TICACOS: Tight Calorie Control in the ICU (2011) - ESBICM® | Educational Society of Bedside Intensive Care Medicine

TICACOS: Tight Calorie Control in the ICU (2011)

“In this single-center pilot study a bundle comprising actively supervised nutritional intervention and providing near target energy requirements based on repeated energy measurements was achievable in a general ICU and may be associated with lower hospital mortality.”

— The TICACOS Study Group

1. Publication Details

Trial Title: The tight calorie control study (TICACOS): a prospective, randomized, controlled pilot study of nutritional support in critically ill patients.
Citation: Singer P, Anbar R, Cohen J, et al. The tight calorie control study (TICACOS): a prospective, randomized, controlled pilot study of nutritional support in critically ill patients. Intensive Care Med. 2011;37(4):601-609. doi:10.1007/s00134-011-2146-z.
Published: April 2011, in Intensive Care Medicine.
Author: Pierre Singer, M.D.
Funding: Not specified in the publication.

2. Keywords

Nutritional Support, Indirect Calorimetry, Energy Expenditure, Critical Illness, Enteral Nutrition, Parenteral Nutrition.

3. The Clinical Question

In mechanically ventilated critically ill patients (Population), does guiding nutritional support by repeated indirect calorimetry measurements (Intervention) compared to a standard weight-based formula (Comparison) reduce hospital mortality (Outcome)?

4. Background and Rationale

Existing Knowledge: Providing adequate nutritional support to critically ill patients is a cornerstone of ICU care. However, the optimal method for determining a patient’s caloric needs was debated. Standard practice often relied on weight-based predictive equations (e.g., 25 kcal/kg/day), which can be inaccurate.
Knowledge Gap: Indirect calorimetry directly measures a patient’s resting energy expenditure (REE), offering a more precise target. It was unknown if this more individualized and accurate approach to setting energy targets would translate into improved patient-centered outcomes compared to standard predictive equations.
Proposed Hypothesis: The authors hypothesized that the outcome of critically ill patients would be improved when nutritional support is guided by repeated measurements of REE compared to a single, initial weight-based calculation.

5. Study Design and Methods

Design: A prospective, single-center, randomized, open-label, controlled pilot trial.
Setting: A single 12-bed general ICU at a university-affiliated hospital in Israel.
Trial Period: A 14-month period between 2007 and 2008.
Population:
- Inclusion Criteria: Adult patients (≥18 years) who were mechanically ventilated and expected to have an ICU stay of more than 3 days.
- Exclusion Criteria: FiO2 >0.6, air leaks, head trauma with GCS <8, or recent open-heart surgery.
Intervention: The “tight calorie control” group. The energy target was determined by repeated indirect calorimetry measurements, and a dedicated study dietitian was responsible for ensuring the target was met, using supplemental parenteral nutrition if needed.
Control: The standard care group. The energy target was calculated using the formula 25 kcal/kg/day, and the standard ICU ward staff was responsible for delivering nutrition.
Management Common to Both Groups: Both groups aimed to provide nutrition primarily via the enteral route, with parenteral nutrition as a supplement. Both had a protocol to maintain blood glucose <150 mg/dL.
Power and Sample Size: This was a pilot study, and no formal power calculation was reported. 130 patients were enrolled.
Outcomes:
- Primary Outcome: Hospital mortality.
- Secondary Outcomes: Length of mechanical ventilation and ICU stay.

6. Key Results

Enrollment and Baseline: 130 patients were randomized (65 to tight calorie control, 65 to control). The groups were well-matched at baseline.
Trial Status: The trial was completed as planned.
Primary Outcome: There was a strong trend towards lower hospital mortality in the tight calorie control group, but this did not reach statistical significance (32.3% vs 47.7%; P=0.058).
Secondary Outcomes: Paradoxically, the tight calorie control group had a significantly longer median duration of mechanical ventilation (16.1 vs 10.5 days; P=0.03) and ICU stay (17.2 vs 11.7 days; P=0.04).
Adverse Events: Not specifically detailed, but the intervention group received significantly more parenteral nutrition in the first three days.

7. Medical Statistics

Analysis Principle: An intention-to-treat analysis was performed.
Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
Primary Outcome Analysis: The proportion of deaths in the hospital was compared between the two groups.
Key Statistic(s) Reported: Hospital mortality: 21/65 (32.3%) in the tight calorie group vs 31/65 (47.7%) in the control group; P=0.058.
Interpretation of Key Statistic(s):
- Odds Ratio (OR) (calculated):
  - Calculation: The OR for hospital mortality was approximately 0.52 (95% CI, 0.26 to 1.02).
  - Clinical Meaning: The odds of death were 48% lower in the tight calorie control group, but this result was not statistically significant.
- Confidence Interval (CI):
  - Calculation: The 95% CI was 0.26 to 1.02.
  - Clinical Meaning: The confidence interval is wide and just touches the line of no effect (1.0), indicating a high degree of uncertainty and confirming the lack of statistical significance. The true effect could range from a 74% benefit to a 2% harm.
- P-value:
  - Calculation: The reported p-value was 0.058.
  - Clinical Meaning: The p-value of 0.058 is just above the conventional threshold of 0.05. This means that while there is a strong trend suggesting a benefit, the result is not considered statistically significant, and the observed difference could still be due to chance.
Clinical Impact Measures:
- Absolute Risk Reduction (ARR):
  - Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
  - Calculation: ARR = 47.7% – 32.3% = 15.4%.
  - Clinical Meaning: For every 100 patients treated with the tight calorie control strategy, about 15 fewer died in the hospital, although this result was not statistically significant.
- Number Needed to Treat (NNT):
  - Formula: NNT = 1 / ARR.
  - Calculation: NNT = 1 / 0.154 = 6.5.
  - Clinical Meaning: If the observed effect were true, approximately 7 patients would need to be treated with the tight calorie control strategy to prevent one additional hospital death.
Subgroup Analyses: Not performed.

8. Strengths of the Study

Study Design and Conduct: This was a randomized controlled trial that addressed a highly important and practical question in ICU nutrition.
Physiologic Rationale: The intervention was based on the strong physiologic principle that accurately meeting a patient’s energy needs is beneficial.

9. Limitations and Weaknesses

Internal Validity (Bias): The trial was unblinded. The most significant limitation was the co-intervention: the intervention group was managed by a dedicated study dietitian, while the control group was not. This makes it impossible to separate the effect of using indirect calorimetry from the effect of having an expert actively managing nutrition.
External Validity (Generalizability): As a small, single-center pilot study, the results are not broadly generalizable.
Other: The trial was a pilot study and not powered for definitive conclusions. The secondary outcomes (longer ventilation and ICU stay) were paradoxical and biologically implausible, which raises serious questions about the validity of the primary outcome finding.

10. Conclusion of the Authors

11. To Summarize

Impact on Current Practice: The TICACOS trial was a highly influential pilot study that generated a strong hypothesis and spurred significant interest in using indirect calorimetry in the ICU. However, due to its major limitations (single-center, unblinded, significant co-intervention, paradoxical secondary outcomes), it did not change clinical practice on its own. Its main impact was to provide the justification for larger, more definitive multicenter trials.
Specific Recommendations:
- Patient Selection: For mechanically ventilated critically ill patients.
- Actionable Intervention: This trial suggests that having a dedicated nutrition expert (like a dietitian) actively managing and ensuring delivery of caloric targets may improve outcomes. It provides weak, hypothesis-generating evidence for using indirect calorimetry.
- Expected Benefit: A potential, but unproven, reduction in hospital mortality.
What This Trial Does NOT Mean: This trial does NOT prove that indirect calorimetry is superior to predictive equations. The benefit seen could be entirely due to the presence of the dedicated dietitian in the intervention arm.
Implementation Caveats: The paradoxical increase in length of stay and ventilation in the intervention group remains unexplained and is a major concern.

12. Context and Related Studies

Building on Previous Evidence: This trial was one of the first RCTs to directly compare measured vs. calculated energy targets in the ICU.
Influence on Subsequent Research: TICACOS was a key predecessor to larger and more methodologically rigorous trials. The subsequent TICACOS International trial (2020) was a multicenter follow-up that failed to show a significant benefit in infection rates or mortality. The topic remains an area of active research.

13. Unresolved Questions & Future Directions

Unresolved Questions: Does indirect calorimetry, when separated from the co-intervention of a dedicated expert, improve patient-centered outcomes compared to modern predictive equations?
Future Directions: Future research is focused on large, multicenter trials to definitively answer this question and to understand how to best integrate measured energy expenditure into a comprehensive nutrition care plan.

14. External Links

Original Article: The tight calorie control study (TICACOS): a prospective, randomized, controlled pilot study of nutritional support in critically ill patients

15. Framework for Critical Appraisal

Clinical Question: The question was highly relevant, addressing a fundamental aspect of ICU care.
Methods: The randomized design was a strength. However, the single-center, unblinded nature and, most importantly, the confounding co-intervention of a dedicated dietitian in only the study group, are major methodological flaws that severely limit the validity of the conclusions.
Results: The primary outcome was a non-significant trend toward benefit (p=0.058). The secondary outcomes were paradoxical and concerning, showing significantly longer ICU stays and duration of ventilation in the group that supposedly did better.
Conclusions and Applicability: The authors’ conclusion is appropriately cautious (“may be associated with”). The trial is best viewed as a hypothesis-generating pilot study. Its results are not directly applicable to practice due to the confounding and paradoxical findings, but they were crucial in stimulating further, higher-quality research in the field.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.