Higher Caloric Exposure in Critically Ill Patients Transiently Accelerates Thyroid Hormone Activation

Liam McKeever; Sarah J. Peterson; Omar Lateef; Sally Freels; Tatiana L. Fonseca; Barbara M. L. C. Bocco; Gustavo W. Fernandes; Kelly Roehl; Kristen Nowak; Marisa Mozer; Antonio C. Bianco; Carol A. Braunschweig

Disclosures

J Clin Endocrinol Metab. 2020;105(2) 

In This Article

Results

Recruitment Summary

A total of 485 patients met the inclusion criteria. Of these, 448 met our exclusion criteria and were not approached for recruitment. Figure 2 details the outcome of the screening process through which patients were excluded. In all, 35 patients were successfully enrolled. One patient dropped out after randomization but prior to intervention.

Figure 2.

Participant eligibility flow chart.

Patient Demographics and Baseline Data

The majority of participants were female (57%) and African American (46%), with an average age of 56 years. Overall, most patients were normally nourished and obese, based on a BMI > 30. The average baseline APACHE II score was 21 andSOFA was 8.8 (Table 1). When analyzing the 2 groups (100% ECN and 40% ECN), no differences between groups were found at baseline for BMI, nutrition status, SOFA Score, APACHE II, SIRS criteria, ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2:FiO2), or blood glucose (Table 1).

Intervention Data

The nutritional intervention was successful, delivering 5.2 more kcals/kg in the 100% vs the 40% ECN group (P = 0.01; Table 2). As would be expected, patients in the 100% ECN group also had higher intake of carbohydrates, protein, and fat (Table 2). Some heterogeneity in calorie exposure was observed in the 100% ECN group (Table 3). This was caused by various events of critical illness that necessitated extended nil per os status, such as gastric hypoperfusion, emesis, and various tests.

Outcome Variables at Baseline

Baseline plasma T3, rT3, T4, and TSH levels as well as plasma T3/rT3 ratio varied from 9% to 29% between groups (Table 4). Except for the T3/rT3 ratio, these differences were not statistically significant, reflecting the effectiveness of the randomization process (Table 4). However, we wished to minimize further the influence of baseline differences and subsequently adjusted all predictive models for their baseline values.

Primary Outcome Variable

Circulating T3/rT3 ratio: Adjusting for baseline values for the plasma T3/rT3 ratio, the parameters defining the fitted curves (intercept, linear effect of study day, and quadratic effect of study day) differed by randomization group (P = 0.001, P = 0.01, and P = 0.02 respectively, Table 5). Plotting these curves revealed that participants in the 100% ECN exhibited a 54% higher ratio vs the 40% ECN group on postintervention day 1, a difference that attenuated over 4 days (Figure 3a). To explore what was driving this elevation and attenuation, similar models were constructed for plasma T3, rT3, T4, and TSH.

Figure 3.

Fitted curves for the effect of feeding group on plasma T3/rT3 ratio (3a), plasma T3 (3b), plasma rT3(3c), and plasma TSH (3d).

Circulating T3, rT3, and T4 Levels

The SOFA score was found to be a significant confounder in the relationship between intervention groups and plasma T3 and rT3 (Table 6, Table 7). Thus, adjusting for baseline plasma T3 and SOFA score, the parameters defining the fitted curves for plasma T3 (intercept, linear effect of study day, and quadratic effect of study day) differed by randomization group but did not achieve statistical significance (P = 0.04, P = 0.12, and P = 0.12, respectively, Table 6). Plots of the fitted curves revealed plasma T3 was 23% higher on study day 1 in the 100% ECN compared with the 40% ECN group. This difference attenuated over 3 to 4 days (Table 6, Figure 3b). Adjusting for SOFA score, as well as for differences in baseline rT3, the parameters defining the fitted curves for plasma rT3 (intercept and linear effect of study day) differed by randomization group (P = 0.04 and P = 0.02, respectively, Table 7). Plots of the fitted curves revealed participants in the 100% ECN group exhibited a 10% lower plasma rT3 on study day 1 compared with the 40% ECN group, which attenuated over time (Figure 3c). Plasma T4 levels were not significantly associated with the intervention groups.

Circulating TSH

Similar mathematical modeling was applied for plasma TSH values, but no relationship was found between intervention group and plasma TSH throughout the study period (Table 8, Figure 3d). However, visual inspection of the curves suggested that differences in plasma TSH existed in the first 4 days of study. Therefore, an exploratory analysis of the plasma TSH data focusing on days 1 to 4 eliminated the interference given by days 5 to 7 and revealed that, after adjusting for baseline plasma TSH, the parameters defining the fitted curves for plasma TSH (intercept, linear effect of study day, and quadratic effect of study day) differed by randomization group (P = 0.07, P = 0.05, and P = 0.04, respectively, Table 9). Plots of the fitted curves revealed that plasma TSH on study day 1 was doubled in the 100% ECN vs the 40% ECN group, a difference that attenuated over the next 3 days (Figure 4). Analogous models (days 1–4) were constructed for T3, rT3, and T4 and yielded findings similar to their 7-day counterparts (Tables S1–3); All supplementary material and figures are located in a digital research materials repository.[31]

Figure 4.

TSH by feeding group adjusted for baseline TSH and restricted to study days 1 to 4.

Clinical Outcome Variables

No differences were found between the 100% ECN and 40% ECN groups on hospital/ICU length of stay, days on mechanical ventilation, nosocomial infection, or disposition. Data collected on the administration of pressor drugs, steroids, propofol, insulin, and PN also revealed no differences between groups (Table 10).

Intragroup Analyses as a Function of Time

Qualitative visual analysis of the group-stratified raw data (Figs. S1–4; All supplementary material and figures are located in a digital research materials repository[31]) implied that the between-group difference in plasma T3/rT3 ratio was driven by an elevation in the 100% ECN group when compared to baseline study day 1. This was confirmed through a paired t test comparing baseline vs day 1. The plasma T3/rT3 ratio in the 100% ECN group rose from a mean of 4.5 (SD, 1.8) at baseline to 5.1 (SD, 1.5) on study day 1 (paired t = 1.83; P = 0.04). No differences were observed between baseline and study day 1 in the 40%-ECN group. A similar increase in plasma T3 was seen when comparing baseline vs study day 1, which was confirmed through a paired t test. Plasma T3 in the 100%-ECN group rose from a mean of 0.83 ng/mL (SD, 0.38) at baseline to 0.92 ng/mL (SD, 0.35) on study day 1 (paired t = 1.72; P = 0.05). No differences were observed between baseline and study day 1 in the 40% ECN group. The incremental daily changes in plasma rT3 levels over time were minimal, not warranting further exploration. At the same time, no differences in plasma TSH were observed between baseline and study day 1 for the 100% ECN and 40% ECN groups.

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