Early enteral supplementation with key pharmaconutrients ... · tion enteral supplement Intestamin (Fre-senius Kabi, Bad Homburg, Germany). Another important consideration is the

Early enteral supplementation with key pharmaconutrientsimproves Sequential Organ Failure Assessment score in criticallyill patients with sepsis: Outcome of a randomized, controlled,double-blind trial*

Richard J. Beale, MB, BS; Tony Sherry, RN; Katie Lei, RN, MSc; Laura Campbell-Stephen, RN;Julie McCook, RN, MSc; John Smith, RN; Werner Venetz, PhD; Birgit Alteheld, PhD; Peter Stehle, PhD;Heinz Schneider, PhD

Nutritional support is vital forcritically ill patients, and im-portant developments in-clude early enteral nutrition,

immunonutrition, postpyloric feeding,and an increasingly scientific, evidence-based approach. However, there are stillmany unanswered questions, and new in-

sights about specific nutrients or nutri-ent combinations are tantalizing ratherthan definite. Clinical trials of enteral nu-trition in the critically ill are difficult,given the size of trial necessary to mini-mize population heterogeneity and dem-onstrate efficacy in severe sepsis andacute lung injury (1, 2). A specific prob-

lem is the inability to deliver feed effec-tively in a proportion of subjects due tovariations in enteral tolerance with pa-tient and disease type. High-quality clin-ical care, employing feeding protocols,avoiding excessive sedation, and usingaperients and prokinetics early, substan-tially minimizes the problem, but full-volume enteral feeding is still difficult orimpossible to achieve early in some in-tensive care unit (ICU) patients (3).

An important motive for feeding crit-ically ill patients early is that the gut-associated lymphoid tissue comprises thelargest collection of immune cells in thebody, and their turnover and the vulner-ability of the gut to ischemia/reperfusion

Objective: To assess the safety and efficacy of an early enteralpharmaconutrition supplement containing glutamine dipeptides,antioxidative vitamins and trace elements, and butyrate in criti-cally ill, septic patients.

Design: A prospective, randomized, controlled, double-blindclinical trial.

Setting: Adult intensive care unit in a university hospital.Patients: Fifty-five critically ill, septic patients requiring en-

teral feeding.Interventions: Patients received either an enteral supplement

(500 mL of Intestamin, Fresenius Kabi) containing conditionallyessential nutrients or a control solution via the nasogastric routefor up to 10 days. Inclusion occurred within 24 hrs of intensivecare unit admission. Additionally, patients received enteral feed-ing with an immunonutrition formula (experimental group) orstandard formula (control group) initiated within 48 hrs afterenrollment.

Measurements and Main Results: Organ dysfunction was as-sessed by daily total Sequential Organ Failure Assessment (SOFA)score over the 10-day study period in both patient groups. Pa-tients receiving the experimental supplement showed a signifi-cantly faster decline in the regression slopes of delta daily total

SOFA score over time compared with control. The differencebetween the regression coefficients of the two slopes was sig-nificant irrespective of the level of analysis: intent to treat �0.32vs. �0.14, p < .0001; per protocol �0.34 vs. �0.14, p < .0001;and completers (patients receiving >80% of the calculated ca-loric target over a period of 6 days), �0.26 vs. �0.16, p � .0005.Vitamin C, as a marker of supplement absorption, increased from10.6 (1.9–159.4) �mol/L (normal range 20–50 �mol/L) on day 1to 58.7 (5.4–189.9) �mol/L by day 3 (p � .002) in the interventiongroup but remained below the normal range in the control group17.0 (2.8–78.5) on day 1 and 14.3 (2.4–179.6) on day 3. Serumlevels of glycine, serine, arginine, ornithine, vitamin E, and �-car-otene all increased significantly with treatment in the supplemen-tation group.

Conclusions: In medical patients with sepsis, early enteral phar-maconutrition with glutamine dipeptides, vitamin C and E, �-caro-tene, selenium, zinc, and butyrate in combination with an immu-nonutrition formula results in significantly faster recovery of organfunction compared with control. (Crit Care Med 2008; 36:131–144)

KEY WORDS: sepsis; early feeding; immune-modulation; organdysfunction; Sequential Organ Failure Assessment; glutamine;antioxidants; enteral nutrition; enteral pharmaconutrition

*See also p. 347.From the Department of Adult Critical Care Medi-

cine, Guy’s and St. Thomas’ Hospital, London, UnitedKingdom (RJB, TS, KL, LCS, JM, JS); Datagen AG,Basel, Switzerland (WV); Department of Nutrition &Food Sciences, University of Bonn, Germany (BA, PS);and HealthEcon AG, Basel, Switzerland (HS).

Supported, in part, by a research grant from Fre-senius Kabi AG, Germany, which continues to provide

research support to Dr. Beale and the Department ofAdult Critical Care Medicine at Guy’s and St Thomas’Hospital.

For information regarding this article, E-mail:[email protected]

Copyright © 2007 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/01.CCM.0000297954.45251.A9

131Crit Care Med 2008 Vol. 36, No. 1

injury in shock states (4, 5) offer poten-tial points of intervention in critical ill-ness. Unfortunately, key components ofgut surface defense are impaired by stan-dard interventions, including antibiotics,which modify normal gut microflora (6);dopamine, which impairs gut motility(7); and hemodynamic and respiratorysupport strategies, which may impair gutperfusion (8, 9). Luminal delivery of keysubstrates as nutrients for enterocytesand as substances to modify the injuryresponse is therefore an attractive con-cept (10). This approach was introducedwith the immunonutrition products thathave been studied in the last 10 yrs.Other than in the planned major surgerypopulation (11), however, immune-enhancing feeds remain controversial, es-pecially arginine-containing feeds in se-vere sepsis (12–14). Moreover, theseformulas contain fixed nutrient doses, soadequate delivery requires fully estab-lished enteral feeding, which excludes ef-fective early dosing except with prefeed-ing before planned major surgery, wherethe strongest benefit is seen (11).

These practical difficulties, and theimportance of the gut as a potential pointof intervention, suggest scope for alter-native approaches. One of these is phar-maconutrition, which involves the cru-cially different step of separating theprovision of key nutrients from routinenutritional support by administering alow-volume enteral supplement contain-ing high doses of the key nutrients asearly as possible, to increase the likeli-hood of effective delivery even in patientswith limited enteral volume tolerance.Standard enteral or parenteral feed canthen be given separately as required. An-tioxidant vitamins and trace elements,glutamine, and short-chain fatty acids,which all modulate gut ischemia-reperfu-sion injury and mucosal immune cellturnover and function, have thereforebeen combined into the pharmaconutri-tion enteral supplement Intestamin (Fre-senius Kabi, Bad Homburg, Germany).

Another important consideration isthe optimal trial end point. Mortality andmorbidity assessments require largestudy populations and have provenlargely unachievable on intent-to-treatanalyses in feeding studies. Length of stayalso requires a large population and isaffected by organizational factors beyondthe influence of the primary intervention.Descriptive organ failure scores that re-late to mortality and morbidity endpoints (via their derivation databases)

therefore offer an attractive alternative.The most widely used is the SequentialOrgan Failure Assessment (SOFA) (15–17), recommended for this purpose by arecent European roundtable (18). Wehave therefore tested the effects of anenteral supplement containing condi-tionally essential nutrients, together withan immune-enhancing feed, on the pat-tern of change in SOFA score in criticallyill patients with sepsis over a 10-day pe-riod.

MATERIALS AND METHODS

This was a prospective, randomized, con-trolled, double-blind, single-center study per-formed in the adult general ICU of Guy’s andSt. Thomas’ Hospital, London, UK. After Eth-ics Committee approval of the protocol, writ-ten consent was obtained from each patient ornext of kin, following procedures according tothe Helsinki Declaration. Enrolled in thestudy were patients with a high probability orsigns of infection, two criteria for systemicinflammatory response syndrome, and at leastone organ dysfunction: a) pulmonary dysfunc-tion, PaO2/FIO2 �250 mm Hg, or �200 mm Hgwith pneumonia or other localized lung dis-ease; b) metabolic acidosis, pH �7.30 or basedeficit �5.0 mEq/L (�5.0 mmol/L) withplasma lactate concentration �2.0 mmol/L; c)oliguria, urine output �0.5 mL/kg/hr for twoconsecutive hours after adequate fluid resus-citation; d) thrombocytopenia, unexplainedthrombocytopenia (platelet count �100,000cells/mm3); e) hypotension, dopamine �5 �g/kg/min or any dose of epinephrine or norepi-nephrine to maintain systolic blood pressure�90 mm Hg for two consecutive hours occur-ring within 24 hrs of ICU admission. Addi-tional inclusion criteria were age �18, AcutePhysiology and Chronic Health Evaluation(APACHE) II score �10, precipitating injury(surgery, trauma, hypovolemia, episode of in-fection/sepsis) within 24 hrs preceding ICU

entry, expected length of stay in the ICU �3days, and likely indication for enteral nutri-tion for �5 days. Major exclusion criteria werecardiogenic shock or severe congestive heartfailure (New York Heart Association class IV);severe, preexisting, parenchymal liver diseasewith clinically significant portal hypertension(Childs C); documented chronic obstructivepulmonary disease; chronic renal failure re-quiring dialysis; pregnancy; acquired immu-nodeficiency syndrome; and immunosuppres-sion (chronic treatment with high-dosesteroids, e.g., 0.3 mg/kg/day methyl pred-nisolone, active radiotherapy or chemotherapywithin preceding year, or, at any time, lym-phoma or documented immunohumoral orcellular immune deficiency state).

Patients were randomized to receive eitherthe enteral pharmaconutrition supplement(Intestamin) or a control supplement (Fig. 1,feed compositions shown in Table 1) within 24hrs after enrollment at 21 mL/hr (500 mL/day;250 kcal) via a nasogastric tube, for up to 10days. From day 2 patients also received a com-plete enteral formula according to the ICU’sfeeding regimen. Patients randomized to In-testamin received immunonutrient-contain-ing Reconvan (Fresenius Kabi, Bad Homburg,Germany—Table 1); patients randomized tocontrol supplement received Fresubin original(also Fresenius Kabi), starting at 20 mL/hrand increasing to 25 kcal/kg within 2–3 days.To offset any initial caloric deficit and to allowtight blood sugar control (80–110 mg/L or4.5–6.0 mmol/L), patients received intrave-nous 20% glucose until their feeding targetwas met.

Routine laboratory measurements weremonitored daily. SOFA and APACHE II scoreswere assessed on the day of admission (day 0)or the next day (day 1) according to the pub-lished methodology (15, 19), and daily there-after. The worst measurement values withineach 24-hr period (from 8 am to 8 am) wereretrieved from the patient data managementsystem and entered into an electronic case

Intestamin® / Reconvan / Glucose 20%

Control supplement / Fresubin® original/ Glucose 20% 20%

Intestamin®

control supplement

day 1

day 1 day 2-10 day 11 - discharge

Reconvan

day 2-10

Fresubin®

originalday 11 - discharge

Figure 1. Study schedule.

132 Crit Care Med 2008 Vol. 36, No. 1

report form. Random weekly checks were per-formed to eliminate data errors, and inconsis-tencies were documented and corrected. Or-gan failure was calculated for all six SOFAcomponents during the study period of (amaximum) 11 consecutive days (as of day 0).The aggregate score, total maximum SOFA,was calculated by summing the worst scoresfor each organ system (15). ICU/hospitallength of stay and ICU/hospital mortality wereassessed at ICU/hospital discharge. The 28-daymortality and 6-month mortality were as-sessed by separate follow-up.

Gastrointestinal tolerance was assesseddaily (aspiration, nausea/vomiting, hiccups,bloating, flatulence, constipation, diarrhea,abdominal cramping, bowel movements). Nu-trient absorption was assessed by measure-ment of plasma levels of glutamine, vitamins Cand E, �-carotene, zinc, and selenium. Plasmaamino acids were determined by reverse-phasehigh-performance liquid chromatography andfluorescence detection (20). Vitamins C and Eand �-carotene were analyzed by high-performance liquid chromatography (21). Im-munologic profiling was undertaken throughsolid-phase enzyme-labeled chemilumines-cent immunometric assay of interleukin (IL)-6(IMMULITE 2000-IL-6, EURO/DPC Ltd, Caer-

narfon, Gwynedd, UK) and IL-10 (IMMULITE1000 IL-10, EURO/DPC Ltd, Caernarfon,Gwynedd, UK) levels. Monocyte human leuko-cyte antigen (HLA)-DR expression was assessedusing two-color flow cytometry (BeckmanCoulter, High Wycombe, UK) to generate amean fluorescence intensity value. Antioxidativestatus was assessed by measurement of thiobar-bituric acid reactive substance (TBARS) (22),thiols, and glutathione (23), all on predefinedstudy days. Safety was evaluated via (serious)adverse event collection and standard laboratoryand clinical assessments.

Statistics. The primary end point was or-gan dysfunction evolution assessed by dailytotal SOFA and delta daily total SOFA scoreover a study period of maximum 10 days. Ourprospectively defined primary analysis in-cluded all randomized patients who received�0 mL of the supplement, with patients ana-lyzed according to treatment group allocation(intent to treat). The trial was designed toenroll 344 patients, with one planned interimanalysis after enrolling 50 patients to confirmstatistical assumptions and for safety monitor-ing. Statistical analysis was performed inde-pendently by HealthEcon AG/Datagen AG(Basel, Switzerland). The primary analysis wasbased on the evolution (slopes) of the daily

total SOFA score and delta daily total SOFAscore (change in daily total SOFA score com-pared with day 0) over 10 study days by com-paring the regression coefficients using Stu-dent’s t-test. Simple Student’s t-tests werealso used for the difference between meanvalues of parametric data. Repeated-measuresanalysis of variance was used to evaluate treat-ment-related effects. Chi-Square and Fisher’sexact test were used for comparison of fre-quency data between groups. All reported pvalues are two-sided, and values �.05 are con-sidered as significant; there are no correctionsfor multiple comparisons.

Analyses were also performed on two pre-defined subgroups: the per protocol group,which excluded patients who were randomizedbut met a study exclusion criteria; and the80% group, comprising patients who received�80% of the calculated cumulative daily ca-loric target over six consecutive days.

RESULTSAfter the interim analysis of data from

50 patients, enrollment was suspended be-cause the difference in the decline of thedelta daily total SOFA score was statisticallysignificant with a benefit in favor of thepatients in the Intestamin/Reconvan group.

Table 1. Product composition

Intestamin500 mL

Control Supplement500 mL

Intestamin �Reconvan

500 mL � 1000 mL

ControlSupplement �

Fresubin Original500 mL � 1000 mL

Energykcal 250 250 1250 1250kJ 1050 1050 5250 5250

Caloric density, kcal/mL 0.5 0.5 0.8 0.8Caloric distribution, %

Protein 72 0 72 22 0 15Carbohydrate 26 100 26 48 100 55Fat 2 0 2 30 0 30

Osmolarity, mosm/L 390 300 390 270 300 250Protein, g 42.5 — 98 38

Glutamine 30 — 40 —Arginine — — 6.7 1.6Glycine 10 11 1.0

Total nitrogen, g 9.0 — 17.8 6.1Fat, g 1 (as tributyrin) — 34 34

Tributyrin 1 — 1 —EPA � DHA — — 2.5 0.4n6/n3 fatty acids — — 2:1 2:1

Carbohydrate 19 50 139 188Dietary fiber — — — —Key vitamins and minerals

�-carotene, mg 10 2 11 3.3Vitamin E, mg TE 500 — 513 13Vitamin C, mg 1500 250 1567 317Sodium, mg 460 460 1840 1210Potassium, mg 260 — 2330 1250Zinc, mg 20 — 32 12Selenium, �g 300 — 367 67

Other vitamins andminerals

Other vitamins andminerals

EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; Mg TE, total equivalent.


Results presented here include data froman additional five patients enrolled duringthe interim analysis period.

Of 55 patients who underwent ran-domization, 27 received Intestamin/Reconvan and 28 the control feeds. Fivepatients in the Intestamin/Reconvangroup and four patients in the controlgroup met at least one exclusion criteriafollowing randomization and were ruleddropouts. Seventeen Intestamin/Recon-van patients and 18 control patients re-ceived �80% of the calculated caloric

target over six consecutive days, formingthe 80% group. The baseline demo-graphic characteristics and severity ofdisease as evaluated by the APACHE IIand total SOFA scores were similar inboth groups (Table 2).

Supplement and Feed Delivery. Sup-plement, feed, and calorie delivery isshown in Table 3. On day 1, both groupsreceived a median of 336 mL (range 105–483 mL) of supplement (Intestamin orControl). From days 2 to 9, both groupsreceived the planned 500 mL/day as me-

dian amount on all days. On day 10, themedian volume was 420 mL (range0–504 mL) in the control group and 500mL (range 137–504 mL) in the experi-mental group. Complete enteral formulas(Reconvan or Fresubin original) were in-troduced on day 2. The median Reconvanvolume on day 2 was 840 mL (range 30–1050 mL), increasing to between 1320and 1480 mL/day (range 0–2160 mL) forthe remainder of the period to day 10; themedian Fresubin original volume on day2 was 835 mL (range 0–1690 mL), in-creasing to between 960 and 1320 mL/day(range 0–2160 mL) for the remainder ofthe period to day 10. The median 20%dextrose volume dropped from 823 mL(range 0–1350) in the control and 855mL (range 60–1345 mL) in the experi-mental group on day 1 to 545 mL (range0 –1260) in the control and 570 mL(range 0–1965 mL) in the experimentalgroup on day 2 and to 0 mL on day 3 inboth groups, indicating strict adherenceto the feeding regimen and good feedtolerance. There were no differences inmedian daily blood sugar or insulin levels(Fig. 2).

Only minor gastrointestinal intoler-ance was reported during the 10-daystudy period for both groups, with onlythe incidence of diarrhea being statisti-cally significantly different (experimentalgroup 21 patients vs. control group 12patients, p � .036). No subject had todiscontinue enteral feeding due to ad-verse effects.

Absorption of Nutrients. Table 4 showsthe serum levels of vitamins C and E and�-carotene, and all three showed signifi-cant treatment-related increases duringthe study (p � .002, p � .001, and p �.019, respectively). In the experimentalgroup, median vitamin C blood levels,determined on days 1, 3, 5, 7, 9, and 11,increased from below normal (20 –50�mol/L) on day 1 to above normal on allother days but remained below normal inthe control group. Differences were sta-tistically significant from day 3 both be-tween groups and from baseline in thetreatment group (p � .01). Median vita-min E values were below normal (20–40�mol/L) on day 1 in both groups andincreased to above normal in the experi-mental group but not in the controlgroup. Differences were statistically sig-nificant between the groups and frombaseline in the treatment group from day3 (p � .001). Median levels of �-carotenewere below the normal range (0.2–0.5�mol/L) in both groups at baseline and

Table 2. Baseline characteristics of intent-to-treat patient population

Characteristic Intestamin � ReconvanControl Supplement �

Fresubin Original

Patients, n 27 28Male gender, % 52 50Mean (SD) age, yrs 57.4 (19.0) 64.3 (16.8)Mean (SD) weight, kg 71.7 (13.7) 73.8 (14.6)Mean (SD) BMI 25.3 (3.9) 26.1 (4.2)Precipitating injury, %

Medical 16 (59) 16 (57)Surgical 5 (19) 6 (22)Trauma 6 (21) 6 (22)

APACHE II scoreMean (SD) 14.0 (5.5) 16.0 (5.6)Median (range) 15.0 (4–25) 16.0 (6–30)

SOFA score on day 0Mean (SD) 7.3 � 2.1 6.7 � 3.5Median (range) 6.5 (2–13) 6 (2–15)

Requiring mechanical ventilation, n (%) 26 (96) 28 (100)Requiring renal replacement therapy during

study period, n (%)16 (60) 17 (61)

Serum creatinine, �mol/L 117.8 � 55.2 132.5 � 105.3Serum bilirubin, �mol/L 14.0 � 7.1 18.8 � 15.1Patients with SIRS, n (%) 27 (100) 28 (100)Patients with sepsis, n (%) 27 (100) 28 (100)

BMI, body mass index; APACHE, Acute Physiology and Chronic Health Evaluation; SOFA, Sequen-tial Organ Failure Assessment; SIRS, systemic inflammatory response syndrome.

Table 3. Feed delivery information on a per-patient basis


Fresubin Original

NumbersIntent to treat 27 28Per protocol 22 24Completers 17 18

Total supplement received perpatient, mean � SD in mL

Intent to treat 2300 � 748 2200 � 876Per protocol 2379 � 598 2288 � 825Completers 2590 � 466 2670 � 265

Total enteral formula received per patient,mean � SD in mL


Total 20% dextrose received per patient,mean � SD in mL



increased to above normal in the experi-mental group but not in the controlgroup. The increase from baseline withtreatment was significant from day 3, and

the difference between groups becamesignificant by day 6 (both p � .05).

No statistically significant treatment-related differences were found for sele-

nium and zinc. Median values were belowthe normal ranges (50 –150 �g/L and10–18 �mol/L, respectively) in the exper-imental group (45 [11–77] �g/L and 5.3

Figure 2. Daily blood glucose levels and insulin infusion dosages. Max, maximum; Min, minimum; IU, interational units.


[1.9–13.0] �mol/L) and in the controlgroup (48 [10–103] �g/L and 5.7 [3.6–12.8] �mol/L) on the first study day (Ta-ble 4). Levels of each trace element in-creased during the study period, withselenium levels normalizing in the exper-imental (66 [40–112] �g/L) and control(64 [27–93] �g/L) groups, but zinc levelsremained slightly below normal (9.8[5.0 –13.7] �mol/L and 9.5 [5.4 –14.5]�mol/L).

Median values of glutamate, glutamine,serine, glycine, arginine, �-amino-butyrate,and ornithine showed significant increasescompared with control from day 3 (Table5), but this was only statistically related totreatment (by analysis of variance) for gly-cine, serine, arginine (all on day 3) andornithine (throughout the study period).Those amino acids (glutamine, serine, andarginine) below the normal range at studyentry showed consistent normalizationonly in the treatment group. Values foralanine, taurine, asparagine, histidine,threonine, citrulline, tyrosine, valine, me-thionine, tryptophane, phenylalanine, iso-leucine, leucine, and lysine were normal onall days without significant differences be-tween the groups.

Antioxidant Status. There were no sig-nificant treatment-related differences be-

tween the groups for the thiols cysteine,-glutamyl-cysteine, homocysteine, cys-teinyl-glycine, and glutathione or forTBARS.

Effect on Mortality, Length of Stay,and Organ Dysfunction. There were nosignificant differences in mortality at ICUor hospital discharge, 28 days, and 6months between the two study groups orin length of ICU and hospital stay (Table6). There were small differences in organdysfunction between the groups mea-sured by the initial SOFA scores (day0/day 1). After normalization of the datausing the delta total SOFA score to cor-rect for these initial imbalances, therewas a more rapid fall in delta daily totalSOFA over the 10-day study period (Fig.3), with statistically significant differ-ences in the coefficients of the regressionlines for the Intestamin/Reconvan groupcompared with control in all three studypopulations: intent to treat, per protocol,and the 80% group completers (Table 7).When a best-fit approach was taken to thedelta daily total SOFA score regressionanalysis, there was a biphasic relation-ship, describing a steeper fall betweendays 0 and 5 and then a more shallowchange thereafter (days 6–11). The firstphase fall was more rapid in the Intesta-

min/Reconvan group than in the controlgroup (Fig. 4), and this was highly signif-icant for all analytical groups (Table 7).There were no organ-specific effects onanalysis of the individual components ofthe total SOFA score. There was a trendtoward lower delta SOFA values (totalmaximum SOFA score minus total SOFAscore on admission, which represents theamount of organ dysfunction/failure oc-curring during the ICU stay) in the inter-vention group in all three study popula-tions: intent to treat, 2.0 � 2.1experimental vs. 2.8 � 2.0 control (p �.1824); per protocol, 2.1 � 2.2 vs. 2.8 �2.1 (p � .2458); and completers, 2.5 �2.3 vs. 2.9 � 2.1 (p � .6367).

Immunologic Data. Immunologicdata are given in Table 8. IL-6 levels wereraised in both groups at study entry andfell over time. In the control group, theIL-6 level rose again at day 7, when it wassignificantly higher than in the treatmentgroup (p � .035), following which thelevel fell once more, but statistically thiscould not be confirmed as a treatmenteffect. IL-10 levels were at or above thetop of the normal range on study entryand did not change significantly. Therewere wide interindividual variations inthe levels of both cytokines. HLA-DR ex-

Table 4. Comparison of vitamin and trace element serum levels

Study DayIntestamin � Reconvan,

Median (Minimum–Maximum)

Control Supplement � FresubinOriginal, Median

(Minimum–Maximum)

p Value

t-Test ANOVA Repeated Measures

Vitamin C (normal range 20–50 �mol/L) .002 (treatment effect)1 10.59 (1.85–159.42) 16.99 (2.77–78.47) .116 vs. day 13 58.65 (5.37–189.86) 14.30 (2.36–179.62) .001 .0095 81.79 (11.31–274.96) 17.09 (2.08–217.58) �.001 .0027 86.31 (25.87–198.87) 15.09 (5.93–148.85) �.001 �.0019 88.78 (51.25–321.96) 12.96 (6.31–85.89) �.001 �.001

11 84.76 (36.7–421.60) 13.72 (6.31–42.78) �.001 .004Vitamin E (normal range 20–40 �mol/L) �.001 (treatment effect)

1 17.28 (3.85–26.31) 14.92 (4.62–29.35) .771 vs. day 13 39.44 (14.83–70.61) 19.22 (6.97–33.39) �.001 �.0016 55.33 (32.08–67.95) 24.16 (7.06–48.54) �.001 �.001

11 68.63 (39.19–103.32) 20.97 (5.60–61.54) �.001 �.001�-Carotene (normal range 0.2–0.5 �mol) .019 (treatment effect)

1 0.08 (0.01–0.34) 0.11 (0.02–1.14) .449 vs. day 13 0.19 (0.03–0.57) 0.18 (0.04–1.00) .741 .0356 0.51 (0.08–1.39) 0.25 (0.06–1.78) .018 .013

11 0.88 (0.13–3.21) 0.13 (0.03–0.62) �.001 .002Se (normal range 50–150 �g/L) .375 (treatment effect)

1 45 (11–77) 48 (10–103) .6483 47 (18–83) 54 (16–117) 1.006 54 (33–96) 53 (21–82) .456

11 66 (40–112) 64 (27–93) .336Zn (normal range 10–18 �mol/L) .641 (treatment effect)

1 5.3 (1.9–13.0) 5.7 (3.6–12.8) .1833 5.7 (2.9–13.5) 6.7 (3.7–14.4) .4026 6.8 (4.4–12.4) 7.2 (3.6–11.8) .804

11 9.8 (5.0–13.7) 9.5 (5.4–14.5) .955

ANOVA, analysis of variance.


pression (as mean fluorescence intensity)was significantly reduced in both groups(Intestamin/Reconvan, day 1 median

0.54, range 0.19–3.38; control, day 1 me-dian 0.94, range 0.24–3.03) comparedwith 25 normal control subjects (median

4.11, range 1.51–8.12) (p � .0001 vs.experimental and control groups) and re-mained depressed throughout the studyperiod (Intestamin/Reconvan, day 11 me-dian 0.60, range 0.16–2.15; control, day11 median 0.82, range 0.31–2.89), butthere were no differences between thetwo groups.

Secondary Infections, Complications,and Safety. There were no significant dif-ferences in the number of secondary in-fections or complications across any ofthe populations analyzed (Table 6). Therewere six serious adverse events in six pa-tients, with no significant difference be-tween the groups (Intestamin/Reconvan,two patients; control, four patients). Theonly biochemical variable that was differ-ent between the two groups was serumurea, which rose from 9.42 � 5.13mmol/L on day 1 to 12.36 � 4.50 mmol/Lon day 6 in the Intestamin/Reconvangroup (p � .045) and fell in the control

Table 5. Comparison of selected serum amino acid levels



Control Supplement �Fresubin Original, Median

(Minimum–Maximum)

p Value


Glutamate (normal range, 7–39 �mol/L) .615 (treatment effect)1 59.50 (14.20–118.30) 57.00 (16.00–131.80) .9693 79.70 (12.10–124.20) 54.10 (19.30–102.40) .0366 87.95 (14.40–133.90) 64.50 (25.80–122.60) .209

11 83.60 (34.10–133.30) 52.60 (24.10–131.80) .125Glutamine (normal range 483–827 �mol/L) .137 (treatment effect)

1 407.00 (157.50–788.10) 479.00 (196.80–2089.10) .3883 554.30 (370.40–1007.00) 449.30 (261.30–1019.20) .0136 593.30 (274.80–972.40) 495.95 (325.50–699.90) .075

11 501.30 (328.40–646.30) 415.50 (243.70–652.90) .686Glycine (normal range 132–380 �mol/L) .004 (treatment effect)

1 171.20 (85.00–465.10) 185.20 (65.20–1161.80) .600 vs. day 13 267.90 (129.90–620.70) 187.90 (68.80–646.20) .015 .0426 253.35 (117.60–552.00) 192.35 (95.80–315.90) .028 .402

11 218.20 (120.00–462.30) 195.80 (113.50–253.00) .153 .904Serine (normal range 74–154 �mol/L) .017 (treatment effect)

1 66.60 (35.20–114.00) 72.60 (23.40–337.00) .268 vs. day 13 100.40 (48.30–153.60) 72.80 (35.40–118.00) .011 .0066 91.50 (47.80–152.00) 78.10 (40.50–147.40) .197 .235

11 79.30 (50.40–116.70) 70.40 (27.80–99.90) .225 .378Arginine (normal range 58–116 �mol/L) .020 (treatment effect)

1 34.80 (18.20–75.60) 39.65 (19.70–154.00) .281 vs. day 13 72.10 (23.60–152.70) 40.30 (16.30–100.10) .001 .0026 80.70 (33.20–136.20) 49.50 (26.50–101.40) .025 .088

11 61.00 (32.90–96.20) 51.80 (16.30–89.30) .319 .163�-amino-butyrate (normal range

10–132 �mol/L).680 (treatment effect)

1 17.70 (0.00–57.80) 18.50 (5.90–200.10) .7933 16.40 (0.00–38.10) 9.70 (0.00–43.60) .0396 18.20 (7.50–47.70) 12.35 (0.00–20.50) .022

11 12.50 (6.20–33.60) 14.10 (0.00–19.30) .788Ornithine (normal range 26–106 �mol/L) .019 (treatment effect)

1 45.70 (9.00–97.70) 56.90 (25.70–636.10) .232 vs. day 13 135.25 (38.90–225.70) 61.50 (15.40–143.60) <.001 <.0016 112.95 (45.70–247.30) 75.15 (0.00–143.90) .002 .016

11 110.50 (35.10–217.80) 77.40 (0.00–129.20) .010 .011


Table 6. Comparison of secondary outcome parameters: intensive care unit (ICU) and hospital lengthof stay (LOS); secondary infections; ICU, hospital, 28-day, and 6-month mortality


Fresubin Original

ICU LOS, mean � SD

Intent to treat 16.6 � 14.8 13.4 � 11.5Per protocol 17.7 � 15.7 14.2 � 11.9Completers 20.7 � 16.6 17.3 � 11.9

Hospital LOS, mean � SD

Intent to treat 43.8 � 36.6 31.3 � 27.2Per protocol 42.9 � 32.4 32.5 � 28.8Completers 41.3 � 31.1 39.7 � 28.8

Total no. of secondary infections 24 19Total no. of secondary respiratory infections 13 9Total no. of secondary bacteremias 11 7ICU mortality (ITT), n (%) 6 (21) 4 (15)Hospital mortality (ITT), n (%) 7 (25) 7 (26)28-day mortality (ITT), n (%) 5 (18) 3 (11)6-month mortality (ITT), n (%) 10 (36) 8 (30)

ITT, intent to treat. No significant differences for any comparisons.


Figure 3. Delta total Sequential Organ Failure Assessment (SOFA) score over time (study days 0–11). ITT, intention to treat; PPP, per protocol; ICU,intensive care unit.


group from 10.00 � 6.63 mmol/L to 7.95 �4.86 mmol/L (p � .264).

DISCUSSION

This is the first randomized trial of theenteral pharmaconutrition concept in pa-tients with sepsis, and it demonstratesthe validity of this concept in this pre-dominantly medical ICU population. Glu-tamine dipeptides, antioxidant vitaminsand trace elements, and tributyrin, in alow-volume supplement (Intestamin),were successfully absorbed via the naso-gastric route and well tolerated. Admin-istration in combination with an im-mune-enhancing feed (Reconvan)resulted in a significantly faster improve-ment in organ dysfunction, as assessed bythe normalized delta daily total SOFAscore.

The innovation in this approach is inadministering high doses of key nutrientsin a low-volume enteral supplement thatis separate from the provision of generalnutrition. This is conceptually differentfrom traditional enteral nutrition, in-cluding immunonutrition, since the fullvolume of a supplement can be adminis-tered much earlier in the patient’s ICUstay, soon after initial resuscitation hasbeen performed. Later, as gastrointestinaltolerance improves, standard enteralfeeding can be added to provide normalnutritional support or parenteral feedingcan be used if necessary. We used naso-gastric feeding successfully in all studypatients, confirmed by the rapid increasesin vitamin levels by study day 3, althoughnasojejunal tubes were allowed withinthe protocol. This is encouraging and fur-ther emphasizes the importance of a pro-

tocolized approach in achieving success-ful feeding (24, 25).

Since mortality is not a feasible endpoint in a small single-center study, es-pecially in patients with sepsis, we usedthe SOFA score as a surrogate outcomemeasure, which was its primary purpose(14–16). Moreover, since the therapeuticconcept is to provide key nutrients to thegut to modulate the injury response, en-courage recovery, and minimize second-ary organ failure, using a daily measureof organ dysfunction is an attractive ap-proach. Given the slight imbalance in thestarting SOFA score between the twogroups, the data were normalized by us-ing the delta total daily SOFA score: thatis, comparing the degree of change on adaily basis to baseline. This showed astrong, consistent difference in the evo-lution of organ dysfunction favoring theIntestamin/Reconvan group, althoughthis was an overall phenomenon ratherthan a specific individual organ systemeffect.

Although we combined the pharmaco-nutrition supplement Intestamin withthe immune-enhancing feed Reconvan,the fact that significant increases in keynutrients and amino acids were seen byday 3, allied with the biphasic delta SOFAresponse, suggests that the effect of theIntestamin predominated, especiallygiven the lack of convincing outcomebenefit seen with immune-enhancingfeeds in general ICU populations (11, 24–26), with the possible recent exception ofthe antioxidant and enriched lipid ap-proach (27). It is therefore important toconsider how the three main componentsof Intestamin (high-dose enteral glu-

tamine, high doses of antioxidant vita-mins and trace elements, and tributyrinas a short chain fatty acids source as fuelfor colonocytes) might have contributedto the greater improvement in deltaSOFA score that we observed.

Glutamine is increasingly consideredto be indispensable in critical illness andappears beneficial in several patientgroups, especially those with burns ormajor trauma, where it received a level Arecommendation in recent ESPEN guide-lines (14). Its potentially beneficial ac-tions include acting as a metabolic fuelfor gut epithelial and immune cells, at-tenuating cytokine release, acting as anantioxidant by enhancing glutathionelevels, and delaying the induction of ni-tric oxide synthase. Apart from its meta-bolic pathway effects, possible mecha-nisms behind these actions include theability of glutamine to up-regulate heatshock protein 70 and peroxisome prolif-erator-activated receptor (26, 28–30)and down-regulate activator protein 1(30). Some or all of these effects combineto protect the gut and reduce the perme-ability defect associated with critical ill-ness (31), which may help to explain thebeneficial effects of glutamine on somemeasures of gut permeability, infectionrates, immune function, and outcome re-ported in several clinical trials (32–37).Glutamine itself is relatively insoluble inwater, difficult to store in solution, andunstable during heat sterilization, whichmade it difficult to incorporate into com-mercially available enteral and parenteralfeeding products before the quite recentintroduction of stable, highly soluble glu-tamine dipeptides (38). Consequently,there is still relatively little clinical out-come information for glutamine adminis-tration, and most data relate to parenteralsolutions containing either alanyl-glutamineor glycyl-glutamine dipeptides. Indeed, a re-cent Canadian meta-analysis of parenteralglutamine administration in critically ill pa-tients showed a significant benefit for bothmortality and infectious complications (39)(www.criticalcarenutrition.com) but couldonly find a mortality benefit for enteralglutamine in patients with burns and re-duced infectious complications in patientswith burns or after trauma (37). Since thisanalysis a further study of enteral glu-tamine supplementation in patients in asurgical trauma ICU has failed to identifyany outcome benefit (40, 41).

Why are studies of enteral glutamineinconsistent? Part of the problem mayrelate to different study populations.

Table 7. Comparison of regression analysis from delta daily total Sequential Organ Failure Assessment(SOFA) scorea


Fresubin Original p Value (Slopes)

Slopes (days 0–11)Intent to treat 0.3232 0.1424 �.0001Per protocol 0.3387 0.1387 �.0001Completers 0.2573 0.1568 .0005

Slopes (1 phase days 0–5)Intent to treat 0.5146 0.2070 .0024Per protocol 0.5458 0.1674 .0004Completers 0.3925 0.2051 .0028

Slopes (2 phase days 6–11)Intent to treat 0.1397 0.0600 .3967Per protocol 0.1236 0.0658 .5348Completers 0.0788 0.0553 .8153

aNormalized via delta total SOFA score to correct for initial imbalances between the two groups inthe total SOFA score upon admission (day 0/day 1).


Figure 4. Delta total Sequential Organ Failure Assessment (SOFA) score over time—biphasic (study days 0–11). ITT, intention to treat; PPP, per protocol;ICU, intensive care unit.


Burn, surgical, trauma, and medical ICUpatients exhibit differing inflammatorystates, and there is increasing evidencethat there may be differential effects ofnutrition, especially regarding the ad-ministration of arginine (42). Indeed,while arginine may induce nitric oxideproduction and increase gut permeability(43), glutamine may have a protectiveeffect against this action (43). More im-portant, perhaps, is the difficulty of deliv-ering sufficient glutamine to the gutearly enough to be effective using stan-dard enteral feeding. In a small study ofnine patients with neurologic injury, Pre-iser and colleagues (44) examined the ef-fects on glutamine levels in plasma andduodenal biopsy samples of a standardfeed and two glutamine-enriched solu-tions, one containing glutamine-richproteins and the other free glutamine.Plasma glutamine levels did not increaseafter 7 days in any of the groups, whileduodenal mucosal glutamine concentra-tion only increased in the patients fed theglutamine-rich protein feed. In two smallpilot studies in which glutamine dipep-tide was given jejunally in the form ofIntestamin to patients after gastrointesti-nal cancer surgery, plasma glutaminelevels increased in one study (45) but notthe other (46). In a recent dose-findingpilot study using glutamine and antioxi-dants in ventilated critically ill patientswith evidence of hypoperfusion, Heylandand colleagues (47) combined intrave-nous glutamine (Dipeptiven) with enteralglutamine as Intestamin and demon-strated normalization in plasma glu-tamine levels, but the small size of thisstudy (seven patients per dosage group)makes it difficult to separate the relative

contributions of the intravenous and en-teral components. In our current study,plasma glutamine levels were just belownormal, rather than being markedly de-pleted, and there was a significantlygreater rise in plasma glutamine on di-rect comparison in the interventiongroup by day 3, with levels then beingmaintained in the normal range, al-though this change did not quite reachsignificance as a treatment effect by anal-ysis of variance (p � .137). This suggeststhat the glutamine dose administeredmay have been sufficient to spill overfrom the gut itself into the systemic pool.This is further supported by the patternof increase in amino acids, although theglycine in the glycyl-glutamine dipeptidein Intestamin may also have contributed,especially to the increase in glycine lev-els. Glycine also has specific effects, in-cluding protecting against the effects oforgan manipulation during liver trans-plantation in animals (48) and reducingliver injury, tumor necrosis factor-� lev-els, and mortality in an endotoxic shockmodel (49). Plasma glutamine levels havebeen reported to rise in other studies ofglutamine-enriched feeds, but less rap-idly than in our study (37, 50). The extraglutamine, glycine, and arginine admin-istered to the treatment group also pro-vided a substantially higher protein load,and although the control group was fedsuccessfully according to the unit proto-col, as in other enteral feeding studies thetotal protein delivery in the control groupwas quite low (51). Nevertheless, it isunclear that such underfeeding is harm-ful, nor are there convincing data to sug-gest that high-protein feeding alonewould account for the difference in SOFA

response in the two groups (39) (www.criticalcarenutrition.com).

The next possibility is the effect of theantioxidant vitamins and trace elementsin Intestamin. Vitamins C and E and�-carotene levels rose rapidly in the in-tervention group, although selenium andzinc levels were not different and re-mained relatively low throughout. Lipidperoxidation (measured as TBARS) wassimilar in the two groups, with TBARSlevels being similar to or lower thanthose for ICU patients either with (2.3 �0.9 mmol/L) or without (1.9 � 0.6mmol/L) systemic inflammatory responsesyndrome recorded in a recent study byMotoyama and colleagues (52) but higherthan those recorded by Senkal and col-leagues (45) in a surgical population(measured in the same laboratory as oursamples). In the most recent version ofthe Canadian nutritional meta-analyses(www.criticalcarenutrition.com), intrave-nous or enteral administration of antioxi-dants was associated with a reduced mor-tality, and Heyland and colleagues (47)recently suggested that high doses of an-tioxidants may minimize mitochondrialdamage in critically ill patients.

The third component of Intestamin istributyrin, which is a novel structuredlipid composed of three molecules of bu-tyrate esterified with glycerol, with 1 g oftributyrin producing 10 mmol of bu-tyrate. Butyrate is an important energysource for large and small bowel and alsoexerts anti-inflammatory effects (53, 54),with the usual source being fermenteddietary fiber in the colon. In critically illpatients, high doses of dietary fiber maycause bloating, abdominal distension,and bacterial overgrowth (55), but these

Table 8. Plasma interleukin (IL)-6 and IL-10 levels



Control Supplement �Fresubin Original, Median

(Minimum–Maximum)

p Value


IL-6 (normal range (0–3.3 ng/L) .237 (treatment effect)1 156 (7–2279) 109 (4–17,683) .7653 31 (2–596) 43 (3–972) .7755 27 (0–179) 27 (5–3951) .7537 25 (1–383) 79 (9–813) .0359 28 (2–191) 39 (7–429) .330

11 27 (3–153) 37 (5–1119) .571IL-10 (normal range 0–9 pg/mL) .599 (treatment effect)

1 10 (�5–60) 11 (�5–1001) .7633 4 (�5–254) 10 (�5–35) .1765 5 (�5–222) 5 (�5–199) .7947 7 (�5–172) 10 (�5–305) .4179 10 (�5–120) 9 (�5–120) .462

11 11 (�5–94) 7 (�5–108) .531



problems have not been observed withenteral tributyrin in experimental (56)and human studies (57), demonstratinggood tolerance and safety, and our resultsfurther support this, although it is un-clear how much of the butyrate generatedfrom tributyrin remains in the gut toreach the large bowel and have an effectthere.

Another important issue is that of ar-ginine, since giving arginine-enrichedfeeds to patients with severe sepsis is con-troversial (12, 58), and Reconvan con-tains 6.7 g/L arginine. In our study, bothpatient groups initially had plasma argi-nine concentrations below normal, butlevels were restored by day 3 in the inter-vention group and remained normalthroughout, even after target Reconvanadministration had been achieved. Thissuggests that the rise in arginine levels inthe early phase of enteral nutritional sup-port (days 1–3) was probably a conse-quence of the conversion of glutamineinto arginine, as shown previously inmultiple trauma patients (59, 60). It isnotable that studies which blame enteralarginine administration for putative ad-verse effects do not provide any aminoacid profiling data to justify such an in-terpretation (13, 61). So while these twoimportant amino acids may have differenteffects in various animal models, espe-cially under conditions of ischemia andreperfusion (28, 29), we have shown herethat it is possible to feed septic patientswith both a high-dose enteral glutaminedipeptide and an arginine-enriched feedwithout causing either an overshoot inarginine production or, since plasma cit-rulline levels did not increase, evidence ofincreased nitric oxide production. Thesereal-life data challenge the theoreticalnotion that arginine supplementation isnecessarily harmful in sepsis (62), andsubsequent studies in this controversialarea must provide amino acid profilingdata to be plausible.

Several previous trials using immune-enhancing feeds or enteral or parenteralglutamine supplementation (63, 64) insurgical and trauma patients have dem-onstrated presumed beneficial effects onimmune status, evidenced by changes ininterleukin levels and HLA-DR activation,with suppressed expression being a poorprognostic sign (65–67). In our septicpatients, initial IL-6 levels were high andfell as the study progressed and mostpatients recovered, without clear differ-ences in interleukin patterns between thetwo groups. HLA-DR expression was ex-

tremely low from the outset and re-mained depressed throughout in spite ofthe relatively low mortality in our studypopulation, with no difference betweenthe groups. In view of the consistency ofthis response, the meaning of this vari-able may need to be better defined.

There were no significant differencesin length of stay or numbers and types ofsecondary infections between the twostudy groups, in spite of the more rapidfall in the delta daily total SOFA in theintervention group. In a small study ofpredominantly medical patients with sep-sis, this is not surprising, since this is amore heterogeneous group than wouldbe the case with trauma or major gastro-intestinal cancer surgery patients. Bloodsugar control was not a factor, since atight blood sugar regimen (68) was used,giving similar blood sugar levels and in-sulin dosage in both groups.

Our study has several important limi-tations. We had originally planned to en-roll 344 patients, but it became apparentat our planned interim analysis that ahighly significant difference in the rate ofdecline in the delta total daily SOFA scorealready existed. In view of this and thepilot nature of the study, we decided tocease enrollment, even though this nec-essarily had the effect of limiting thestrength of the analysis, especially forsome of the secondary outcomes. Theother major limitation of our study de-sign relates to the use of Intestamin andReconvan in combination, rather thanusing Intestamin or placebo followed by asingle standard feed, or even the scien-tific ideal of studying specific feed com-ponents individually. This makes it moredifficult to disentangle the effects of In-testamin from those of Reconvan, al-though the pattern in changes of vita-mins, amino acids, and the biphasic deltatotal daily SOFA response all suggest thatit was probably the effect of Intestaminthat predominated and also make it im-possible to know which individual com-ponents are most important. Addition-ally, the patient group we enrolled hadmedium severity of illness, and the sepsiswas predominantly medical in origin, soit is unclear whether similar results areachievable in other patient populations.

CONCLUSIONS

We believe that our results provideencouraging early data on the use of thepharmaconutrition concept with Intesta-min, demonstrating its feasibility in a

population of patients with predomi-nantly medical sepsis. The new supple-ment was safely and effectively absorbedwhen administered by the nasogastricroute and, in combination with the im-mune-enhancing feed Reconvan, was as-sociated with a significantly more rapidfall in the delta total daily SOFA scorecompared with control, indicating a sig-nificantly faster recovery of organ func-tion. Its use should be investigated fur-ther in other populations of critically illpatients.

ACKNOWLEDGMENTS

We thank the staff and patients of thegeneral adult ICU at St Thomas’ Hospital,London.

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