use of a concentrated enteral nutrition solution to increase calorie delivery to critically ill...

delivery to critically ill patients: a randomized double-blind clinical trial Use of a concentrated enteral nutrition solution to increase calorie

Version 1 AJCN/2014/086322

The American Journal of Clinical Nutrition

Marianne J Chapman Stephanie N O'Connor, Emma J Ridley, Patricia J Williams, and

Peake, Andrew R Davies, Adam M Deane, Kylie Lange, John L Moran, TARGET Investigators and the ANZICS Clinical Trials Group, Sandra L

. Active ReviewsReviewer Area and click on , and log in to your account. Enter the http://submit.ajcn.orgview, go to

available in the Full MS Info view of the manuscript. To reach this manuscript link[Download Supplemental Files]additional materials, click on the

This paper includes additional materials for review purposes. To view

http://www.ajcn.org/site/misc/ifa.xhtmlInformation for Authors:

The American Journal of Clinical Nutrition AJCN/2014/086322 Version 1 The American Journal of Clinical Nutrition AJCN/2014/086322 Version 1

http://submit.ajcn.org

http://submit.ajcn.org

http://www.ajcn.org/site/misc/ifa.xhtml

http://www.ajcn.org/site/misc/ifa.xhtml

1

Use of a concentrated enteral nutrition solution to increase calorie delivery to critically ill patients: a randomized double-blind clinical trial

Authors

TARGET Investigators and the ANZICS Clinical Trials Group

Sandra L Peake, Andrew R Davies, Adam M Deane, Kylie Lange, John L Moran,

Stephanie N O’Connor, Emma J Ridley, Patricia J Williams and Marianne J

Chapman.

Department of Intensive Care, Queen Elizabeth Hospital, Adelaide, SA. (SLP, JLM,

PJW)

School of Medicine, University of Adelaide, Adelaide, SA (SLP)

Department of Epidemiology & Preventive Medicine, Monash University, The Alfred

Centre, Melbourne, VIC (SLP, ARD, EJR)

Intensive Care Unit, Royal Adelaide Hospital, Adelaide, SA. (AMD, SNOC MJC)

Discipline of Acute Care Medicine, University of Adelaide, Adelaide, SA (AMD,

SNOC, PJW, MJC)

Centre of Research Excellence (CRE) in Translating Nutritional Science to Good

Health, Discipline of Medicine, The University of Adelaide, Adelaide, SA. (KL)

Corresponding Author

Assoc Prof Marianne Chapman

Director of ICU Research,

Intensive Care Unit,

Royal Adelaide Hospital,

The American Journal of Clinical Nutrition AJCN/2014/086322 Version 1

2

North Terrace, Adelaide, SA 5000

AUSTRALIA

Ph: +61 8 8222 4624

Fax: +61 8 8222 2367

Email: [email protected]

Financial Support

This study was supported by the Royal Adelaide Hospital and the Australian and

New Zealand College of Anaesthetists. Provision and blinding of the study feed and

importation and delivery to the sites was provided by Fresenius Kabi (Germany).

Fresenius Kabi had no influence over the study protocol or the analysis or

interpretation of the results.

Short Running title

Increased calorie delivery to the critically ill

MeSH terms

Intensive Care, nutritional support, enteral feeding, critical illness, energy delivery,

outcome.

List of Abbreviations:

APACHE II: Acute Physiology and Chronic Health Evaluation II

ANZICS: Australia & New Zealand Intensive Care Society

BMI: Body Mass Index


3

CI: Confidence Interval

EN: Enteral Nutrition

GRV: Gastric Residual Volume

IBW: Ideal Body Weight

ICU: Intensive Care Unit

IQR: Inter Quartile Range

PN: Parenteral Nutrition

SD: Standard Deviation

SE: Standard Error

SI: Small Intestine

TARGET: The Augmented versus Routine approach to Giving Energy Trial

Trial Registration

Australian New Zealand Clinical Trials Registry number ACTRN 12611000793910

http://www.anzctr.org.au/


4

Abstract: 300 words 1

Background: Critically ill patients usually only receive about 60% of estimated 2

calorie requirements. 3

Objectives: (1) To determine if the substitution of a 1.5 kcal/ml liquid enteral 4

nutrition solution for a 1.0 kcal/ml solution resulted in greater calorie delivery to 5

critically ill patients. (2) To establish the feasibility of conducting a multicenter, 6

double-blind, randomized trial evaluating the effect of increased calorie delivery on 7

clinical outcomes. 8

Design: Prospective, randomized, double-blind, parallel-group, multicenter study. 9

Setting: Five Australian intensive care units. 10

Patients: One hundred and twelve mechanically ventilated patients expected to 11

receive enteral nutrition for at least two days. 12

Interventions: Patients were randomized to receive 1.5 (n=57) or 1.0 (n=55) kcal/ml 13

enteral nutrition solution at a rate of 1ml/kg/hour (ideal body weight) for up to 10 14

days. Protein and fiber content in the two solutions were equivalent. 15

Results: The two study groups had similar baseline characteristics (1.5 versus 1.0 16

kcal/ml): mean [SD]: 56.4[16.8] versus 56.5[16.1] years; 74% versus 75% male, 17

APACHE II score 23[9.1] versus 22[8.9]; NS). The groups received similar mean 18

volumes of enteral nutrition solution (1221[95% CI (1120, 1322)] versus 1259[95% 19

CI (1143, 1374)] ml/day; P=0.628) leading to a 46% increase in daily calories in the 20

group given the 1.5 kcal/ml solution (1832[95% CI (1681, 1984)] versus 1259[95% CI 21

(1143, 1374)] kcal/day; P<0.001). The 1.5 kcal/ml solution was not associated with 22

larger gastric residual volumes or diarrhea. In this pilot study there was a trend to 23

fewer deaths in those given 1.5 kcal/ml (11 [20%] versus 20 [37%] patients; 24

P=0.057) ninety days after enrolment. 25


5

Conclusions: Substitution of a 1.0 kcal/ml with a 1.5 kcal/ml enteral nutrition 26

solution administered at the same rate resulted in a 46% increase in calorie delivery 27

without adverse effects. These pilot data suggest that increased calorie delivery may 28

influence outcome in the critically ill and warrant further investigation.29


6

Introduction 30

The optimal calorie delivery for critically ill patients is unclear. While some authors 31

recommend matching energy delivery to expenditure (measured using calorimetry) 32

(1), this strategy has not been conclusively associated with better clinical outcomes. 33

In the absence of convincing evidence, many guidelines recommend a calorie goal 34

of 25 kcal/kg/day (2-4). There is controversy in the literature on how calorie delivery 35

influences outcomes during acute critical illness. Some authors recommend 36

intentional underfeeding (5-7), some suggest that the amount of calories delivered 37

makes no difference (8), and some propose that increasing calorie delivery can 38

improve survival (9, 10). Unfortunately, there is little robust evidence regarding 39

optimal calorie delivery for the critically ill. The few randomized studies conducted 40

have all been open label, making interpretation difficult. Finally, while the enteral 41

route is preferred, most investigators have failed to achieve caloric goals in critically 42

ill patients using enteral delivery alone (10, 11). Most studies report delivery of 43

around 50-60% of caloric goals despite measures to improve delivery; thus 44

compromising the ability to determine the relationship between enteral calorie 45

delivery and survival. 46

47

The primary aim of this study was to determine if the substitution of a 1.0 kcal/ml 48

enteral nutrition solution with a 1.5 kcal/ml solution resulted in the delivery of more 49

calories to critically ill patients over the first 10 days of their enteral nutrition therapy. 50

Secondary aims were to determine the feasibility of delivering masked enteral 51

nutrition solutions to allow blinding and to determine baseline data necessary for the 52

planning of an adequately powered randomized controlled study to investigate 53


7

whether additional enteral calorie delivery to critically ill adults affects clinically 54

important outcomes. 55

56

Subjects and Methods 57

Setting 58

This study was conducted in five, Australian university-affiliated, tertiary-referral, 59

intensive care units (ICUs). 60

61

Patients 62

Patients aged 18 years or over, undergoing invasive mechanical ventilation and 63

expected to receive enteral nutrition for at least two days, were randomized to 64

receive either a 1.5 or 1.0 kcal/ml enteral nutrition solution. Patients were excluded if 65

they had already received more than 12 hours of enteral or parenteral nutrition 66

during their ICU stay or for whom the study goal rate was contraindicated (e.g. 67

requirement for fluid restriction), or there was a requirement for a specific enteral 68

nutrition solution (as determined by the treating clinician). Eligible patients were 69

randomized in a 1:1 ratio using a permuted block method with variable block sizes, 70

stratified by site. Allocation concealment was maintained using a centralized, web-71

based randomization schedule accessible 24 hours a day. 72

73

Patients were recruited between January 23rd and May 4th 2013 and the study was 74

carried out in accordance with the Helsinki Declaration of 1975 as revised in 1983. 75

All participating institutional ethics committees approved the study and allowed 76

delayed consent to be sought from either the next-of-kin or the patient . (Australian 77

and New Zealand Clinical Trials Registry 12611000793910). 78


8

79

Study Design 80

This was a multicenter, randomized controlled, parallel group, clinical feasibility trial. 81

The patients, clinicians and all study personnel were blinded to the caloric content of 82

the study enteral nutrition solutions. 83

84

Intervention 85

The blinded enteral nutrition solutions were supplied by Fresenius Kabi in identical 86

1L bags, differing only in terms of caloric concentration (“Fresubin 2250 Complete” 87

1.5 kcal/ml versus “Fresubin 1000 Complete” 1.0 kcal/ml; Fresenius Kabi 88

Deutschland GmbH) (Appendix 2). This difference in caloric concentration was 89

shared between fat (0.058 g/ml versus 0.027 g/ml – a 114% difference) and 90

carbohydrate (0.18 g/ml versus 0.125 g/ml – a 44% difference). Protein and fiber 91

content in the study solutions were similar: 0.056 g/ml versus 0.055 g/ml and 0.015 92

g/ml versus 0.02 g/ml for the 1.5 and 1.0 kcal/ml solutions respectively. The two 93

study interventions were clinically indistinguishable in color and packaging. The 94

effectiveness of the blind was confirmed in a formal study. In addition, to confirm 95

successful delivery of allocated enteral nutrition solutions, independent analysis of 96

the osmolality of the 1.5 kcal/ml (430 mOsm/kg H2O) and 1.0 kcal/ml (360 mOsm/kg 97

H2O) solutions was obtained for a random sample of 261 study bags using freezing 98

point depression osmometry. 99

100

Study enteral nutrition was delivered at a goal rate of 1 ml/kg ideal body weight 101

(IBW) per hour in both groups. IBW was calculated from measured height as: IBW 102

men = (height (in cm) – 152.4) x 0.9 + 50; IBW women = (height (in cm) – 152.4) x 103


9

0.9 + 45.5 (8). Patients received study enteral nutrition for the duration of their ICU 104

stay up to a maximum of 10 days, unless enteral nutrition was ceased earlier. To 105

reduce the risk of potential over-nutrition (3, 4, 12), the maximum goal rate was 100 106

ml/h for all patients; and at the discretion of treating clinicians, study enteral nutrition 107

could be ceased if the goal rate was achieved for 5 consecutive days. Patients for 108

whom consent to continue the study intervention was withdrawn were analyzed 109

according to the intention-to-treat principle, unless consent for data collection was 110

refused. 111

112

Other than goal rate, the duration and method of enteral nutrition delivery was at the 113

discretion of the treating clinician according to the usual unit nutrition protocols, 114

including commencement rate, increments, the use of promotility drugs and small 115

intestinal feeding tubes. It was recommended that goal rate be achieved within 48 116

hours of the commencement of enteral nutrition. If supplemental parenteral nutrition 117

was deemed necessary (e.g. enteral nutrition intolerance), it was assumed that 118

patients were receiving a 1.25 kcal/ml enteral nutrition solution in order to calculate 119

total calorie delivery and to determine the amount of parenteral nutrition to 120

administer. Stool samples were obtained from all patients with diarrhea during the 121

intervention period and screened for infectious causes and Clostridium difficile toxin. 122

Diarrhea was defined as 4 or more loose bowel actions within a 24-hour period or 123

the use of a fecal management system for diarrhea control. 124


10

125

Blood glucose management was standardized, aiming for a blood glucose level less 126

than or equal to 10 mmol/L. Blood glucose levels less than or equal to 2.2 mmol/L 127

were defined as a serious adverse event. 128

129

Data collection 130

Baseline data included: patient demographics (age, sex, ideal and actual weight); 131

ICU admission diagnosis, category (elective or emergency surgical, medical) and 132

Acute Physiology and Chronic Health Evaluation (APACHE) II score; chronic co-133

morbidities (including diabetes mellitus); and dietitian assessment of nutritional 134

requirements. Data were collected daily for up to 14 days post-randomization for: 135

study enteral nutrition and non-study nutrition administration (parenteral nutrition, 136

incidental calories e.g. 50% dextrose, propofol); intolerance to enteral nutrition 137

(gastric residual volumes, diarrhea, promotility agents), highest and lowest blood 138

glucose concentrations and insulin administration. 139

140

Outcomes 141

The primary outcome was daily calorie delivery (kcal/day) from study enteral 142

nutrition. Secondary outcomes were: 1) daily total calorie delivery from enteral 143

nutrition, parenteral nutrition and incidental calories; 2) daily enteral and total calorie 144

delivery calculated per unit of ideal body weight (kcal/kg/day); 3) ICU and hospital 145

length of stay; 4) ventilator-free days (defined as the number of days between 146

successful weaning from mechanical ventilation and day 28 after study enrolment in 147

patients who survive to 28 days) and; 5) ICU, hospital and 28- and 90-day mortality. 148

149


11

Statistical analysis 150

The sample size of 112 patients for the feasibility trial was based on data from 151

previous studies by our group and from other nutrition studies conducted in Australia 152

and New Zealand (13). Assuming a mean (standard deviation) daily calorie delivery 153

with enteral nutrition of 1300 (400) kcal/day in the 1.0 kcal/ml (usual treatment) group 154

and expecting at least a 20% increase in calorie delivery with the higher 155

concentration 1.5 kcal/ml solution, using a 2-groups t-test at 5% significance and 156

80% power, the estimated minimum required sample size was 38 per group (i.e. 76 157

in total). To allow for more reliable estimates of recruitment rate and baseline 158

mortality and to compensate for some recruited patients receiving less than the 159

anticipated two days of enteral nutrition, 112 patients (56 per group) were enrolled. 160

161

All analyses were conducted according to the intention-to-treat principle. No stopping 162

rules or interim analyses were planned. For missing data, the number of available 163

observations is reported and missing values were not imputed. Continuous variables 164

are reported as mean (standard deviation) or median (interquartile range). 165

Proportions are reported as percentages with 95% confidence intervals (CI). 166

Differences between groups were analyzed, as appropriate, using Student’s t-test or 167

Mann-Whitney U tests for continuous variables and Pearson chi-square or Fisher’s 168

exact test for categorical variables. Overall calorie delivery was calculated as total 169

intake divided by the number of days fed and expressed as intake per 24 hours. 170

Daily intakes were analyzed in linear mixed effects models with fixed effects for 171

group, day and the group by day interaction, with a heterogeneous first-order 172

autoregressive covariance structure for repeated measurements. 173

174


12

Ventilator-free days to day 28 were calculated as previously described (14). Patients 175

who died prior to day 28 were assigned zero ventilator-free days. Absolute risk 176

differences with 95% CI for 90-day all-cause mortality are reported. Survival time 177

from randomization to Day 90 was compared using Kaplan-Meier analysis and the 178

log-rank test. Length of stay was analyzed using log rank tests with deaths 179

considered a competing event that precluded discharge. Deaths were censored at 180

values after the last observed discharge for ICU and hospital stay. 181

182

Statistical analyses were performed with IBM SPSS Statistics version 20 (IBM Inc; 183

2011). Statistical significance was defined as a P value <0.05. 184

185

Results 186

Study patients 187

Of 415 patients assessed for eligibility, 112 were enrolled and randomized to receive 188

1.5 kcal/ml (57 patients) or 1.0 kcal/ml (55 patients) enteral nutrition solution (Figure 189

1). All patients were assessed for the primary outcome. One patient in the 1.5 190

kcal/ml group requested to be withdrawn from the study on day 4 and one patient in 191

the 1.0 kcal/ml group was lost to follow-up by day 90. 192

193

Baseline characteristics 194

The mean age was 56.4(16.4) years and the majority were male (74%) with an 195

APACHE II score of 23(9.0). Seventy one percent had a medical and 14% an 196

emergency surgical condition. No differences in baseline characteristics were 197

observed between the two groups (Table 1). The time from ICU admission to 198

randomization was not different (21 hours for both). A dietitian assessment of calorie 199


13

requirements was performed on 88 (79%) patients, most commonly using a fixed 200

prescription of 20-25kcal/kg in 43 patients (48%) or the Schofield equation (with or 201

without a stress factor) in 40 patients (45%). The dietitian-estimated daily calorie 202

requirements for the 1.5 kcal/ml and 1.0 kcal/ml groups were 1909(312) and 203

1840(318) kcal/day (P=0.306). 204

205

Primary outcome 206

The number of days study enteral nutrition was delivered over the 10-day 207

intervention period was 7(4-9) and 4(3-9) for the 1.5 and 1.0 kcal/ml groups 208

respectively (P=0.245). On day 10, 15 (27%) and 14 (25%) patients were still 209

receiving study enteral nutrition in the 1.5 and 1.0 kcal/ml groups respectively. 210

Between days 11 and 14, 33 patients continued to receive enteral nutrition: 17 211

patients (30%) in the 1.5 kcal/ml group; 16 patients (29%) in the 1.0 kcal/ml group. 212

213

The daily volume of study enteral nutrition delivered in the two groups was similar: 214

(1.5 kcal/ml,1221 [95% CI (1120, 1322)] ml versus 1.0 kcal/ml, 1259 [95% CI (1143, 215

1374)] ml; P=0.628) (Table 2). Overall, there were a total of 364 feeding days in the 216

1.5 kcal/ml group and daily goal rate (based on 1 ml/kgIBW/hr) was achieved on 136 217

days (37%). In the 1.0 kcal/ml group, there were a total of 311 feeding days and daily 218

goal rate was achieved on 137 days (44%). The number of patients achieving goal 219

rate on one or more days was 45 (82%) and 47 (85%) in the 1.5 and 1.0 kcal/ml 220

groups respectively. The time to achieving goal rate was the same for both groups, 2 221

(1-3) days. Reasons for not achieving the goal rate on any day were similar between 222

the 2 groups, and included planned endotracheal extubation or procedure outside 223


14

the ICU (63%), vomiting or regurgitation (22%), large gastric residual volumes (26%) 224

and enteral tube removal or blockage (16%). 225

226

Administration of the 1.5 kcal/ml enteral nutrition formula resulted in a 46% increase 227

in daily calorie delivery (1832 [95% CI (1681, 1984)] kcal versus 1259 [95% CI 228

(1143, 1374)] kcal; P<0.001) (Figure 2). The proportion of estimated daily calorie 229

requirements (based on the dietitian’s assessment) delivered by the study enteral 230

nutrition was 102% and 72% for the 1.5 and 1.0 kcal/ml groups respectively 231

(P<0.001). The number of patients achieving their estimated daily caloric 232

requirements on one or more study feeding days was 40 (89%) and 7 (16%) for the 233

1.5 and 1.0 kcal/ml groups (Figure 3). Protein delivery was the same for both groups 234

(Table 2); 75% of that estimated by the dietitian in the 1.5 kcal/ml group and 79% of 235

estimated in the 1.0 kcal/ml group. 236

237

Independent analysis of the osmolality of a random sample of study bags confirmed 238

delivery of the allocated solutions (1.5kcal/ml [n=147]; 496[488-507] mOsm/kg H2O 239

vs. 1.0 kcal/ml [n=114]; 383[377-388] mOsm/kg H2O; P<0.001). 240

241

Secondary outcomes 242

Enteral nutrition calories delivered per kilogram of ideal body weight was 243

substantially greater in the group given 1.5 kcal/ml compared to those receiving 244

1.0kcal/ml; (27.3[7.4] kcal/kg/day versus 19.0[6.0] kcal/kg/day; P<0.001) (Table 2). 245

Total daily calorie delivery from study, parenteral nutrition and other calorie sources 246

combined was also higher for the 1.5 kcal/ml group (P<0.001). 247

248


15

At 90 days, 11 patients (20%) in the 1.5 kcal/ml and 20 patients (37%) in the 1.0 249

kcal/ml group had died (P=0.057) (Table 3). The absolute risk reduction in mortality 250

for the 1.5 kcal group as compared to the 1.0 kcal/ml group was 17% (95% CI 0.6-251

33%). The survival time from randomization to day 90 tended to be longer in patients 252

receiving 1.5kcal/ml formula (P=0.057) (Figure 4) and there was no difference in the 253

proximate cause of death (P=0.882) (Table 3). ICU, hospital and 28-day mortality 254

were not different between the two treatment groups. One patient in the 1.5 kcal/ml 255

group and 6 patients in the 1.0 kcal/ml group died after hospital discharge. The 256

number of mechanical ventilation-free days to day 28, ICU and hospital length of 257

stay (for survivors only) and destination at hospital discharge were also not different 258

(Table 3). 259

260

Complications of therapy 261

Enteral nutrition was never ceased because of treating clinician concerns of over-262

nutrition. Supplemental parenteral nutrition was administered to 4 patients (1.5 263

kcal/ml, 2; 1.0 kcal/ml, 2). There was no difference between the groups in terms of 264

gastrointestinal intolerance (large gastric residual volumes, use of promotility or 265

laxative agents, diarrhea) (Table 2). Two of 40 patients with diarrhea had Clostridium 266

difficile toxin detected. The increased calorie delivery in the 1.5 kcal/ml group was 267

associated with a trend to a slightly higher peak blood glucose concentration over 268

the 10-day study period (1.5 kcal/ml; 12.4[3.9] versus 1.0 kcal/ml; 12.0[3.9] mmol/L; 269

P=0.056); but the number of patients requiring insulin on one or more days was no 270

greater in the 1.5 kcal/ml group (1.5 kcal/ml; 54% versus1.0 kcal/ml; 42%; P=0.183). 271

No episodes of hypoglycemia (≤ 2.2 mmol/L) were reported. 272

273


16

Discussion 274

In this multicenter, randomized, double-blind study, the administration of a 1.5 275

kcal/ml enteral nutrition formula resulted in a near 50% increase in calorie delivery 276

compared to a 1.0 kcal/ml formula in mechanically ventilated patients. This is the first 277

study to our knowledge in this patient population to describe the use of a 278

concentrated enteral nutrition formula to deliver more calories to patients in a double-279

blind fashion. Furthermore, in this feasibility study the inclusion criteria have 280

successfully identified a cohort of critically ill patients whose outcome may be 281

improved by increased calorie delivery (i.e. longer stay, mechanically ventilated 282

patients with a 90 day mortality of around 28%). 283

284

Previous studies designed to deliver more calories to critically ill patients have used 285

techniques including nutrition protocols (13, 15-17) and small intestinal feeding 286

catheters (18-20). Both these strategies have had small effects on calorie delivery. 287

The administration of promotility drugs and/or supplemental parenteral nutrition have 288

resulted in greater calorie delivery, but it is unclear if this offers advantages in terms 289

of clinically-meaningful outcomes (7, 10, 21, 22). It is also possible that potential 290

benefits from increased calorie delivery may be outweighed by adverse effects from 291

the method used. In the EDEN study, a difference in enteral calorie delivery was 292

achieved, but in the ‘full feeding’ group only around 1300 kcal/day were delivered, a 293

similar amount of calories as was given to our 1.0 kcal/ml (standard care) group 294

(1259 kcal/day or 19.0 kcal/kg/day) (8). In contrast, we have demonstrated that over 295

1800 kcal/day (27 kcal/kgIBW/day) was delivered to a heterogeneous population of 296

critically ill patients using a 1.5 kcal/ml enteral nutrition solution. While the results 297

from the EDEN study suggested there was no difference in clinical outcomes when 298


17

comparing the administration of 1300 versus 400 kcal/day for the first week of ICU 299

nutrition therapy, it remains a plausible hypothesis that the delivery of 1800 kcal/day 300

(being closer to the expected requirements) could be associated with improved 301

clinical outcomes. 302

303

The use of concentrated enteral nutrition solutions has become popular in recent 304

years in ICU patients (23). Concentrated solutions may be prescribed when a patient 305

is intolerant to enteral nutrition on the assumption that delivery of a lower volume, 306

greater caloric content solutions may be better tolerated to allow increased calorie 307

delivery (23). This premise has never been proven. Conversely, it is possible that 308

concentrated enteral nutrition solutions may be less well tolerated due to the 309

concentrated formula being emptied more slowly from the stomach into the small 310

intestine, leading to increased gastric residual volumes (24). There have also been 311

concerns that concentrated enteral nutrition solutions may be associated with 312

increased osmotic diarrhea (25) although studies have refuted this (26). The effects 313

of concentrated enteral nutrition solutions on clinical outcomes, including mortality, 314

has also been questioned in an observational study of critically ill trauma and 315

surgical patients (22). This current study has demonstrated that the use of a 316

concentrated solution is both safe and effective in delivering more calories. There 317

was no increase in either gastric residual volumes or diarrhea and there was also a 318

suggestion of improved survival at 90-days (although the study was not powered to 319

detect this). 320

321

This study is the first enteral nutrition study looking at the effect of calorie delivery on 322

outcome to successfully blind the study intervention, thus eliminating a potential 323


18

source of bias associated with other enteral nutrition studies in this patient population 324

(6, 8). Concealment of the intervention is important to prevent inadvertent bias (27). 325

In previous studies, blinding of the intervention has not been undertaken which 326

raises concerns about reported differences in outcomes particularly when outcomes 327

are subject to ascertainment bias (e.g. nosocomial infections, functional outcomes) 328

(1, 10, 21). We were able to overcome the substantial logistical problems of 329

designing a double-blind enteral nutrition study by using two commercially-available 330

enteral nutrition solutions which were similar in color, indistinguishable at the bedside 331

and delivered at the same flow rate and volume to both study groups. 332

333

This feasibility study has several limitations. It was not powered to demonstrate an 334

effect on survival. Nevertheless it is of interest to note that less deaths after hospital 335

discharge contributed to a perceived improvement in survival at 90 days in the group 336

receiving more calories. It is possible, given the small sample size, that there was an 337

undetected baseline imbalance which may have resulted in an apparent strong trend 338

for improved survival in patients given more calories. On the other hand, if calorie 339

delivery affects outcomes, it is likely to be late, possibly after ICU discharge. Our 340

findings suggest that the effects of nutritional interventions on post-ICU discharge 341

mortality should be rigorously sought. A further limitation of our study is that we did 342

not assess functional outcomes. Functional outcomes are likely to be important in 343

studies of calorie delivery. There was no difference between the two groups in 344

destination after hospital discharge which could possibly be considered a crude 345

measure of functional outcome. The ARDSnet group looked at functional outcomes 346

in a subset of patients enrolled in the EDEN study and determined that there was no 347

benefit in the administration of 1300 compared to 400kcal/day on functional 348


19

outcomes out to 12 months; but as only 174 patients were included in this analysis 349

this sub-study may have been underpowered to show an effect (28). Future studies 350

investigating the effect of nutrition in this population should also include functional 351

outcomes. 352

353

Finally it is important to emphasize that in this study the aim was to isolate the likely 354

differing effects of calorie and protein delivery. Hence protein delivery in terms of 355

gm/kg/day was standardized in the two groups. The optimal dose of protein 356

administration in critical illness is unclear. The patients in this study received around 357

1gm/kg/day. The difference in calorie delivery in this study reflects a difference in 358

carbohydrate and lipid concentrations in the two formulae. The effect of 359

macronutrient composition on clinical outcomes is an area that needs further 360

attention. 361

362

Conclusions 363

Substitution of a standard 1.0 kcal/ml enteral nutrition solution with a concentrated 364

1.5 kcal/ml solution, administered at the same rate, resulted in an almost 50% 365

increase in calorie delivery. The delivery of more calories was achieved in a blinded 366

fashion and was also associated with a trend to improved survival. These data 367

support the conduct of a large, multicenter, randomized, double-blind trial to 368

determine whether the delivery of more calories using a concentrated enteral 369

nutrition solution can result in improved survival and functional outcomes for critically 370

ill patients. 371

372

373


20

Acknowledgements 374

The authors have no conflict of interest to disclose. All authors who contributed to 375

the manuscript are listed in Appendix 1. The authors are grateful for the assistance 376

provided by Ms Donna Goldsmith for unblinded management of the study formulae 377

distribution.378


21

References

1. Singer P, Anbar R, Cohen J, Shapiro H, Shalita-Chesner M, Lev S, Grozovski E, Theilla M, Frishman S, Madar Z. The tight calorie control study (TICACOS): a prospective, randomized, controlled pilot study of nutritional support in critically ill patients. Intensive care medicine 2011;37(4):601-9.

2. Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, Griffiths R, Kreyman G, Leverve X, Pichard C, et al. ESPEN Guidelines on Parenteral Nutrition: intensive care. Clin Nutr 2009;28(4):387-400.

3. Kreymann KG, Berger MM, Deutz NE, Hiesmayr M, Jolliet P, Kazandjiev G, Nitenberg G, van den Berghe G, Wernerman J, Ebner C, et al. ESPEN Guidelines on Enteral Nutrition: Intensive care. Clin Nutr 2006;25(2):210-23.

4. Martindale RG, McClave SA, Vanek VW, McCarthy M, Roberts P, Taylor B, Ochoa JB, Napolitano L, Cresci G. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: Executive Summary. Crit Care Med 2009;37(5):1757-61. doi: 10.1097/CCM.0b013e3181a4011600003246-200905000-00031 [pii].

5. Krishnan JA, Parce PB, Martinez A, Diette GB, Brower RG. Caloric intake in medical ICU patients: consistency of care with guidelines and relationship to clinical outcomes. Chest 2003;124(1):297-305.

6. Arabi YM, Tamim HM, Dhar GS, Al-Dawood A, Al-Sultan M, Sakkijha MH, Kahoul SH, Brits R. Permissive underfeeding and intensive insulin therapy in critically ill patients: a randomized controlled trial. Am J Clin Nutr 2011;93(3):569-77.

7. Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, et al. Early versus late parenteral nutrition in critically ill adults. The New England journal of medicine 2011;365(6):506-17.

8. Rice TW, Wheeler AP, Thompson BT, Steingrub J, Hite RD, Moss M, Morris A, Dong N, Rock P. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 2012;307(8):795-803.

9. Alberda C, Gramlich L, Jones N, Jeejeebhoy K, Day AG, Dhaliwal R, Heyland DK. The relationship between nutritional intake and clinical outcomes in critically ill patients: results of an international multicenter observational study. Intensive care medicine 2009;35(10):1728-37.

10. Heidegger CP, Berger MM, Graf S, Zingg W, Darmon P, Costanza MC, Thibault R, Pichard C. Optimisation of energy provision with supplemental parenteral nutrition in critically ill patients: a randomised controlled clinical trial. Lancet 2013;381(9864):385-93. doi: 10.1016/S0140-6736(12)61351-8S0140-6736(12)61351-8 [pii].

11. De Beaux I, Chapman M, Fraser R, Finnis M, De Keulenaer B, Liberalli D, Satanek M. Enteral nutrition in the critically ill: a prospective survey in an Australian intensive care unit. Anaesth Intensive Care 2001;29(6):619-22.

12. Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr 2003;27(5):355-73.

13. Doig GS, Simpson F, Finfer S, Delaney A, Davies AR, Mitchell I, Dobb G. Effect of evidence-based feeding guidelines on mortality of critically ill adults: a cluster randomized controlled trial. JAMA 2008;300(23):2731-41.

14. Schoenfeld DA, Bernard GR. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med 2002;30(8):1772-7.


22

15. Martin CM, Doig GS, Heyland DK, Morrison T, Sibbald WJ. Multicentre, cluster-randomized clinical trial of algorithms for critical-care enteral and parenteral therapy (ACCEPT). Cmaj 2004;170(2):197-204.

16. Heyland DK, Cahill NE, Dhaliwal R, Wang M, Day AG, Alenzi A, Aris F, Muscedere J, Drover JW, McClave SA. Enhanced protein-energy provision via the enteral route in critically ill patients: a single center feasibility trial of the PEP uP protocol. Crit Care 2010;14(2):R78. doi: 10.1186/cc8991cc8991 [pii].

17. Heyland DK, Murch L, Cahill N, McCall M, Muscedere J, Stelfox HT, Bray T, Tanguay T, Jiang X, Day AG. Enhanced protein-energy provision via the enteral route feeding protocol in critically ill patients: results of a cluster randomized trial. Crit Care Med 2013;41(12):2743-53. doi: 10.1097/CCM.0b013e31829efef5.

18. White H, Sosnowski K, Tran K, Reeves A, Jones M. A randomised controlled comparison of early post-pyloric versus early gastric feeding to meet nutritional targets in ventilated intensive care patients. Crit Care 2009;13(6):R187.

19. Davies AR, Morrison SS, Bailey MJ, Bellomo R, Cooper DJ, Doig GS, Finfer SR, Heyland DK. A multicenter, randomized controlled trial comparing early nasojejunal with nasogastric nutrition in critical illness. Crit Care Med 2012;40(8):2342-8.

20. Deane AM, Dhaliwal R, Day AG, Ridley EJ, Davies AR, Heyland DK. Comparisons between intragastric and small intestinal delivery of enteral nutrition in the critically ill: a systematic review and meta-analysis. Crit Care 2013;17(3):R125. doi: cc12800 [pii]10.1186/cc12800.

21. Doig GS, Simpson F, Sweetman EA, Finfer SR, Cooper DJ, Heighes PT, Davies AR, O'Leary M, Solano T, Peake S. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA 2013;309(20):2130-8. doi: 10.1001/jama.2013.51241689534 [pii].

22. Nguyen NQ, Chapman M, Fraser RJ, Bryant LK, Burgstad C, Holloway RH. Prokinetic therapy for feed intolerance in critical illness: One drug or two? Crit Care Med 2007.

23. Peake SL, Chapman MJ, Davies AR, Moran JL, O'Connor S, Ridley E, Williams P. Enteral nutrition in Australian and New Zealand intensive care units: a point-prevalence study of prescription practices. Crit Care Resusc 2012;14(2):148-53.

24. Chapman M, Fraser R, Vozzo R, Bryant L, Tam W, Nguyen N, Zacharakis B, Butler R, Davidson G, Horowitz M. Antro-pyloro-duodenal motor responses to gastric and duodenal nutrient in critically ill patients. Gut 2005;54(10):1384-90.

25. Montejo JC. Enteral nutrition-related gastrointestinal complications in critically ill patients: a multicenter study. The Nutritional and Metabolic Working Group of the Spanish Society of Intensive Care Medicine and Coronary Units. Crit Care Med 1999;27(8):1447-53.

26. Edes TE, Walk BE, Austin JL. Diarrhea in tube-fed patients: feeding formula not necessarily the cause. Am J Med 1990;88(2):91-3. doi: 0002-9343(90)90454-L [pii].

27. Crossley NA, Sena E, Goehler J, Horn J, van der Worp B, Bath PM, Macleod M, Dirnagl U. Empirical evidence of bias in the design of experimental stroke studies: a metaepidemiologic approach. Stroke 2008;39(3):929-34. doi: 10.1161/STROKEAHA.107.498725STROKEAHA.107.498725 [pii].

28. Needham DM, Dinglas VD, Morris PE, Jackson JC, Hough CL, Mendez-Tellez PA, Wozniak AW, Colantuoni E, Ely EW, Rice TW, et al. Physical and Cognitive Performance of Patients with Acute Lung Injury 1 Year after Initial Trophic versus Full Enteral Feeding. EDEN Trial Follow-up. Am J Respir Crit Care Med 2013;188(5):567-76. doi: 10.1164/rccm.201304-0651OC.


23

Table 1. Baseline characteristics of the study patients

Variable

1.5

kcal/ml

(n=57)

1.0

kcal/ml

(n=55)

p

value

Age (years) 56.4 (16.8) 56.5 (16.1) 0.964

Sex (male), n (%) 42 (74) 41 (75) 0.917

APACHE II score 23 (9.1) 22 (8.9) 0.560

APACHE III diagnostic code, n (%)

Cardiovascular 12 (21) 8 (15)

0.442

Respiratory 9 (16) 12 (22)

Gastro-intestinal 4 (7) 3 (6)

Neurological 8 (14) 15 (27)

Sepsis 7 (12) 4 (7)

Trauma 11 (19) 6 (11)

Other 6 (11) 7 (13)

ICU admission category, n (%)

Emergency operative 11 (19) 5 (9)

0.095 Emergency non-operative 35 (61) 44 (80)

Elective operative 11 (19) 6 (11)

Past medical history diabetes mellitus, n (%) 13 (23) 13 (24) 0.917

BMI (kg/m2) 27.8 (7.9) 26.2 (6.4) 0.241

Actual weight (kg)* 83 (23.2) 77 (16.4) 0.118

IBW (kg)# 67 (9.2) 67 (9.1) 0.675

Energy requirements (kcal/day)& 1909 (312) 1840 (318) 0.306


24

Data are mean and standard deviation (in parentheses) unless otherwise stated.

* Actual weight was measured or estimated if not possible.

# IBW was calculated using measured height and the following formulae: IBW for men = (height (cm) – 152.4) x 0.9 + 50; IBW for women = (height (cm) – 152.4) x 0.9 + 45.5).

& Energy and protein requirements were estimated by the dietitians at the site at study entry.

kcal: kilocalorie; ml: milliliter; n: number; BMI: body mass index; kg: kilogram; m: meter; IBW: ideal body weight; ICU: intensive care unit; IQR: interquartile range; SI: small intestinal; cm: centimeter.

Protein requirements (gram/day)& 91 (16) 87 (12) 0.178

Time from ICU admission to randomization

(hrs), median (IQR) 21 (13-36) 21 (13-41) 0.836

SI tube, n (%) 4 (7) 1 (2) 0.364


25

Table 2. Nutrition data

Variable

1.5

kcal/ml

(n=57)

1.0

kcal/ml

(n=55) p value

Calories Overall, per 24 hours of

study period

Study EN (kcal) 1832

(381)

1259

(428) < 0.001

Study EN/kg (kcal/kg) 27.3 (7.4) 19.0 (6.0) < 0.001

Study EN minus GRV (kcal) 1699 (682)

1194

(454) <0.001

(EN + PN + other) (kcal) 2040 (578)

1504

(573) < 0.001

(EN + PN + other) minus GRV (kcal) 1617 (740)

1291

(623) 0.014

Protein Overall, per 24 hours of

study period

Study EN (g) 68 (21) 69 (24) 0.847

Study EN/kg (g/kg) 1.02

(0.28)

1.05 (0.33)

0.618

(EN + PN + other) (g) 70 (20) 74 (30) 0.395

Volume Overall, per 24 hours of

study period

Study EN (ml) 1221 1259 0.628


26

Data are mean and standard deviation (in parentheses) unless otherwise stated.

“other” refers to incidental calorie intake provided by propofol and dextrose infusions

kcal: kilocalorie; ml: milliliter; n: number; kg: kilogram; GRV: gastric residual volume; EN: enteral nutrition; PN: parenteral nutrition; g: gram; ml: milliliter; IQR: interquartile range; UI: international units; mmol: millimole; l:litre”

(381) (428)

Gastric residual

volume (ml), median (IQR)

Total volume, per 24 hours 166 (48-324)

80 (37-261)

0.260

Returned, per 24 hours 126 (41-262)

70 (29-145)

0.050

Largest individual measurement 200 (50-360)

105 (40-278)

0.129

Regurgitation (over study period), n (%) 12 (21) 13 (24) 0.743

Promotility drugs (over study period), n (%) 28 (49) 25 (46) 0.697

Laxative drugs (over study period), n (%) 36 (63) 29 (53) 0.263

Fecal management system, n (%)

(over study period)

8 (14) 13 (24) 0.193

Diarrhea, n(%) 20 (35) 20 (36) 0.888

Day first had diarrhea, median (IQR) 5 (3-8) 4 (2-6) 0.369

Insulin dose, mean dose/day (UI), median (IQR)

55 (22-131)

43 (24-67) 0.308

Blood glucose level ≤2.2 mmol/l, n (%)

0 (0) 0 (0)


27

Table 3. Clinical outcome data

Variable

1.5 kcal/ml

(n=57)

1.0 kcal/ml

(n=55) p value

Number of ventilator-free days to day

28, median (IQR)

21.1

(3.4-25.0)

18.7

(0-25.6) 0.638

Duration of ICU stay (days), median

(IQR)

9.6

(5.9-22.6)

11.8

(6.9-22.8) 0.408

Duration of hospital stay (days), median

(IQR)

34.5

(16.9-83.6)

30.6 (15.2-

undefined) 0.700

Destination at hospital discharge, n

(%)

Home 21 (48) 19 (50)

0.953 Rehabilitation facility 10 (23) 7 (18)

Another acute care hospital 9 (21) 9 (24)

Chronic care facility 4 (9) 3 (8)

Mortality

ICU mortality, n (%) 6 (11) 9 (16) 0.419

Hospital mortality, n (%) 10 (19) 14 (27) 0.357

28-day mortality, n (%) 11 (20) 18 (33) 0.135

90-day mortality, n (%) 11 (20) 20 (37) 0.057

Duration of survival (days), mean (SE) 77 (4.5) 68 (5.6) 0.057

Proximate cause of death, n (%)

Cardiovascular 4 (36) 6 (30) 0.882

Respiratory 2 (18) 6 (30)


28

Neurological 4 (36) 7 (35)

Other 1 (9) 1 (5)

The interquartile range is undefined when more than 25% of patients died or were

not discharged from the primary hospital.

kcal: kilocalorie; ml: milliliter; n: number; IQR: interquartile range; ICU: intensive care

unit; SE: standard error.


29

Figure Legends

Figure 1. Patient Flow Diagram

Number of patients enrolled in the study, randomly assigned to 1.5kcal/ml or

1.0kcal/ml enteral nutrition solution and included in the final analysis.

EN: enteral nutrition; PN: parenteral nutrition; kcal: kilocalorie; ml: milliliter.

*1. n=1 lost to follow-up excluded from secondary outcome analysis: 90 day

mortality.

*2. n=1 withdrawal of consent study day 4. (Included in intention-to-treat analysis of

primary endpoint but data not available beyond study day 4 for secondary

outcomes.)

Figure 2. Daily calorie delivery over the 10-day study intervention period

Figure 2A. Calories provided by study enteral solution (kcal), mean (SD)

Figure 2B. Calories per kilogram ideal body weight provided by study enteral solution (kcal/kg), mean (SD)

Figure 2C. Calories provided by study enteral solution (kcal) minus gastric residual volume (kcal), mean (SD)

Figure 2D. Total calories provided by study enteral solution (kcal) plus intravenous nutrition, propofol and glucose infusions (kcal), mean (SD)

Kcal: kilocalorie; ml: milliliter; kg: kilogram; SD: standard deviation.

Figure 3. Estimated goal calories* delivered per day from the 1.5 and 1.0 kcal/ml enteral nutrition solutions

Kcal: kilocalorie; ml: milliliter; SD: standard deviation.

*estimated daily caloric requirements based on the dietitian’s assessment at study entry (available in 88 patients [79%])


30

Figure 4. Kaplan-Meier estimates of survival time to day 90

Kcal: kilocalorie; ml: milliliter;


31

Appendix 1.

Writing Committee

Co-Chairs – Marianne J Chapman, Sandra L Peake

Members – Andrew R Davies, Adam M Deane, Kylie Lange, John L Moran,

Stephanie N O’Connor, Emma J Ridley, Patricia J Williams

Department of Intensive Care, Royal Adelaide Hospital, Adelaide, SA. (MJC, AMD,

SNOC)

Department of Intensive Care, Queen Elizabeth Hospital, Adelaide, SA. (SLP, JLM,

PJW)

Department of Intensive Care, The Alfred Hospital, Melbourne, VIC (ARD, EJR)

Discipline of Medicine, The University of Adelaide, Adelaide, SA. (KL)

Management Committee members (alphabetical order)

Co-chairs: Marianne J Chapman, Sandra L Peake

Committee members: Andrew R Davies, Adam M Deane, Stephanie N O’Connor,

Emma J Ridley, Patricia J Williams

Participating site investigators: Austin Health; Rinaldo Bellomo, Leah Peck,

Helen Young; Royal Adelaide Hospital, Stephanie N O’Connor, Justine A Rivett,

Sonya L Kloeden, Royal Prince Alfred Hospital; Suzie Ferrie, Heidi Buhr, Megan

Keir; The Canberra Hospital; Sumeet S Rai, Helen Rodgers, Louise Herlihy; The

Queen Elizabeth Hospital; Sandra L Peake, Joanne McIntyre, Jennie Phillips-

Hughes.

Appendix 2. Study enteral nutrition product information


32

1.0kcal/ml enteral nutrition solution (“Fresubin 1000 Complete Tube Feed”)

1.5kcal/ml Enteral Nutrition Solution (“Fresubin 2250 Complete Tube Feed”)


33


Screened

(n=415)

Excluded (n=303)

Not meeting inclusion criteria (n=141)

EN or PN >12 hours already (n=115)

Specific nutrition therapy (n=27)

Study goal rate contraindicated (n=19)

Previously enrolled (n=3)

Other reasons (n=15)

o Not expected to survive

o Study EN unavailable

o Refused consent

Primary outcome analysed (n=55)

1.0 kcal/ml solution

(n=55)

1.5 kcal/ml solution

(n=57)

Primary outcome analysed (n=57)

Secondary outcomes analysed

(n=54) *1

Secondary outcomes analysed

(n=56) *2

Randomized

(n=112)


0

500

1000

1500

2500

3000

2000

Study Day

Cal

ori

es p

er D

ay

0 1 2 3 4 5 6 7 8 9 10

Study Day

Cal

ori

es p

er D

ay

0 1 2 3 4 5 6 7 8 9 10

Study Day

Cal

ori

es p

er D

ay

0 1 2 3 4 5 6 7 8 9 1005

10

15

20

3035

40

25

Study Day

Cal

ori

es/k

g/d

ay

1.0 Kcal/ml 1.5 Kcal/mlA B

C D

0

500

1000

1500

2500

3000

2000

0

500

1000

1500

2500

3000

2000

0 1 2 3 4 5 6 7 8 9 10

No. of patients1.0 kcal/ml1.5 kcal/ml

5557

5155

4450

3644

2837

2636

2331

2025

1719

1415

No. of patients1.0 kcal/ml1.5 kcal/ml

5557

5155

4450

3644

2837

2636

2331

2025

1719

1415


Group

1.5 kcal/ml1.0 kcal/ml

140

120

100

80

60

40

20

01 2 3 4 5 6 7 8 9 10

Study Day

%


Group

1.5 kcal/ml1.0 kcal/ml

0.8

0.6

0.4

0.2

0.0

1.0

CummulativeSurvival

Duration of survival (days)

0 10 20 30 40 50 60 70 80 90


use of a concentrated enteral nutrition solution to increase calorie delivery to critically ill...

Documents