3g/dl) upon
admission of patients to surgical icu due to vascular insufficiency, hip fractures, gastrointestinal
bleeding , cancer , perforated viscus, intra-abdominal infection or bowel obstruction. Complications
were higher in patients with hypoalbuminemia (36.9%) and mortality of (5.8%).

In a study by Beghetto et al.106 done on 434 patients who were evaluated for the accuracy of
nutritional assessment tools for predicting adverse hospital outcomes, it was concluded that serum
albumin level was the strongest predictive parameter for death and hospital infection(<3.5g/dl). A
BMI <18.5 kg/m2 was also associated with death and infection postoperatively and length of
hospital stay.

Liop et al.107 found that a serum albumin below 3.5g/dl at the onset of treatment was a predictor of
kidney and liver failure, hospital infection, and mortality in 12 patients strata.

Hirsch et al.108 in prospective study assessed the preoperative nutritional status of surgical patients
and its relation to postoperative outcomes. Preoperative nutritional assessment included
anthropometry and biochemical indices. The more useful parameters were preoperative weight loss
and low serum albumin levels.

A study by Arozullah et al.109 on the preoperative evaluation for postoperative pulmonary

complications showed that low albumin levels was associated with respiratory failure and higher
postoperative mortality and morbidity rates. Moreover morbidity increases exponentially as
albumin levels fall below 4g/dl. Patients with >10% weight loss in 6 months prior to surgery are at
increased risk for pneumonia and respiratory failure.

• INFECTION

Wound infection prolongs the inflammatory phase, delays collagen synthesis, prevents
epithelialization and increases the production of inflammatory cytokines, which may lead to
additional tissue destruction. If the bacterial count in the wound exceeds 105 organisms per gram of
tissue, or if any betahemolytic Streptococcus is present, the wound will not heal by any means,
including flap closure, skin graft placement, or primary sutures.110 The bacteria prolong the
inflammatory phase and interfere with epithelialization, contraction, and collagen deposition. The
endotoxins themselves stimulate phagocytosis and the release of collagenase, which contributes to
collagen degradation and destruction of surrounding, previously normal tissue. Wound
contamination in association with tissue hypoxia potentially suppresses macrophage-regulated
fibroblast proliferation.111

• DIABETES MELLITUS

Impaired wound healing in diabetes patients is well established. The wound repair in patients with
DM is characterised by reduced collagen synthesis and deposition and decreased tensile strength. A
direct relationship between tensile strength and glycosylated haemoglobin levels have been
described. The differences in wound repair may be partially explained by increased levels of
proteases, decreased levels of proliferative cytokines and abnormal insulin levels. DM can also
results in compromised perfusion, patients with DM are at high risk of microvascular diseases.
1134Consequently the delivery of micronutrients at the capillary level is impaired and there is an
increase in vascular permeability. The end result seems to be increased risk of infection with
diminished support for healing.Experimental studies of diabetic animal models and wound healing
show decreased granulation, decreased collagen in granulation tissue, and defects in collagen
maturation.113

35
• OBESITY

It is a risk factor for impaired wound healing. Adipose tissue is poorly vascularised. In addition
cardiac function is frequently compromised in obese patients, further diminishing tissue perfusion.
As a result infection, seroma formation and wound dehiscence are all more common among the
obese population.

• CORTICOSTEROIDS

Anti-inflammatory steroid medications globally inhibit cell growth and production.114 They are
also well known to have widespread negative effects on the wound-healing process. This is seen
clinically and experimentally. A decreased inflammatory infiltrate is the most obvious effect of
steroids.115 The macrophage response to chemotactic factors is inhibited. Effective phagocytosis by
polymorphonuclear neutrophils and macrophages also is decreased as a result of the stabilising
effect of steroids on lysosomes.116 Because of the lack of an appropriate initial inflammatory
response, these cells do not produce the typical growth factor profile.117 This has been shown
experimentally. Glucocorticoids also inhibit epithelial regeneration. The application of
hydrocortisone to epidermal cultures decreases cell proliferation.

Steroids have a direct inhibitory effect on the fibroblast genome, which has been shown in cell
culture.118 Corticosteroid-treated rat fibroblasts have minimal endoplasmic reticulum, indicating a
low-secretory state.119 Without the appropriate deposition and maturation of collagen, there is less
wound strength and wound dehiscence is likely. Vitamin A restores the inflammatory response and
promotes epithelialisation and the synthesis of collagen and ground substances. Vitamin A does not
reverse the detrimental effects of glucocorticoids on wound contraction and infection.The
recommended dose of vitamin A is 25,000 IU by mouth daily preoperatively120 and for 3 days
postoperatively. Vitamin A supplementation should not be given to pregnant women.

• STRESS

Both psychological and physiological stress has been implicated as a potential cofactor in impaired
wound healing. Stress elevates serum corticosteroid levels, which compromises immune function,
and sympathetic stimulation which compromises perfusion due to vasoconstriction.

"36
• IMMUNOSUPPRESSION

Immunosuppression can retard wound healing and increase susceptibility to infection. This is
attributed primarily to impairment of the inflammatory process.

• RADIATION THERAPY AND CHEMOTHERAPY

Ionising radiation either directly damages the genome or injures the DNA through the production of
free radicals.121 This effect has short- and longterm consequences for radiated tissue. In patients
with acute radiation injury, the skin becomes erythematous and edematous. Histologically, dilation
of fine blood vessels, endothelial edema, and lymphatic obliteration are seen. As the acute response
abates, thrombosis and fibrinoid necrosis of capillaries occur122. In this setting, although perfusion
of radiation-damaged skin is seen with fluorescein injection123, effective tissue oxygenation is
inadequate. Blood vessel appearance is varied, either thick-walled, telangiectatic, or thrombosed.
The deposition of dense, hyalinized collagen characterises radiated dermis. The endpoint of chronic
radiation damage is the non-healing ulcer. Obvious necrotic tissue is seen, and there is loss of
epithelial coverage124.

The mechanisms of radiation damage and inhibited wound healing are currently being studied.
Experimentally, healing immediately after irradiation is hampered by slowed fibroblast
proliferation, migration, and contraction125. Impairment of the acute inflammatory response and
granulation formation also occurs126 .

Fibroblast cultures from radiation ulcers proliferate at a slower rate compared with cultures of cells
from nearby unirradiated tissue127. Effects vary between patients. Each person has a differing
sensitivity to radiation injury. Human fibroblasts cultured from patients with severe radiation
reactions have poor survival rates relative to those from patients who have a less severe injury128.
Thus, fibroblast defects have emerged as a central problem in the inhibited healing of chronic
radiation injury.

Cellular mechanisms of phagocytosis and bactericidal metabolic functions in polymorphonuclear

neutrophils harvested from tissue with chronic radiation damage also are impaired. The local wound
environment is the spotlight of the problem. Irradiated tissue may not “prime” the neutrophils with
the appropriate cytokines and growth factors needed for activation129, which has a major effect on
the incidence of postoperative infection in previously irradiated patients.
The association between radiation damage and postoperative complications has been debated. In
retrospective studies, patients undergoing surgery after failing primary radiotherapy for early-stage
tumours do not show an increase in severity of complications or length of hospital stay130. One
prospective trial comparing antibiotic regimens did not show any increase in wound infection rate
in radiated patients131, although other investigators have shown increased rates of postoperative
infections132 and major wound complications133. With the advent of more aggressive radiation
regimens, concern regarding increased operative complications has surfaced. Twice-a-day
hyperfractionation protocols versus once-a-day radiation do not seem to increase the surgical
morbidity134.

• CIGARETTE SMOKING

Many studies have since confirmed that smoking is harmful to a healing wound. Goldminz and
Bennett135 reviewed 916 flaps and full-thickness grafts and found that 1-pack-per-day smokers had
three times the frequency of necrosis as nonsmokers and that 2-pack-per-day smokers had necrosis
six times more frequently than nonsmokers did. The mechanism of these harmful effects is likely
multifactorial. Nicotine is an addictive and vasoconstrictive substance that decreases proliferation
of erythrocytes, macrophages, and fibroblasts. Hydrogen cyanide is inhibitory to oxidative
metabolism enzymes. Carbon monoxide decreases the oxygen-carrying capacity of haemoglobin by
competitively inhibiting oxygen binding136. In one study using human volunteers, subcutaneous
partial pressure of oxygen decreased significantly after 10 minutes of cigarette smoking. The effect
lasted for almost 1 hour137. Taken together, this triad has obvious implications for reduction of the
cellular response and efficiency of the healing process.

Smoking also increases platelet aggregation and blood viscosity and decreases collagen deposition
and prostacyclin formation, all of which negatively affect wound healing138. Vasoconstriction
associated with smoking is not a transient phenomenon. Smoking a single cigarette may cause
cutaneous vasoconstriction for up to 90 minutes; hence, a pack-a-day smoker sustains tissue
hypoxia for most of each day.

• LOCAL FACTORS

Such as wound bed desiccation, ph, hypothermia, excess wound fluid, and/ or heavy bacterial
colonisation can affect the repair process. Wound healing is best supported by a moist, clean wound
surface that is maintained at a temperature of about 30 degree Celsius.
SURGICAL SITE INFECTION

These are the infections present in any location along the surgical tract after a surgical procedure.
Centre for disease control and prevention defines SSI as the one that can occur anytime from 0 to
30 days after the operation or up to 1 year after a procedure that has involved the implantation of
foreign material (mesh, vascular grafts, prosthetic joint and so on).

Wound infection following spinal surgery results in prolonged hospitalisation, increased costs, and a
compromised outcome139-141. Infection involving instrumented fusion carries a 2–6 % risk and
presents a treatment dilemma for surgeons, because even combined debridement and antibiotics
therapy may still be inadequate to eradicate the bacterial colonisation of the implants142-144.

Xing et al.145 reviewed evidence-based independent risk factors between 1998 and 2012, and
identified six strong factors, including obesity, longer operation times, diabetes, smoking, previous
surgical site infection, and types of surgical procedure.

Classification—

Incisional superficial SSI

Incisional deep SSI

Organ/space related
SUPERFICIAL INCISIONAL SSI

Infection which occurs within 30 days of surgery involving only skin and subcutaneous tissue and
at least one of the following

a. Purulent discharge

b. Organisms isolated from aseptically cultured fluid and tissue

c. At least one sign of infection : pain or tenderness, localised swelling , redness or heat and incision
is deliberately opened by surgeon unless the incision is culture negative

d. Diagnosis of SSI by surgeon or attending physician.

DEEP INCISIONAL SSI

Infection occurring within 30 days of surgery or within 1 year of operation if implants are in place;
and infection involving deep soft tissue; and at least one of the following

a. Purulent discharge

b. Deep incision spontaneously dehisces or is deliberately opened by a surgeon when the patient has
at least one of the following symptoms; fever more than 38 degree Celsius, localised pain or
tenderness unless the site is culture negative

c. Evidence of deep infection on direct examination , during reoperation or on radiological

examination

d. Diagnosis of SSI by surgeon or attending physician.

ORGAN/SPACE SSI:

Infection occurring within 30 days of surgery or within 1 year of operation if implants are in place
and infection involving any part of anatomy that was manipulated during an operation, other than
the incision and at least one of the following:

a. Purulent discharge that is placed through a stab wound into the organ space.
b. Organisms isolated from and aseptically cultured fluid or tissue. Evidence of deep infection on
the direct examination, during reoperation, or on radiological examination.

c. Diagnosis of SSI by surgeon or attending physician.

SSI are the most common nosocomial infection and constitute 38% of all infection in surgical
patients. Incisional infections are the most common. They account for 60-80% of all SSI’s and have
better prognosis than organ/space related SSI’s do, with the latter accounts for 93% of SSI related
mortality146. Staphylococcus aureus remains the most common pathogen in SSI followed by
coagulase negative staphylococcus, enterococci , and E.coli. Bacterial contamination > 10 5
organisms frequently causes infection whereas contamination with < 10 5 organisms usually does
not.

TREATMENT OF MALNUTRITION

Keeping in mind that the nutritional status is a risk factor for postoperative complications,
Enhanced recovery after surgery (ERAS) guidelines recommend liberal subscription of oral
supplements pre- and postoperatively147. Equally ERAS protocols support early oral intake for the
return of gut function. From a metabolic and nutritional point of view, the key aspects of
perioperative care include:

• integration of nutrition into the overall management of the patient

• avoidance of long periods of preoperative fasting

• re-establishment of oral feeding as early as possible after surgery

• start of nutritional therapy early, as soon as a nutritional risk becomes apparent metabolic control
e.g. of blood glucose

• reduction of factors which exacerbate stress-related catabolism or impair gastrointestinal function

• minimise time on paralytic agents for ventilator management in the postoperative period

• early mobilisation to facilitate protein synthesis and muscle function.

Nutrition therapy. Synonym: nutritional support is defined according to the European Society for
Clinical Nutrition and Metabolism (ESPEN) as148 - Nutrition therapy is the provision of nutrition or
nutrients either orally (regular diet, therapeutic diet, e.g. fortified food, oral nutritional supplements)
or via enteral nutrition (EN) or parenteral nutrition (PN) to prevent or treat malnutrition.

Oral intake, including clear liquids, shall be initiated within hours after surgery in most patients.It is
recommended to adapt oral intake according to individual tolerance and to the type of surgery
carried out with special caution to elderly patients.

The enteral route should always be preferred except for the following contraindications:

Intestinal obstructions or ileus,

Severe shock

Intestinal ischaemia

High output fistula

Severe intestinal haemorrhage

If the energy and nutrient requirements cannot be met by oral and enteral intake alone (<50% of
caloric requirement) for more than seven days, a combination of enteral and parenteral nutrition is
recommended (GPP). Parenteral nutrition shall be administered as soon as possible if nutrition
therapy is indicated and there is a contraindication for enteral nutrition, such as in intestinal
obstruction.

"42
 MATERIALS AND METHODS

"43
This study was conducted at the Spinal disorder surgery unit, Department of Orthopaedics at the
Christian Medical College, Vellore. This study included all the patient who were treated surgically
with fusion of more than 3 levels for any pathological condition between June 2017 to June 2019 .

Participants:
Inclusion criteria:
1) Patients undergoing 3 or more level instrumentation/ Fusion surgery at thoracic, lumbar or
lumbosacral level.
2) Patients between Age 18 to 80 years.

Exclusion criteria:
1. Renal dysfunction
2. Corticosteroid therapy
3. Liver dysfunction
4. Age <18 years and > 80 years
5. Previous or revision surgery within 2 months of first surgery
6. Previous radiotherapy at same surgical site.

This study is a prospective study to determine the effect of nutritional status on major spine
surgery. Patients who were planned for a spine surgery involving instrumentation of 3 or more
levels and fulfilling the inclusion criteria and giving consent to participate in the study were
included in the study. They were evaluated clinically and apart from the pre operative
investigations, nutritional biochemical parameters- Albumin, Prealbumin, Transferrin, Total and
differential counts to determine total lymphocyte count were recorded pre operatively. Post
operatively both clinical and biochemical parameters were analysed. Clinically, SSI, wound healing
problems, ICU stay, hospital stay were analysed. Biochemically, Pre-albumin, Total lymphocyte
counts, Albumin and Transferrin levels were assessed and compared to that of the pre-operative
values. Patients were followed up to look for any wound healing problems and surgical site
infections . The duration of hospital stay, ICU admission was also noted. The patients post operative
nutritional status was also monitored by repeating the same biochemical investigations in the post
operative day 5 and at 3 months. The biochemical results and their relationship to clinical outcomes
were analysed statistically .

Statistical analysis
The sample size is calculated using nMaster software version 2.0.

With the expected proportion of 0.135,6% precision and 95% confidence level , the study
required totally 180 patients. p value less than or equal to less than 0.05 was
considered statistically significant.

45

 RESULTS

"46
Patient demographics

The study population during this 2 year period was 162 patients. All the patients were
analysed both clinically and biochemically. All of the patients had their nutritional assessment for
the immediate post operative period. However only 32 patients had their 3 months value recorded.
Due to the small number of patients with 90th day nutritional values the study was restricted to the
preoperative and Post operative day 5 values.
The average age of the patients in our study was 44 yrs with range from 18 to 76 years.
The total number of males were 103(63%) and the total number of females were 59 (36%).
All the four nutritional parameters included in the study were studied and analysed separately with
respect to the wound related complication , duration of hospital stay and ICU stay. Albumin less
than or or equal to 3.5g/dL , Absolute lymphocyte count less than or equal to 1500 mm3,
Prealbumin less than or equal to 15 mg/dL and Transferrin equal to or less than 204 mg/dL were
considered as malnutrition.

Table 2: Prevalence of malnutrition in pre operative and post operative patients.

Preop Postop No. of new instances of

malnourishment postop

Albumin <= 3.5 45 130 + 85 (52%)

Total Lymphocyte <=1500 64 125 + 61 (37%)

Prealbumin <= 15 30 81 + 51 ( 31%)

Transferin <= 204 49 135 + 88 (54%)125

47 (29%) 111 (68%) 71.25 (44%)

The prevalence of malnutrition in our study differed with respect to the nutritional parameter. It was

as high as 39% (64 patients) when malnutrition was taken with respect to Total lymphocyte count

and low as 18% (30 patients) when taken with respect to prealbumin.
There was 44% on average newly diagnosed patients with malnutrition in the postoperative period

in our study.

Table 3.0: Chi – Square test of association between Preoperative malnourished and
incidence of complication

Preop Malnourishment Complication No complications

Albumin <= 3.5 6 (p=0.780) 39

Total Lymphocyte <=1500 10 ( p = 0.132) 54

Prealbumin <= 15 4 (p=0.914) 26

Transferin <= 204 6 (p= 0.99) 43

We observed that in our study none of the low biochemical nutritional markers in the pre operative
period had an significant association with increased complication rates(p was > 0.05)

Table 3.1: Chi – Square test - Preoperative Well nourished and incidence of complication

Preop Well nourishished Complication No Complication

Albumin > 3.5 18 Not Associated (p 144

=0.7802)

Total Lymphocyte >1500 8 Not associated ( p = 0.2218) 90

Prealbumin > 15 14 Not associated (p=0.9146) 118

Transferin > 204 12 Not associated (p= 0.9906) 101

We observed that in our study none of the normal biochemical nutritional markers in the pre
operative period had an significant association with increased complication rates(p was > 0.05)

48

Table 4.0: Chi – Square test of association between Postoperative malnutrition and

incidence of complication

Postop Complication No complications

Malnourishment

Albumin <= 3.5 17 (p=0.196) 113

Total Lymphocyte <=1500 16 ( p = 0.36) 109

Prealbumin <= 15 15 (p=0.05) 66

Transferin <= 204 17 (p= 0.314) 118

We also observed that low Albumin, Total Lymphocyte counts and transferrin in the post operative

period did not have a significant association with complications. Only Low Prealbumin in the post

operative period had a significant association with complication rates.(p > 0.05)

Table 4.1: Chi – Square test of association between Post operative Well

nourished and complication .

Postop Well nourishment Complication No complication

Albumin > 3.5 1 Not Associated (p =0.1968) 31

Total Lymphocyte >1500 2 Not associated ( p = 0.3373) 35

Prealbumin > 15 3 Associated (p=0.06) 78

Transferin > 204 1 Not associated (p= 0.3143) 26

We observed that in our study none of the normal biochemical nutritional markers in the post operative
period had an significant association with increased complication rates(p was > 0.05)

49

Table 5.0: Complications and Drop in nutritional status

Mean Difference Mean Difference Mean Mean

in Albumin– in TLC– Preop Difference in Difference in
Preop and Postop and Postop Prealbumin– Transferin–
Preop and Preop and
Postop Postop

Complication 1.06 1025.33 9.72 68.61

No Complication 0.76 810.51 7.67 58.25
Correlation 0.18 0.08 0.12 0.09

P-Value 0.01 0.33 0.04 0.25

We observed that the severity of drop in the nutritional status after surgery with respect to Serum

Albumin and Serum Prealbumin had a significant statistical association with complications.

Table 5.1: Chi – Square test of association between Preoperative and postoperative

malnourished and complication .

Pre-op and postop malnourished Complication No complication

Albumin 6 Not Associated (p =0.5871) 35

Total Lymphocyte 10 Not associated ( p = 0.085) 46

Prealbumin 4 Not associated (p=0.2805) 15

Transferin 6 Not associated (p= 0.8784) 41

We observed that in our study none of the patients with low biochemical nutritional

markers in the pre and post operative period had an significant association with

increased complication rates(p was > 0.05)

"50
Table 5.2: Chi – Square test of association between Preop well nourished and postop

malnourished and complication at 5% level of significance

Pre-op well nourished and Complication No complications

postop malnourished

Albumin 11 Not Associated (p 78

=0.7588)
Total Lymphocyte 6 Not associated ( p = 0.5553) 63

Prealbumin 11 Not associated (p=0.0632) 51

Transferin 11 Not associated (p= 0.717) 77

We observed that in our study none of the patients with normal nutritional parameters in pre op and
low biochemical nutritional markers in the post operative period had an significant association with
increased complication rates(p was > 0.05)

Table 6: Chi – Square test of association between Preoperative malnutrition and incidence of

ICU stay

Preop Malnourishment ICU Stay No ICU stay

Albumin <= 3.5 12 (p = 1) 33

Total Lymphocyte <=1500 16 (p=0.809) 48

Prealbumin <= 15 7 (p=0.8321) 23

Transferin <= 204 14 (p= 0.873) 35

We observed in our study that none of the pre operative nutritional parameters could significantly

predict the need for ICU in patients undergoing major spine surgery.

"51
Table 7: Chi – Square test of association between Postoperative malnutrition and incidence of

ICU stay

Postop ICU Stay No ICU stay

Malnourishment
Albumin <= 3.5 42 (p = 0.001) 88

Total Lymphocyte <=1500 32 (p=0.962) 93

Prealbumin <= 15 30 (p=0.004) 51

Transferin <= 204 41 (p=0.025) 94

We observed that there is a statistically significant association between low Post operative Albumin,

prealbumin and Low post operative transferrin and Icu stay among our study population.

Table 8 : Pre-op Nourishment Vs Average Duration of Hospital Stay

Pre-Op Malnourished & Pre-Op Well nourished &

Average Duration of Hospital Average Duration of Hospital
Stay (in days) Stay (in days)

Albumin <= 3.5 15 (p = 0.06) 12

Lymphocyte count <=1500 14 (p = 0.027) 11

Prealbumin <= 15 14 (p = 0.140) 12

Transferin <= 204 14 (p = 0.082) 12

We observed in our study that low pre operative lymphocyte count could significantly predict the

need for prolonged hospital stay in patients undergoing major spine surgery.
Table 9: Post-op Nourishment Vs Average Duration of Hospital Stay

Post-Op Malnourished & Post-Op Well nourished &

Average Duration of Hospital Average Duration of Hospital
Stay (in days) Stay (in days)

Albumin > 3.5 13 (p = 0.0002) 10

Total Lymphocyte >1500 12 (p = 0.846) 13

Prealbumin > 15 14 (p = 0.033) 11

Transferin > 204 13 (p = 0.285) 11

Similarly, we observed in our study that low post operative albumin and prealbumin could

significantly predict the need for prolonged hospital stay in patients undergoing major spine

surgery.

Complications
In our study totally 18/162 (11%) patients had wound related complications.
8 patients had superficial wound infection or delayed wound healing and 10 patients had deep
infection.
All patients with deep wound infection had revision surgery- Wound wash out.

!53
 DISCUSSION

"54
INCIDENCE OF MALNUTRITION
The incidence of malnutrition as per the biochemical parameters albumin < 3.5 mg/dL and
Lymphocyte count <1500 cells /mm3 was 39.5%(64 patients) which is comparable to other
studies13. The number of patients with malnutrition in operative day 5 was 68.5% (111 patients).
None of the studies in literature have reported the prevalence of malnutrition post surgery.
Jensen et al13. in a prospective study on 129 patients , found that trauma and major surgery resulted
in the highest incidence of malnutrition (58.6%), and suboptimal nutrition correlated with an
increased risk of complications, including sepsis, wound- healing complications, and pulmonary
complications.
INCIDENCE OF COMPLICATIONS
The total number of wound related complications in our study group was 11 %.The reported
incidence of surgical site infections following spine surgery according to different studies ranges
from 0.5 to 18.8% 140,150. Such wide-ranging results from different reports are most probably due to
significant variations in operative factors such as the use of implants, case complexity, and the
surgical approach itself. Additionally, in some cases, the discitis may be self-limited and may not be
reported to the surgeon, whereas in other cases, patients may suffer from fulminant sepsis with
abscess development.Since most our our study patients were of etiologies which required
instrumentation and complex surgeries the higher rates of surgical site infections in our study could
be justified.
The rate of surgical complications and infection was dependent on the aetiology . Justin S. Smith et
al.13, based on 108,419 spine surgery cases from the SRS M&M database, reported that the overall
rates of postoperative superficial and deep wound infections are 0.8% and 1.3%, respectively. For
both adult and paediatric patients, the rates of postoperative wound infection were lowest for
procedures performed for degenerative spine disease and highest for procedures performed for
spine deformity. Procedures with spinal fusion or implants had a significantly higher rate of
postoperative wound infection, likely reflective of the greater complexity and associated risk of
cases that require fusion or the use of implants. Compared with a traditional open approach, use of a
minimally invasive approach was associated with a lower rate of infection for lumbar discectomy
and for TLIF.
MALNUTRITION AND COMPLICATIONS
In our study we found that none of the preoperative nutritional parameters had significant relation to
increased risk of wound related complications. Although most of the literature demonstrates an
association between these serologic laboratory values and infection, an other retrospective
multicenter case-control study of 210 neuromuscular scoliosis surgeries by Sponseller et al , found
no statistically significant association between undernutrition, as defined by serum albumin less
than 3.5 mg/dL and total lymphocyte count less than1,500 per cubic millimetre nor was there
increased risk of infection153.
However, Jevsevar and Karlin 151 reported that preoperative albumin less than 3.5 mg/dL and total
lymphocyte count less than1,500 cells per cubic millimetre were associated with higher rates of
overall infection in 44 patients with cerebral palsy after spinal surgery. Similarly, in a review of
patients undergoing elective spine surgery, Beiner et al152 reported higher rates of postoperative
infection and poor wound healing in patients with serum albumin levels ,3.5 mg/dL and total
lymphocyte counts ,1,500 per cubic millimetre.
But we found there is a significant correlation (p= 0.05) between post operative low Prealbumin and
increased complications. Prealbumin has a short half life of 2 to 3 days compared to albumin of 14
to 20 days. The short half life of prealbumin reflects as an acute drop in its value compared to other
parameters154 and its significance with increased complication rate indicates that the drop in
nutritional status of patient with the surgery has a significant correlation with complication rates.
Similar to the above finding , we noticed that there is a significant correlation between “drop in
nutritional parameters” with surgery and complications. Drop in nutritional parameter was
measured by the difference between the preoperative and postoperative nutritional parameters. We
found a significant correlation with drop in albumin (1.0 g/dL) and drop in prealbumin(9.7 mg/dL)
values and increased complication rates. With major spine surgeries there is a catabolic breakdown
of body nutritional reserves resulting in a malnutrtional status. This change in nutritional status can
result in complications due to impaired immunity and healing potential9.
We also analysed the number patients with pre operative low nutritional status and post operatively
low nutritional status with incidence of complications and also analysed number of patients with pre
operatively good nutritional status and post operatively low nutritional status (Table 5.1, Table 5.2)
and found that it did not have a statistical significance. This indicates that it is the magnitude of
drop in nutritional status which was more important predictor of complications, rather than a single
nutritional parameter value .

MALNUTRITION AND ICU STAY AND HOSPITAL STAY

In our study we observed that patients with low Lymphocyte counts in preoperative period and Low
Albumin or low Prealbumin in post operative period were at risk of longer duration of hospital
stay(Table 8, Table 9). Similarly, in a study by Pedersen et al., they observed that malnourished
patients (determined on the basis of weight loss, triceps skinfold thickness, and serum albumin and
prealbumin levels) were more likely to have impaired wound-healing, more medical complications
(including cardiac-related complications), and longer hospitalisation after surgery155.
We also observed low transferrin or low Albumin or low Prealbumin in post operative patients was
associated with higher risk of ICU admission (Table 7). No other literature we find where this
association was studied or linked to.

Given the high prevalence of malnutrition in spine patients and the impact on the outcomes in
patients with drop in nutritional parameters , the surgeon should assess preoperative serum albumin
level, total lymphocyte count, and transferrin level, and patients whose laboratory values fall below
the cutoffs described above should undergo a nutritional consultation. Similarly in the post
operative period in patients who have underwent major surgeries the nutritional intake must be
cared for.
If a patient is found to be malnourished, we recommend discussing with the patient the possibility
of delaying elective surgery until the patient’s nutritional status has improved. To our knowledge,
no study has shown improved outcomes as a result of correcting nutritional status preoperatively;
however, given that the literature supports a link between malnutrition and increased morbidity after
orthopaedic surgery, we believe that addressing malnutrition pre- operatively is a reasonable
approach in the attempt to reduce the risk of complications. Future studies should focus on whether
improving pre- operative nutritional status improves patient outcomes by decreasing the risk of
morbidity after orthopaedic surgery.
Patients undergoing major spine surgery are at risk of nutritional depletion . Preoperative and Post
operative nutritional status must be assessed with serum albumin and Prealbumin and nutritional
support must be provided in patients with significant drop in nutritional status to reduce wound
related complications.
 Basic history-taking, including food intake combined with physical examination of the patient, can
help in the diagnosis of malnutrition. Laboratory tests, including a total lymphocyte count and the
assessment of albumin, prealbumin, and transferrin levels, may assist in the diagnosis but can be
unreliable in the setting of trauma or perioperatively with the release of acute- phase proteins.
Limitations of our study-
1. The Sample Size was less.

2. Patients with different pathology , who were undergoing major surgery were included. Tumour
and infection patient groups are more vulnerable to nutritional depletion than patients with a
degenerative pathology and a similar study on those patient groups would be valuable.

"58
CONCLUSION

!59
1) The magnitude of drop in nutritional status due to the surgery with respect to
albumin and prealbumin is significant predictor of wound related
complications , rather than a single nutritional parameter assessed at a point
of time.
2) Serum Prealbumin is a useful biochemical test to assess acute changes in
nutritional status.
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