Accepted Manuscript The 2013 Arvid Wretlind lecture: Evolving concepts in parenteral nutrition Mette M. Berger, MD Ph.D PII:
S0261-5614(14)00080-6
DOI:
10.1016/j.clnu.2014.03.005
Reference:
YCLNU 2325
To appear in:
Clinical Nutrition
Received Date: 14 January 2014 Revised Date:
2 March 2014
Accepted Date: 18 March 2014
Please cite this article as: Berger MM, The 2013 Arvid Wretlind lecture: Evolving concepts in parenteral nutrition, Clinical Nutrition (2014), doi: 10.1016/j.clnu.2014.03.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
The 2013 Arvid Wretlind lecture:
2
Evolving concepts in parenteral nutrition
3
Mette M Berger, MD Ph.D Service of Adult Intensive Care & Burns, Lausanne University Hospital - CHUV, Lausanne Correspondence :
Adult Intensive Care & Burns,
RI PT
4 5 6 7 8 9 10
CHUV BH 08.612,
12
Rue du Bugnon 46, 1011 Lausanne, Switzerland.
13
Tel +41 21 31 42 095
14
E-mail: [email protected]
18
N= 4546
M AN U
Key words:
Overfeeding, underfeeding, glucose control, trace element, deficiency, requirements
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ACCEPTED MANUSCRIPT Abstract
20
Fifty years after the clinical introduction of total parenteral nutrition (TPN) the Arvid
21
Wretlind lecture is an opportunity to critically analyse the evolution and changes that
22
have marked its development and clinical use. The standard crystalline amino acid
23
solutions, while devoid of side effects, remain incomplete regarding their composition
24
(e.g. glutamine). Lipid emulsions have evolved tremendously and are now included in
25
bi- and tri-compartmental feeding bags enabling a true “total” PN provided daily
26
micronutrients are prescribed.
27
The question of exact individual energy, macro- and micro-nutrient requirements is
28
still unsolved. Many complications attributed to TPN are in fact the consequence of
29
under- or over-feeding: the historical hyperalimentation concept is the main cause,
30
along with the use of fixed weight based predictive equations (incorrect in 70% of the
31
critically ill patients). In the late 80’s many complications (hyperglycemia, sepsis, fatty
32
liver, exacerbation of inflammation, mortality) were attributed to TPN leading to its
33
near abandon in favour of enteral nutrition (EN). Enteral feeding, although desirable
34
for many reasons, is difficult causing a worldwide recurrence of malnutrition by
35
insufficient feed delivery. TPN indications have evolved towards its use either alone
36
or in combination with EN: several controversial trials published 2011-13 have
37
investigated TPN timing, an issue which is not yet resolved. The initiation time varies
38
according to the country between admission (Australia and Israel), day 4 (Swiss) and
39
day 7 (Belgium, USA). The most important issue may prove to be and individualized
40
and time dependent prescription of feeding route, energy and substrates.
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ACCEPTED MANUSCRIPT Introduction
43
Fifty years after the clinical introduction of total parenteral nutrition (TPN), it is time to
44
perform a critical analysis of the changes that have occurred in the concepts and
45
tools underlying this feeding technique. Trained as physician and pharmacist, Prof
46
Arvid Wretlind was the person who developed the modern amino acid solutions and
47
invented a human compatible lipid emulsion 1. He thereby made “total” parenteral
48
nutrition (PN) possible. I am honoured through this lecture to be able to pay tribute to
49
him.
50
Complete PN was indeed realized for the first time by Arvid Wretlind and his team in
51
the early 60’s in Sweden 1 with parallel developments in the U.S. 2. This feeding
52
technique was first applied to patients with gastrointestinal failure, mainly short bowel
53
syndromes, saving many lives previously doomed to a rapid death. The first
54
successes of long term TPN, later called home TPN, were such that generalist
55
newspapers reported about these “miraculous survivals”. In the 60’s PN aimed at
56
filling metabolic gaps of patients unable to absorb the nutrients due to a failing or
57
absent gut. Another aim was to provide the most balanced and physiological
58
compositions of amino acids (AA), carbohydrates and fats. The importance of trace
59
elements and vitamine was not yet understood. The first patients were severely
60
underfed, in the context of cancer or short bowel: this prompted the development of
61
the concept of hyperalimentation, the first name given to TPN. Since its glorious start,
62
PN has evolved tremendously, with changes in the technical and metabolic
63
paradigms which have generated numerous debates. The present paper will describe
64
the issues that have led to the actual composition and indications of PN.
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Life-saving PN – a clinical case
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Critically ill burn patients are typically fed by the enteral route 3. But parenteral
68
feeding may prove vital as in the hereafter case. A 28 year old woman suffered 55%
69
body surface area burn and inhalation injury in a bombing. She was repatriated to the
70
burn intensive care (ICU) on the 4th day after injury, infected with gram negative
71
bacteria: she had not been fed. Her history included sigmoid diverticulosis for the last
72
3 years. Her pre-injury weight was 49 kg with a BMI of 18, putting her at very high
73
risk of acute underfeeding (Nutrition Risk Score NRS 3+3+0=6) 4. Complications 3
ACCEPTED MANUSCRIPT started rapidly with an early ventilator associated pneumonia causing acute
75
respiratory failure and refractory hypoxemia leading to cardiac arrest requiring
76
cardiopulmonary resuscitation (CPR) on day 9 after injury. Thereafter she suffered 3
77
episodes of septic shock caused by the imported gram negative Acinetobacter
78
baumannii. On admission her energy target was 2050 kcal/day according to the initial
79
calorimetry, which she was fully delivered on her 3rd day in the ICU by enteral
80
nutrition (EN), and some additional glucose from drug dilution and fat from sedation
81
(Figure 1). Debridement and grafting procedures progressed until day 28 when a
82
massive peroperative haemorrhage caused a refractory shock and acute renal
83
failure: the latter was treated with a few days of continuous renal replacement
84
therapy. Thereafter she presented a progressive gastrointestinal paresis and ileus,
85
lactic acidosis and shock. Investigations showed an acute colon ischemia motivating
86
a subtotal colon resection and terminal ileostomy. The patient was not fed for 48
87
hours and TPN was then introduced. On day 40, the patient developed an alithiasic
88
cholecystis, requiring cholecystectomy. Severe malnutrition, attributed to failing
89
gastrointestinal tract, was diagnosed and TPN was re-introduced until day 90. After a
90
week enteral postpyloric nutrition was restarted, but progressed poorly; combined PN
91
was maintained at low level due to the suspicion of malabsorption. The weight went
92
down to 39 kg (-21% of initial) with obvious signs of malnutrition (Figure 1). The
93
clinical course was complicated by several septic episodes which delayed wound
94
healing. On day 155, acute bowel dysfunction and ileus recurred, which were treated
95
medically. An acetaminophen test was carried out, consisting in the injection of 15
96
mg/kg into the postpyloric feeding tube. This test provides a semi quantitative
97
assessment of absorption capacity comparing the patient’s values with standard
98
curves established in patients with normal absorption capacity 5. Her sequential
99
paracetamol plasma concentrations were far below normal (Figure 2) which
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motivated the maintenance of combined EN and PN feeding for a further month until
101
reasonable recovery of bowel function. The test was repeated 23 days later, showing
102
modest improvement of absorption. Concomitant maldigestion could not be excluded,
103
and would have reinforced the need for PN. The clinical course was then slowly
104
favourable, and the patient was finally discharged.
105
This young patient would have died in absence of TPN and combined EN-PN with a
106
pathology which is exceptionally PN dependent, showing the importance of the 4
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continued clinical reassessment of the patient’s condition, particularly in the patients
108
with prolonged stays 6.
109
Progress and controversies
111
The understanding of current controversies and priorities is facilitated by observing
112
the development steps of PN1 which are summarized in Figure 3. The current issues
113
may actually be referred back as far as 1919, i.e. before PN, with the publication by
114
Harris & Benedict of their predictive equation of energy needs for healthy people.
115
The main problems facing artificial nutrition can be summarized as follows:
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1) the difficulties in appreciating the real energy requirements in acute conditions with the use of inexact predictive equations, while the relation between
118
measured energy expenditure (EE) and needs is not yet firmly established
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2) the still incomplete amino acid profiles in the industrial solutions, which reduces the metabolic efficiency
121
3) the still unbalanced or incomplete fat emulsions composition
122
4) Using incomplete PN, particularly in the US (no fat, high glucose)
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5) a poor blood glucose control before 2001, which compromises the interpretation of PN studies conducted before 2002
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6) Excessive proportions of total energy (>25-30%) delivered as fat
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7) the lack of monitoring of nutritional therapy
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8) the recent discovery of the very narrow range existing between under- and
128
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over-feeding.
All these issues have resulted in PN associated complications: as PN is more easily
130
delivered than EN it easily may result in overfeeding 7. As the latter is unfrequently
131
associated with EN, PN was considered the culprit. It has since been shown that PN
132
per se was not deleterious 8.
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The evolution of PN
135
The indications to TPN in the first patients were to replace an absent gut, to
136
compensate for a severe underfeeding, and to provide the best available blend of
137
substrates, closest possible to natural feeding (Table 2).
5
ACCEPTED MANUSCRIPT 138 139
A. Amino acids: The preparation of the AA solutions was the first obstacle. Plasma proteins were the
141
first source in the 30ies. A major progress was made with the classic studies by
142
William Rose in the 30’s, who determined the essential AA in humans and proposed
143
the ideal mixture of AA that could support protein synthesis in healthy subjects: the
144
original paper was published in 1949 1. Robert Elman, a surgeon, was the first to
145
report the successful intravenous administration of a mixture of amino acids obtained
146
from the hydrolysis of casein, using strong acids of hydrolysis. The incomplete
147
processing of the proteins and resulting di- and tripeptides were responsible for low
148
nitrogen utilization and hyperammoniemia. Arvid Wretlind refined the technique using
149
an enzymatic hydrolysis, further dialyzing the solution to get rid of the larger peptides.
150
But this form of AA production had the disadvantage of producing solutions with fixed
151
composition, determined by the composition of the “mother protein”. Paradoxically
152
the initial solutions, contaminated with small peptides, contained glutamine, which
153
contributed to their metabolic efficiency. It took until the 60’s to develop the crystalline
154
amino acids 9, leading to the disappearance of the hydrolysates from the market in
155
the early 70’s. There was one major side effect to this progress: the purified solutions
156
did not contain glutamine or trace elements anymore, which led to the development
157
of a series of deficiencies (cf. below).
158
For stability reasons, tyrosine, cysteine-cystine, and glutamine were difficult to
159
include in the solutions. Fürst et al were finally able to solve the glutamine issue in
160
the early 80s with the concept of the ALA-GLN dipeptide 10. The industrial solutions
161
are still not “complete”; e.g. they do not contain cysteine-cystine which remains
162
unstable even as dipeptide, so there is still room for progress and for elaboration of
163
AA profiles adapted to the different periods of life..
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B. Fat emulsions:
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Developing lipid emulsions was the most difficult part to solve, and fostered intensive
167
research in both Europe and U.S: the solutions were first tested in animals, and
168
especially in dogs which are characterised by a higher tolerance to fat and therefore
169
not enabling the detection of the human side effects when testing strictly gram per kg 6
ACCEPTED MANUSCRIPT equivalent doses. The 15% cotton seed oil, which was the first product on the
171
American market, resulted in severe complications such as chills, fever, nausea,
172
vomiting, hypoxia, hypotension and haemolytic anaemia, and deaths in animals. The
173
solution was withdrawn after a few years. The complications observed with these
174
emulsions lead to the use of incomplete PN (i.e. without lipids) for fear of adverse
175
reactions. The animal models used before the 60’s did not enable detecting the
176
adverse human responses. In 1960, Wretlind and Håkanson developed the “9
177
gram/kg method” in dogs, which provided a better comparison tool, using biologically
178
equivalent fat doses compared to humans 11 . In Europe though, thanks to the
179
invention of the soybean solution (Intralipid®, Kabi-Vitrum) using egg yolk
180
phospholipids as the emulsifying agent by Arvid Wretlind and his team, PN was
181
complete from 1962, i.e. was a “total PN” from the start, about 15 years earlier than
182
the U.S. Nowadays the FDA continues to be very suspicious about fat emulsions.
183
Their development is contextualized in Figure 3.
184
Of note, the separate substrates were at that time provided in separate glass bottles.
185
Technical advances in plastics made it possible to develope of double- and tri-
186
compartmental bags since the 90’s, separating the macro-substrates, easy to handle,
187
and providing the necessary guaranties regarding stability and sterility of the
188
solutions, reducing contamination and errors in prescription to a minimum, while
189
reducing costs 12 .
190
The latest developments of lipid emulsions, recently reviewed by Philip Calder 13 14,
191
show that particularly the n-3 PUFAs might act as pharmaco-nutrients with modestly
192
supra-nutritional doses being able to achieve independent anti-inflammatory effects
193
15
194
proportion of the total energy provided by fat, a proportion which might vary in the
195
different patient conditions, being possibly lower in the critically ill than in stabilized or
196
home PN patients.
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. The issues today are to find the optimal combination of fatty acids, and the optimal
197 198
C. Micronutrients:
199
In 1977 Jeejeebhoy et al showed that long term TPN caused a reversible chromium
200
deficiency 16. This first demonstration of trace element (TE) deficiency was followed
201
by several others (copper 17, selenium 18, iron19, and zinc
202
deficiencies. It took several years for the industry to finally produce in the late 70’s
20, 21
), as well as of vitamin
7
ACCEPTED MANUSCRIPT balanced vitamin and TE solutions preventing deficiencies. While vitamin solutions
204
were upgraded and completed several times over the last 4 decades, the trace
205
element solutions were not developed similarly. Particularly, there is still today no
206
ready to use solution adapted to the specific requirements of the critically ill patients
207
at high risk of deficiency such as major burns, major trauma, or patients with septic
208
shock or requiring continuous renal replacement therapy. Home PN requirements
209
have been addressed specifically 22. TEs have some characteristics which
210
complicate their prescription and delivery 23 as summarized in the below Table 2.
211
Balance studies have shown that some categories of patients suffer acute TE losses
212
with the biological fluids that characterise these conditions, threatening their
213
micronutrient homeostasis. This occurs in major burns 24, 25and trauma26, or during
214
continuous renal replacement therapy 27 or dialysis. It also occurs in patients with
215
high output intestinal fistulae, or massive gastric aspirations and diarrhoea. Zinc is
216
then at highest risk of deficiency.
217
In major burns, sequential randomised, double blind, controlled repletion trials have
218
shown that the compensation of the large losses through the exudates of Cu, Se and
219
Zn restores immunity, reduces infectious complications, improves wound healing and
220
shorten length of stay in the ICU 28, 29. The reduction in nosocomial pneumonia was
221
highly significant 30. Skin biopsies show that these changes occur through
222
normalization of Se and Zn content in the skin, with subsequent normalisation of
223
wound AOX enzyme activity and reduced catabolism 29. In major trauma, i.e. patients
224
with a mean injury severity score (ISS) of 30, also characterised by negative
225
balances26, a placebo controlled randomized trial comparing 5 days of repletion with
226
placebo, resulted in a mean reduction of hospital stay of 11 days’ 31.
227
After the observation in the 80’s that Cu and Zn deficiency could not be corrected in
228
burned children with enteral administration of both TEs 32 because of the absorption
229
competition existing at the mucosal level: the consequence is that intravenous
230
delivery is required when large amounts of these two elements is required to bypass
231
an absorption antagonism which reduces availability particularly of Cu.
232
The unpredictable bioavailability related to the enteral route is an important issue
233
when aiming at high and immediate availability as has been proposed in acute
234
conditions characterised by an elevated oxidative stress. The intravenous route is
235
then the only way to ensure delivery in the sickest patients who frequently suffer from
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8
ACCEPTED MANUSCRIPT 236
overhydration: as the latter is associated with intestinal oedema 33, absorption is
237
potentially further compromised.
238
This has been the argument underlying the high intravenous Se dose delivery in
239
antioxidant (AOX) trials 34, 35. A few TEs are particularly important for endogenous
240
AOX defences, as they are part or structure of intra- and extra-cellular AOX enzymes
241
36
242
in CuZn superoxide dismutase, and several others 37. Se has repeatedly been shown
243
to be a candidate for supplementation, particularly in patients with intense
244
inflammatory response such as present in septic shock 38: a recent review and meta-
245
analysis confirms its potential therapeutic role 39.
246
But some TE such as Cu, Fe and Se are double-edged swords, and under
247
circumstances may become pro-oxidant. Tuning the delicate balance between anti-
248
and pro-oxidation using pharmacological doses of TE requires caution and further
249
research.
250
Collier et al conducted a trial comparing the major trauma outcomes before and after
251
the introduction of an AOX protocol: they showed significant benefits in a series of
252
4294 patients 40, 41. The AOX protocol was composed of large doses of ascorbic acid,
253
α-tocopherol, and selenium (≅ 20 times the recommended daily allowances): it was
254
associated with a significant reduction in respiratory failure, ventilator-dependence,
255
length of stay and a 28% reduction of mortality. In addition, AOX were associated
256
with a marked decrease in abdominal wall complications, including abdominal
257
compartment syndrome and surgical site infections.
258
The demonstration of the consequences of acute deficit being prevented by repletion
259
of body stores, with restoration of normal biological functions was my first “Aha”
260
experience (Table 3). According to the Merriam-Webster dictionary this interjection is
261
used when something is suddenly seen, found, or understood, i.e. a moment of
262
insight, the recognition of a problem not previously identified. Indeed, after this
263
recognition the diagnostic and therapeutic issues became “if there is an acute/sub
264
acute deficit of substance Z, the replace the gap”. The understanding that repletion is
265
biologically different from supplementation proved to be applicable to other
266
substrates.
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. This is the case for selenium in the glutathione peroxidase (GPX) family, for zinc
267 9
ACCEPTED MANUSCRIPT 268
D. Glucose: Glucose administration was long not considered to be a problem, and large
270
hyperosmolar quantities were delivered through central venous catheters, as a
271
protein sparing strategy to attempt reducing the repeatedly observed loss of lean
272
body mass. The large glucose loads was supposed to suppress endogenous glucose
273
production and to prevent amino acid oxidation: both hypothesis have since been
274
proven wrong 42. The discovery of a maximal glucose oxidation capacity of 4-5
275
mg/kg/min in both adults and children raised questions as to the glucose tolerance.
276
The question was even more important as the US nutritionists long did not dispose of
277
lipid emulsions, forcing them to deliver large (possibly excessive?) amounts of
278
dextrose to cover the assumed energy requirements, at a time where the aim of
279
nutrition was “hyperalimentation”.
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The hyperalimentation concept and TPN abuse
282
The availability and rapid technical improvement of TPN as well as its rather easy
283
prescription and delivery compared to enteral nutrition (EN) 43 was associated with its
284
wide use in Europe, and particularly in Scandinavia, often in patients without
285
complete gastrointestinal failure. This occurred despite the potential for complications
286
associated with a central venous access, particularly line infections, and the still then
287
unknown complications of hyperglycemia and overfeeding. While PN has obviously
288
saved many lives, its overuse along with hyperalimentation and hyperglycemia has
289
certainly contributed to worsen outcome in many patients: in absence of indirect
290
calorimetry in most studies, it is difficult though to precisely define the amplitude of
291
the over prescription and magnitude of these side effects. Enteral feed delivery
292
remains a nursing technique that is poorly mastered by many clinical teams resulting
293
is serious underfeeding 44, 45.
294
The second major series of concerns arose from the deliberate initial aim to realize a
295
“hyperalimentation”, in order to prevent the critical illness catabolism. This term was
296
first used by Jonathan Rhoads 46: it implied that depleted or hypermetabolic patients,
297
and particularly cancer patients, should receive on purpose more than their “normal”
298
nutrient requirements. This concept in fact accentuated the anabolic responses
299
observed in many of the early patients 47, but this was not understood at that time.
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ACCEPTED MANUSCRIPT Delivering more than 3000 kcal/day was very common in the 80’s, while glucose
301
metabolism was left to its spontaneous evolution: hyperglycemia in the ranges 10-15
302
mmol/l was considered normal and adaptive, and generally not treated. The high
303
glucose loads generated complications such as excessive CO2 production,
304
respiratory failure, fever, high metabolic stress with significant elevations of
305
endogenous cortisol epinephrine and glucagon, and liver complications with steatosis
306
and cytolysis 13. It became obvious that PN was associated with increased infectious
307
complications, in much higher proportions than EN 48. Typically burns were an
308
example of overfeeding using the combination of EN and PN 49. But it also occurred
309
in general intensive care and ward patients resulting in increased rates of blood
310
stream infections 50. It is only after the 2001 Leuven trial that the medical community
311
became aware of the importance of controlling blood glucose levels by means of
312
continuous intensive insulin therapy. The first trials aimed at blood glucose levels
313
between 4.1 and 6 mmol/l 51: it was subsequently demonstrated that such a tight
314
glucose control might be dangerous (Nice Sugar 52, Glucontrol 53): a more reasonable
315
target was needed, resulting in the now prevailing 5-8 mmol/l glucose range. But still
316
it was not understood that parenteral overfeeding was the generator of
317
hyperglycemia in many cases.
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The decline of TPN and the return of underfeeding
320
Entangled in the hyperalimentation issue, a major concern arose after Fong et al 54
321
showed that feeding PN versus EN to healthy subjects for 5 days before an
322
endotoxin challenge exacerbated of the inflammatory response, a serious concern in
323
the critically ill patients. Simultaneously several studies were published showing that
324
infectious complications were more frequent with PN that with EN. These studies
325
nearly annihilated the PN concept, especially as the Veterans’ study in 1991 showed
326
absence of benefits and even deleterious effects of perioperative PN in patients
327
without malnutrition 48.
328
These observations lead to a worldwide reduction of use of PN including in the
329
Lausanne ICU , with an increase of the proportion of days on EN 43 (Figure 4). As
330
EN is much more difficult to realize, requiring important nursing skills, this lead to the
331
development of a rather generalized unintentional underfeeding 55, 56, the
332
phenomenon being observed in all parts of the world44. The recurrence of severe
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ACCEPTED MANUSCRIPT malnutrition associated with pure EN has brought attention to secondary indications
334
to PN (Table 2).
335
The protein requirements in critically ill have been difficult to determine, but is
336
generally considered to be around 1.3 g/kg/day 57. The importance of delivering
337
adequate amounts of proteins has been recently stressed with the demonstration that
338
both targets might be independent. The largest study conducted in 886 consecutive
339
mechanically ventilated patients showed that achieving both the protein and the
340
energy targets right significantly reduced mortality, by nearly 50% 58. The second
341
study with 113 ICU patients while not powered for mortality, showed shorter ICU
342
stays (p
S0261-5614(14)00080-6
DOI:
10.1016/j.clnu.2014.03.005
Reference:
YCLNU 2325
To appear in:
Clinical Nutrition
Received Date: 14 January 2014 Revised Date:
2 March 2014
Accepted Date: 18 March 2014
Please cite this article as: Berger MM, The 2013 Arvid Wretlind lecture: Evolving concepts in parenteral nutrition, Clinical Nutrition (2014), doi: 10.1016/j.clnu.2014.03.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
The 2013 Arvid Wretlind lecture:
2
Evolving concepts in parenteral nutrition
3
Mette M Berger, MD Ph.D Service of Adult Intensive Care & Burns, Lausanne University Hospital - CHUV, Lausanne Correspondence :
Adult Intensive Care & Burns,
RI PT
4 5 6 7 8 9 10
CHUV BH 08.612,
12
Rue du Bugnon 46, 1011 Lausanne, Switzerland.
13
Tel +41 21 31 42 095
14
E-mail: [email protected]
18
N= 4546
M AN U
Key words:
Overfeeding, underfeeding, glucose control, trace element, deficiency, requirements
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EP
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15 16 17
SC
11
1
ACCEPTED MANUSCRIPT Abstract
20
Fifty years after the clinical introduction of total parenteral nutrition (TPN) the Arvid
21
Wretlind lecture is an opportunity to critically analyse the evolution and changes that
22
have marked its development and clinical use. The standard crystalline amino acid
23
solutions, while devoid of side effects, remain incomplete regarding their composition
24
(e.g. glutamine). Lipid emulsions have evolved tremendously and are now included in
25
bi- and tri-compartmental feeding bags enabling a true “total” PN provided daily
26
micronutrients are prescribed.
27
The question of exact individual energy, macro- and micro-nutrient requirements is
28
still unsolved. Many complications attributed to TPN are in fact the consequence of
29
under- or over-feeding: the historical hyperalimentation concept is the main cause,
30
along with the use of fixed weight based predictive equations (incorrect in 70% of the
31
critically ill patients). In the late 80’s many complications (hyperglycemia, sepsis, fatty
32
liver, exacerbation of inflammation, mortality) were attributed to TPN leading to its
33
near abandon in favour of enteral nutrition (EN). Enteral feeding, although desirable
34
for many reasons, is difficult causing a worldwide recurrence of malnutrition by
35
insufficient feed delivery. TPN indications have evolved towards its use either alone
36
or in combination with EN: several controversial trials published 2011-13 have
37
investigated TPN timing, an issue which is not yet resolved. The initiation time varies
38
according to the country between admission (Australia and Israel), day 4 (Swiss) and
39
day 7 (Belgium, USA). The most important issue may prove to be and individualized
40
and time dependent prescription of feeding route, energy and substrates.
SC
M AN U
TE D
EP
AC C
41
RI PT
19
2
ACCEPTED MANUSCRIPT Introduction
43
Fifty years after the clinical introduction of total parenteral nutrition (TPN), it is time to
44
perform a critical analysis of the changes that have occurred in the concepts and
45
tools underlying this feeding technique. Trained as physician and pharmacist, Prof
46
Arvid Wretlind was the person who developed the modern amino acid solutions and
47
invented a human compatible lipid emulsion 1. He thereby made “total” parenteral
48
nutrition (PN) possible. I am honoured through this lecture to be able to pay tribute to
49
him.
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Complete PN was indeed realized for the first time by Arvid Wretlind and his team in
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the early 60’s in Sweden 1 with parallel developments in the U.S. 2. This feeding
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technique was first applied to patients with gastrointestinal failure, mainly short bowel
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syndromes, saving many lives previously doomed to a rapid death. The first
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successes of long term TPN, later called home TPN, were such that generalist
55
newspapers reported about these “miraculous survivals”. In the 60’s PN aimed at
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filling metabolic gaps of patients unable to absorb the nutrients due to a failing or
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absent gut. Another aim was to provide the most balanced and physiological
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compositions of amino acids (AA), carbohydrates and fats. The importance of trace
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elements and vitamine was not yet understood. The first patients were severely
60
underfed, in the context of cancer or short bowel: this prompted the development of
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the concept of hyperalimentation, the first name given to TPN. Since its glorious start,
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PN has evolved tremendously, with changes in the technical and metabolic
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paradigms which have generated numerous debates. The present paper will describe
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the issues that have led to the actual composition and indications of PN.
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Life-saving PN – a clinical case
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Critically ill burn patients are typically fed by the enteral route 3. But parenteral
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feeding may prove vital as in the hereafter case. A 28 year old woman suffered 55%
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body surface area burn and inhalation injury in a bombing. She was repatriated to the
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burn intensive care (ICU) on the 4th day after injury, infected with gram negative
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bacteria: she had not been fed. Her history included sigmoid diverticulosis for the last
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3 years. Her pre-injury weight was 49 kg with a BMI of 18, putting her at very high
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risk of acute underfeeding (Nutrition Risk Score NRS 3+3+0=6) 4. Complications 3
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respiratory failure and refractory hypoxemia leading to cardiac arrest requiring
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cardiopulmonary resuscitation (CPR) on day 9 after injury. Thereafter she suffered 3
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episodes of septic shock caused by the imported gram negative Acinetobacter
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baumannii. On admission her energy target was 2050 kcal/day according to the initial
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calorimetry, which she was fully delivered on her 3rd day in the ICU by enteral
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nutrition (EN), and some additional glucose from drug dilution and fat from sedation
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(Figure 1). Debridement and grafting procedures progressed until day 28 when a
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massive peroperative haemorrhage caused a refractory shock and acute renal
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failure: the latter was treated with a few days of continuous renal replacement
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therapy. Thereafter she presented a progressive gastrointestinal paresis and ileus,
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lactic acidosis and shock. Investigations showed an acute colon ischemia motivating
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a subtotal colon resection and terminal ileostomy. The patient was not fed for 48
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hours and TPN was then introduced. On day 40, the patient developed an alithiasic
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cholecystis, requiring cholecystectomy. Severe malnutrition, attributed to failing
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gastrointestinal tract, was diagnosed and TPN was re-introduced until day 90. After a
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week enteral postpyloric nutrition was restarted, but progressed poorly; combined PN
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was maintained at low level due to the suspicion of malabsorption. The weight went
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down to 39 kg (-21% of initial) with obvious signs of malnutrition (Figure 1). The
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clinical course was complicated by several septic episodes which delayed wound
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healing. On day 155, acute bowel dysfunction and ileus recurred, which were treated
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medically. An acetaminophen test was carried out, consisting in the injection of 15
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mg/kg into the postpyloric feeding tube. This test provides a semi quantitative
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assessment of absorption capacity comparing the patient’s values with standard
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curves established in patients with normal absorption capacity 5. Her sequential
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paracetamol plasma concentrations were far below normal (Figure 2) which
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motivated the maintenance of combined EN and PN feeding for a further month until
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reasonable recovery of bowel function. The test was repeated 23 days later, showing
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modest improvement of absorption. Concomitant maldigestion could not be excluded,
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and would have reinforced the need for PN. The clinical course was then slowly
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favourable, and the patient was finally discharged.
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This young patient would have died in absence of TPN and combined EN-PN with a
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pathology which is exceptionally PN dependent, showing the importance of the 4
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continued clinical reassessment of the patient’s condition, particularly in the patients
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with prolonged stays 6.
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Progress and controversies
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The understanding of current controversies and priorities is facilitated by observing
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the development steps of PN1 which are summarized in Figure 3. The current issues
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may actually be referred back as far as 1919, i.e. before PN, with the publication by
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Harris & Benedict of their predictive equation of energy needs for healthy people.
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The main problems facing artificial nutrition can be summarized as follows:
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1) the difficulties in appreciating the real energy requirements in acute conditions with the use of inexact predictive equations, while the relation between
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measured energy expenditure (EE) and needs is not yet firmly established
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2) the still incomplete amino acid profiles in the industrial solutions, which reduces the metabolic efficiency
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3) the still unbalanced or incomplete fat emulsions composition
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4) Using incomplete PN, particularly in the US (no fat, high glucose)
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5) a poor blood glucose control before 2001, which compromises the interpretation of PN studies conducted before 2002
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6) Excessive proportions of total energy (>25-30%) delivered as fat
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7) the lack of monitoring of nutritional therapy
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8) the recent discovery of the very narrow range existing between under- and
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over-feeding.
All these issues have resulted in PN associated complications: as PN is more easily
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delivered than EN it easily may result in overfeeding 7. As the latter is unfrequently
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associated with EN, PN was considered the culprit. It has since been shown that PN
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per se was not deleterious 8.
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The evolution of PN
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The indications to TPN in the first patients were to replace an absent gut, to
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compensate for a severe underfeeding, and to provide the best available blend of
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substrates, closest possible to natural feeding (Table 2).
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A. Amino acids: The preparation of the AA solutions was the first obstacle. Plasma proteins were the
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first source in the 30ies. A major progress was made with the classic studies by
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William Rose in the 30’s, who determined the essential AA in humans and proposed
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the ideal mixture of AA that could support protein synthesis in healthy subjects: the
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original paper was published in 1949 1. Robert Elman, a surgeon, was the first to
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report the successful intravenous administration of a mixture of amino acids obtained
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from the hydrolysis of casein, using strong acids of hydrolysis. The incomplete
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processing of the proteins and resulting di- and tripeptides were responsible for low
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nitrogen utilization and hyperammoniemia. Arvid Wretlind refined the technique using
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an enzymatic hydrolysis, further dialyzing the solution to get rid of the larger peptides.
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But this form of AA production had the disadvantage of producing solutions with fixed
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composition, determined by the composition of the “mother protein”. Paradoxically
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the initial solutions, contaminated with small peptides, contained glutamine, which
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contributed to their metabolic efficiency. It took until the 60’s to develop the crystalline
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amino acids 9, leading to the disappearance of the hydrolysates from the market in
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the early 70’s. There was one major side effect to this progress: the purified solutions
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did not contain glutamine or trace elements anymore, which led to the development
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of a series of deficiencies (cf. below).
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For stability reasons, tyrosine, cysteine-cystine, and glutamine were difficult to
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include in the solutions. Fürst et al were finally able to solve the glutamine issue in
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the early 80s with the concept of the ALA-GLN dipeptide 10. The industrial solutions
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are still not “complete”; e.g. they do not contain cysteine-cystine which remains
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unstable even as dipeptide, so there is still room for progress and for elaboration of
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AA profiles adapted to the different periods of life..
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B. Fat emulsions:
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Developing lipid emulsions was the most difficult part to solve, and fostered intensive
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research in both Europe and U.S: the solutions were first tested in animals, and
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especially in dogs which are characterised by a higher tolerance to fat and therefore
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not enabling the detection of the human side effects when testing strictly gram per kg 6
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American market, resulted in severe complications such as chills, fever, nausea,
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vomiting, hypoxia, hypotension and haemolytic anaemia, and deaths in animals. The
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solution was withdrawn after a few years. The complications observed with these
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emulsions lead to the use of incomplete PN (i.e. without lipids) for fear of adverse
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reactions. The animal models used before the 60’s did not enable detecting the
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adverse human responses. In 1960, Wretlind and Håkanson developed the “9
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gram/kg method” in dogs, which provided a better comparison tool, using biologically
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equivalent fat doses compared to humans 11 . In Europe though, thanks to the
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invention of the soybean solution (Intralipid®, Kabi-Vitrum) using egg yolk
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phospholipids as the emulsifying agent by Arvid Wretlind and his team, PN was
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complete from 1962, i.e. was a “total PN” from the start, about 15 years earlier than
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the U.S. Nowadays the FDA continues to be very suspicious about fat emulsions.
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Their development is contextualized in Figure 3.
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Of note, the separate substrates were at that time provided in separate glass bottles.
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Technical advances in plastics made it possible to develope of double- and tri-
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compartmental bags since the 90’s, separating the macro-substrates, easy to handle,
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and providing the necessary guaranties regarding stability and sterility of the
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solutions, reducing contamination and errors in prescription to a minimum, while
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reducing costs 12 .
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The latest developments of lipid emulsions, recently reviewed by Philip Calder 13 14,
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show that particularly the n-3 PUFAs might act as pharmaco-nutrients with modestly
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supra-nutritional doses being able to achieve independent anti-inflammatory effects
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15
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proportion of the total energy provided by fat, a proportion which might vary in the
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different patient conditions, being possibly lower in the critically ill than in stabilized or
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home PN patients.
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. The issues today are to find the optimal combination of fatty acids, and the optimal
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C. Micronutrients:
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In 1977 Jeejeebhoy et al showed that long term TPN caused a reversible chromium
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deficiency 16. This first demonstration of trace element (TE) deficiency was followed
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by several others (copper 17, selenium 18, iron19, and zinc
202
deficiencies. It took several years for the industry to finally produce in the late 70’s
20, 21
), as well as of vitamin
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were upgraded and completed several times over the last 4 decades, the trace
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element solutions were not developed similarly. Particularly, there is still today no
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ready to use solution adapted to the specific requirements of the critically ill patients
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at high risk of deficiency such as major burns, major trauma, or patients with septic
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shock or requiring continuous renal replacement therapy. Home PN requirements
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have been addressed specifically 22. TEs have some characteristics which
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complicate their prescription and delivery 23 as summarized in the below Table 2.
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Balance studies have shown that some categories of patients suffer acute TE losses
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with the biological fluids that characterise these conditions, threatening their
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micronutrient homeostasis. This occurs in major burns 24, 25and trauma26, or during
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continuous renal replacement therapy 27 or dialysis. It also occurs in patients with
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high output intestinal fistulae, or massive gastric aspirations and diarrhoea. Zinc is
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then at highest risk of deficiency.
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In major burns, sequential randomised, double blind, controlled repletion trials have
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shown that the compensation of the large losses through the exudates of Cu, Se and
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Zn restores immunity, reduces infectious complications, improves wound healing and
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shorten length of stay in the ICU 28, 29. The reduction in nosocomial pneumonia was
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highly significant 30. Skin biopsies show that these changes occur through
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normalization of Se and Zn content in the skin, with subsequent normalisation of
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wound AOX enzyme activity and reduced catabolism 29. In major trauma, i.e. patients
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with a mean injury severity score (ISS) of 30, also characterised by negative
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balances26, a placebo controlled randomized trial comparing 5 days of repletion with
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placebo, resulted in a mean reduction of hospital stay of 11 days’ 31.
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After the observation in the 80’s that Cu and Zn deficiency could not be corrected in
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burned children with enteral administration of both TEs 32 because of the absorption
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competition existing at the mucosal level: the consequence is that intravenous
230
delivery is required when large amounts of these two elements is required to bypass
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an absorption antagonism which reduces availability particularly of Cu.
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The unpredictable bioavailability related to the enteral route is an important issue
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when aiming at high and immediate availability as has been proposed in acute
234
conditions characterised by an elevated oxidative stress. The intravenous route is
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then the only way to ensure delivery in the sickest patients who frequently suffer from
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overhydration: as the latter is associated with intestinal oedema 33, absorption is
237
potentially further compromised.
238
This has been the argument underlying the high intravenous Se dose delivery in
239
antioxidant (AOX) trials 34, 35. A few TEs are particularly important for endogenous
240
AOX defences, as they are part or structure of intra- and extra-cellular AOX enzymes
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36
242
in CuZn superoxide dismutase, and several others 37. Se has repeatedly been shown
243
to be a candidate for supplementation, particularly in patients with intense
244
inflammatory response such as present in septic shock 38: a recent review and meta-
245
analysis confirms its potential therapeutic role 39.
246
But some TE such as Cu, Fe and Se are double-edged swords, and under
247
circumstances may become pro-oxidant. Tuning the delicate balance between anti-
248
and pro-oxidation using pharmacological doses of TE requires caution and further
249
research.
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Collier et al conducted a trial comparing the major trauma outcomes before and after
251
the introduction of an AOX protocol: they showed significant benefits in a series of
252
4294 patients 40, 41. The AOX protocol was composed of large doses of ascorbic acid,
253
α-tocopherol, and selenium (≅ 20 times the recommended daily allowances): it was
254
associated with a significant reduction in respiratory failure, ventilator-dependence,
255
length of stay and a 28% reduction of mortality. In addition, AOX were associated
256
with a marked decrease in abdominal wall complications, including abdominal
257
compartment syndrome and surgical site infections.
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The demonstration of the consequences of acute deficit being prevented by repletion
259
of body stores, with restoration of normal biological functions was my first “Aha”
260
experience (Table 3). According to the Merriam-Webster dictionary this interjection is
261
used when something is suddenly seen, found, or understood, i.e. a moment of
262
insight, the recognition of a problem not previously identified. Indeed, after this
263
recognition the diagnostic and therapeutic issues became “if there is an acute/sub
264
acute deficit of substance Z, the replace the gap”. The understanding that repletion is
265
biologically different from supplementation proved to be applicable to other
266
substrates.
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. This is the case for selenium in the glutathione peroxidase (GPX) family, for zinc
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D. Glucose: Glucose administration was long not considered to be a problem, and large
270
hyperosmolar quantities were delivered through central venous catheters, as a
271
protein sparing strategy to attempt reducing the repeatedly observed loss of lean
272
body mass. The large glucose loads was supposed to suppress endogenous glucose
273
production and to prevent amino acid oxidation: both hypothesis have since been
274
proven wrong 42. The discovery of a maximal glucose oxidation capacity of 4-5
275
mg/kg/min in both adults and children raised questions as to the glucose tolerance.
276
The question was even more important as the US nutritionists long did not dispose of
277
lipid emulsions, forcing them to deliver large (possibly excessive?) amounts of
278
dextrose to cover the assumed energy requirements, at a time where the aim of
279
nutrition was “hyperalimentation”.
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The hyperalimentation concept and TPN abuse
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The availability and rapid technical improvement of TPN as well as its rather easy
283
prescription and delivery compared to enteral nutrition (EN) 43 was associated with its
284
wide use in Europe, and particularly in Scandinavia, often in patients without
285
complete gastrointestinal failure. This occurred despite the potential for complications
286
associated with a central venous access, particularly line infections, and the still then
287
unknown complications of hyperglycemia and overfeeding. While PN has obviously
288
saved many lives, its overuse along with hyperalimentation and hyperglycemia has
289
certainly contributed to worsen outcome in many patients: in absence of indirect
290
calorimetry in most studies, it is difficult though to precisely define the amplitude of
291
the over prescription and magnitude of these side effects. Enteral feed delivery
292
remains a nursing technique that is poorly mastered by many clinical teams resulting
293
is serious underfeeding 44, 45.
294
The second major series of concerns arose from the deliberate initial aim to realize a
295
“hyperalimentation”, in order to prevent the critical illness catabolism. This term was
296
first used by Jonathan Rhoads 46: it implied that depleted or hypermetabolic patients,
297
and particularly cancer patients, should receive on purpose more than their “normal”
298
nutrient requirements. This concept in fact accentuated the anabolic responses
299
observed in many of the early patients 47, but this was not understood at that time.
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301
metabolism was left to its spontaneous evolution: hyperglycemia in the ranges 10-15
302
mmol/l was considered normal and adaptive, and generally not treated. The high
303
glucose loads generated complications such as excessive CO2 production,
304
respiratory failure, fever, high metabolic stress with significant elevations of
305
endogenous cortisol epinephrine and glucagon, and liver complications with steatosis
306
and cytolysis 13. It became obvious that PN was associated with increased infectious
307
complications, in much higher proportions than EN 48. Typically burns were an
308
example of overfeeding using the combination of EN and PN 49. But it also occurred
309
in general intensive care and ward patients resulting in increased rates of blood
310
stream infections 50. It is only after the 2001 Leuven trial that the medical community
311
became aware of the importance of controlling blood glucose levels by means of
312
continuous intensive insulin therapy. The first trials aimed at blood glucose levels
313
between 4.1 and 6 mmol/l 51: it was subsequently demonstrated that such a tight
314
glucose control might be dangerous (Nice Sugar 52, Glucontrol 53): a more reasonable
315
target was needed, resulting in the now prevailing 5-8 mmol/l glucose range. But still
316
it was not understood that parenteral overfeeding was the generator of
317
hyperglycemia in many cases.
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The decline of TPN and the return of underfeeding
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Entangled in the hyperalimentation issue, a major concern arose after Fong et al 54
321
showed that feeding PN versus EN to healthy subjects for 5 days before an
322
endotoxin challenge exacerbated of the inflammatory response, a serious concern in
323
the critically ill patients. Simultaneously several studies were published showing that
324
infectious complications were more frequent with PN that with EN. These studies
325
nearly annihilated the PN concept, especially as the Veterans’ study in 1991 showed
326
absence of benefits and even deleterious effects of perioperative PN in patients
327
without malnutrition 48.
328
These observations lead to a worldwide reduction of use of PN including in the
329
Lausanne ICU , with an increase of the proportion of days on EN 43 (Figure 4). As
330
EN is much more difficult to realize, requiring important nursing skills, this lead to the
331
development of a rather generalized unintentional underfeeding 55, 56, the
332
phenomenon being observed in all parts of the world44. The recurrence of severe
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334
to PN (Table 2).
335
The protein requirements in critically ill have been difficult to determine, but is
336
generally considered to be around 1.3 g/kg/day 57. The importance of delivering
337
adequate amounts of proteins has been recently stressed with the demonstration that
338
both targets might be independent. The largest study conducted in 886 consecutive
339
mechanically ventilated patients showed that achieving both the protein and the
340
energy targets right significantly reduced mortality, by nearly 50% 58. The second
341
study with 113 ICU patients while not powered for mortality, showed shorter ICU
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stays (p
