Nutrition Journal Vitamin C in plasma is inversely related to blood pressure and change in blood pressure during the previous year in young Black and White women

Gladys Block firstname.lastname@example.com
School of Public Health
50 University Hall
University of California
94720BerkeleyCAUSA

Christopher D Jensen firstname.lastname@example.com
School of Public Health
50 University Hall
University of California
94720BerkeleyCAUSA

Edward P Norkus email@example.com
Department of Medical Research
Montefiore Medical Center North Division
600 East 233Street10466BronxNYUSA

Mark Hudes firstname.lastname@example.com
Nutritional Sciences and Toxicology
University of California
119 Morgan Hall94720BerkeleyCAUSA

Patricia B Crawford email@example.com
Nutritional Sciences and Toxicology
University of California
119 Morgan Hall94720BerkeleyCAUSA

Nutrition Journal Vitamin C in plasma is inversely related to blood pressure and change in blood pressure during the previous year in young Black and White women
10.1186/1475-2891-7-35BioMed Central Page 1 of 9 (page number not for citation purposes) Research * Corresponding author
Background:The prevalence of hypertension and its contribution to cardiovascular disease risk makes it imperative to identify factors that may help prevent this disorder. Extensive biological and biochemical data suggest that plasma ascorbic acid may be such a factor. In this study we examined the association between plasma ascorbic acid concentration and blood pressure (BP) in young-adult women.Methods: Participants were 242 Black and White women aged 18-21 yr from the Richmond, CA, cohort of the National Heart, Lung and Blood Institute Growth and Health Study. We examined the associations of plasma ascorbic acid with BP at follow-up year 10, and with change in BP during the previous year.Results:In cross-sectional analysis, plasma ascorbic acid at year 10 was inversely associated with systolic BP and diastolic BP after adjusting for race, body mass index, education, and dietary intake of fat and sodium. Persons in the highest one-fourth of the plasma ascorbic acid distribution had 4.66 mmHg lower systolic BP (95% CI 1.10 to 8.22 mmHg, p = 0.005) and 6.04 mmHg lower diastolic BP (95% CI 2.70 to 9.38 mmHg, p = 0.0002) than those in the lowest one-fourth of the distribution. In analysis of the change in BP, plasma ascorbic acid was also inversely associated with change in systolic BP and diastolic BP during the previous year. While diastolic blood pressure among persons in the lowest quartile of plasma ascorbic acid increased by 5.97 mmHg (95% CI 3.82 to 8.13 mmHg) from year 9 to year 10, those in the highest quartile of plasma vitamin C increased by only 0.23 mmHg (95% CI -1.90 to +2.36 mmHg) (test for linear trend: p < 0.0001). A similar effect was seen for change in systolic BP, p = 0.005.Conclusion:Plasma ascorbic acid was found to be inversely associated with BP and change in BP during the prior year. The findings suggest the possibility that vitamin C may influence BP in healthy young adults. Since lower BP in young adulthood may lead to lower BP and decreased incidence of age-associated vascular events in older adults, further investigation of treatment effects of vitamin C on BP regulation in young adults is warranted.

Background

Elevated blood pressure (BP) is a major public health problem in the United States with almost 60% of American adults having pre-hypertension or hypertension [1]. The disorder is prevalent in all major ethnic groups, although Blacks are disproportionately affected [1]. As elevated BP is a strong and independent risk factor for cardiovascular and renal disease morbidity and mortality [2], identifying preventive measures is an important public health goal.

The Dietary Approaches to Stop Hypertension (DASH) trial demonstrated that diet is an important factor in BP regulation. In that study, a diet rich in vegetables, fruit, low-fat dairy foods, and with reduced saturated and total fat intake significantly reduced systolic BP and diastolic BP over a period of 8 weeks compared to a control diet [3]. DASH diet constituents believed to contribute to the observed BP-lowering effect include calcium, magnesium, potassium, dietary fiber, and the reduced fat content of the diet [3,4]. The DASH diet is also rich in vitamin C, another possible contributor to the observed BP effect [5]. Mechanistic studies have demonstrated a role of vitamin C in maintaining the normal production and biological activity of endothelium-derived nitric oxide which plays a role in vascular tone and reactivity [6,7]. Thus, plasma ascorbic acid concentration should be investigated for its possible role in lowering or maintaining normal BP.

Numerous cross-sectional studies have observed highly significant inverse relationships between BP and circulating ascorbic acid concentration [8][9][10][11][12][13][14][15][16][17][18]. Almost all such studies have focused on populations that are middle-aged and older, and intervention research has typically focused on treatment of those with already elevated blood pressure. However, we hypothesized that an ascorbic acid association in a young normotensive population might provide clues to the primary prevention of hypertension. Examining this relationship in young adults is potentially important because maintaining healthy BP in healthy young adults may lead to a lower BP in older adults, and consequently a lower incidence of age-associated vascular events [2]. Therefore, we investigated this relationship among 18-21 year old Black and White women enrolled in the National Heart, Lung, and Blood Institute (NHLBI) Growth and Health Study. We hypothesized that plasma ascorbic acid concentration at the 10th annual follow-up visit would be inversely associated with BP, and inversely associated with change in BP during the previous year, in this population group.

Methods

Participants

In 1985, the NHLBI initiated the Growth and Health Study, a 10-year longitudinal multicenter study to investi-gate the development of obesity in Black and White girls during adolescence, along with its environmental, psychosocial, and cardiovascular disease risk factor correlates. Black and White girls, ages 8 to 11 years, were recruited from Richmond, CA, Cincinnati, OH, and Washington, DC areas. Institutional review board approval was obtained at all participating centers. The parents or guardians of participants gave informed consent for the children to participate. Girls were followed annually through ages 18 to 21 years, with a follow-up rate of 90% at the 10 th annual follow-up visit. The sample design, recruitment and selection procedures used for the Growth and Health Study have been previously described [19]. For this investigation, plasma ascorbic acid samples were obtained only from girls in the Richmond, CA cohort at the 10 th annual visit. The blood draw for plasma ascorbic acid was implemented midway through the annual data collection period and a total of 335 participants were seen in the clinic after plasma sample collection was initiated. Plasma samples were successfully obtained from 242 participants (72%), consisting of 155 Blacks and 87 Whites. The 93 who did not participate in the extra blood draw were either seen on a day when the ascorbic acid study staff was not present to take their blood, were pregnant, or refused the extra procedure.

Data collection

BP BP measurements were obtained by trained examiners according to a standard protocol [20]. Participants were seated with feet resting flat on a surface and the right arm resting at heart level. Participants were seated for at least 5 minutes before BP measurements were begun. The appropriate cuff was selected from 5 cuff sizes and placed around the upper arm. Using a standard mercury sphygmomanometer (Baum Desktop model with V-Lok cuffs), three consecutive readings were taken using the same arm and waiting at least 30 seconds between readings. The second and third readings were averaged to determine the mean systolic BP, defined as the onset of the first two consecutive beats (first Korotkoff phase), and the mean diastolic BP, defined as the point at which the sound disappeared (fifth Korotkoff phase). BP was obtained at both the 9th and 10 th annual visits.

Plasma ascorbic acid

Participants were instructed to fast for at least 12 hours before the blood draw. Plasma ascorbic acid was determined using the 2,4-dinitrophenylhydrazine method [21], which has been shown to correlate well with HPLC methods [22]. Plasma was stabilized with 10% metaphosphoric acid, frozen at -70°C within 4 hours of the collection, and analyzed within six months. Plasma ascorbic acid was assayed only at the 10 th annual visit. Blood stored from earlier visits could not be used for assaying ascorbic acid because it had not been stabilized with metaphosphoric acid.

Anthropometry

At the 10 th annual visit, participants were weighed using an electronic scale (SECA Alpha 770) in gowns without shoes. Height was measured using a custom portable stadiometer (Creative Health Products, Plymouth, MI). Participants wore socks and were positioned with heels together, toes apart at a 45 degree angle, and head in the Frankfort horizontal plane. Both weight and height were measured twice and repeated a third time if values differed by more than 0.3 kg and 0.5 cm, respectively. Body mass index (BMI) was calculated as kg/m 2 .

Socioeconomic and lifestyle variables

Information on socioeconomic and lifestyle variables was ascertained by questionnaire at the 10 th annual visit.

Smoking was assessed by asking how many days participants smoked in the past 30 days and how many cigarettes were smoked per day. The number of smoking days/ month was then multiplied by the number of cigarettes/ day to create a continuous variable, cigarettes smoked/ month. Alcohol consumption was assessed in a similar fashion, with 1 drink being equivalent to 12 oz. (355 mL) of beer or 6 oz. (177 mL) of wine. The number of hours/ week of television or videos watched was assessed as a proxy for physical inactivity. Pregnancy history and current contraceptive use was also obtained.

Dietary variables

Dietary information at the 10 th annual visit was determined using 3-day dietary records, covering two consecutive weekdays and one weekend day. Participants used rulers, pictures, and thickness guides to measure and quantify the amount of food consumed. Dietary records were reviewed with a dietitian and analyzed for nutrient composition by the Cincinnati Dietary Center using the University of Minnesota Nutrition Coordinating Center database. The method used for estimating nutrient intake had been previously validated in this population [23]. All micronutrient intake estimates include amounts provided by supplements. Estimates of dietary sodium intake were from food only and no attempt was made to collect information on added dietary salt intake.

Statistical analyses

Unpaired two-tailed t-tests and Wilcoxon two-sample tests were used to compare baseline characteristics of Black and White study participants. Plasma ascorbic acid at year 10 was divided into quartiles, and least squares mean diastolic and systolic BP, adjusted for race, BMI, education, and intake of fat and sodium, were calculated for each quartile using analysis of covariance. Change in BP was calculated as the systolic and diastolic values at year 10 minus their respective values at year 9, and adjusted changes were calculated using analysis of covariance; year 9 BP was included as a covariate in the model. The relationships between plasma ascorbic acid and BP at the 10 th annual visit, as well as between plasma ascorbic acid at year 10 and change in BP in the previous year, were also examined as continuous variables using multivariable linear regression models. The interaction of race and BMI with the independent variable was assessed using cross-product terms in the regression models. Annual household income and education were highly correlated. However, education explained more of the variance, and consequently education was used in the models. A number of other covariates were considered as potential confounders, including intake of total energy, potassium, calcium, dietary antioxidants, and fiber, pregnancy history, use of birth control pills, smoking, alcohol consumption, and number of hours/week of television or video watching. However, none was statistically significant and these variables were not included in the final models. Statistical analyses were conducted with SAS 9.1.

Results

Descriptive characteristics and comparisons of the total sample and by race are presented in Table 1. Mean diastolic BP, age, weight, BMI, energy intake, and plasma ascorbic acid concentrations did not differ significantly by race. Black women had higher mean systolic BP, watched more hours/week of television or videos, consumed more fat/ day, and lived in households with lower incomes as compared to White women. Blacks also smoked significantly fewer cigarettes, drank less alcohol, and were more likely to have been pregnant (data not shown.) However, race did not significantly modify the relationship between plasma ascorbic acid and BP (interaction terms for systolic and diastolic BP were p = 0.42 and p = 0.47, respectively). Therefore, statistical models included all 242 subjects and were not stratified by race.

For comparison of BP in categories of plasma ascorbic acid, the plasma ascorbic acid distribution among participants at visit 10 was divided into fourths. Mean concentrations of ascorbic acid, by quartile, were as follows: In cross-sectional analyses, we examined BP across quartiles of plasma ascorbic acid at the 10 th annual visit. There was a significant inverse linear trend in both systolic BP ( Figure 1) and diastolic BP (Figure 2) across the quartiles of plasma ascorbic acid concentration (unadjusted p = 0.0001, respectively). In regression analysis using the quartiles as predictor variables, after adjustment for BMI, race, education, and dietary fat and sodium intake, these inverse linear trends remained significant for both systolic BP and diastolic BP, with substantial differences in BP across the quartiles. Persons in the upper one-fourth of the plasma ascorbic acid distribution had 4.66 mmHg lower systolic BP (95% CI 1.10 to 8.22 mmHg, p = 0.005) than those in the lower one-fourth of the plasma ascorbic acid distribution. For diastolic BP, persons in the upper one-fourth of the plasma ascorbic acid distribution had 6.04 mmHg lower diastolic BP (95% CI 2.70 to 9.38 mmHg, p = 0.0002) than those in the lower quartile of ascorbic acid. We also performed multiple regression analysis of ascorbic acid as a continuous variable, with BP as the dependent variable, plasma ascorbic acid as the primary predictive variable, and adjusting for BMI, race, education, dietary fat and sodium intake. Cross-sectionally, as plasma ascorbic acid concentration increased by 1 mg/dL (56.8 μmol/L), systolic BP decreased by 4.1 mmHg (95% CI -6.6 to -1.7 mmHg) and diastolic BP decreased by 4.0 mmHg (95% -6.4 to -1.7 mmHg).

We also examined the association between plasma ascorbic acid concentration at year 10 and change in BP between years 9 and 10. Change in both systolic BP and diastolic BP was inversely associated with plasma ascorbic acid concentration at year 10 ( Figure 3) after adjustment for BMI, race, education, and dietary fat and sodium intake. Systolic BP increased by 1.40 mmHg (95% CI -0.76 to +3.57 mmHg) among those in the lowest quartile of the plasma ascorbic acid distribution, but decreased in persons in higher quartiles of plasma ascorbic acid (test for linear trend in change in BP across quartiles of year 10 ascorbic acid: p = 0.005). Diastolic BP increased overall, but the increase was less with increasing quartiles of plasma ascorbic acid. While diastolic blood pressure among persons in the lowest quartile of plasma ascorbic acid increased by 5.97 mmHg (95% CI 3.82 to 8.13 mmHg) from year 9 to year 10, those in the highest quartile of plasma vitamin C increased by only 0.23 mmHg (95% CI -1.90 to +2.36 mmHg) (test for linear trend: p < 0.0001). Control for weight change between years 9 and 10 made essentially no difference in these results (data not shown).

Discussion

We found plasma ascorbic acid concentration to be inversely associated with systolic and diastolic BP in young-adult Black and White women, independent of race, BMI, education, diet, and lifestyle factors. A 1 mg/dL (56.8 μmol/L) increase in plasma ascorbic acid levels was associated with 4.1 mmHg lower systolic blood pressure and 4.0 mmHg lower diastolic blood pressure. Plasma ascorbic acid levels in this cohort ranged from 0.22 to 3.13 mg/dL (12.5 to 177.8 μmol/L), indicating that a 1 mg/dL change in plasma ascorbic acid level is achievable in this young population.

Plasma ascorbic acid concentration was also inversely and significantly associated with change in BP during the previous year. It is particularly notable that there was very little increase in diastolic BP in persons in the highest quartile of ascorbic acid. The magnitude of the decrease in systolic and diastolic blood pressure associated with plasma ascorbic acid is consistent with the range of values found in other crosssectional studies [8][9][10][11][12][13][14][15][16][17][18]. A review by Ness [18] found that the blood pressure difference associated with a 50 μmol/L (0.88 mg/dL) difference in ascorbic acid concentration ranged from -2.6 to -9.4 mmHg for diastolic blood pressure, and from -3.6 to -17.8 mmHg for systolic blood pressure.

Intervention trials have been less consistent [24][25][26][27][28][29][30][31][32][33][34][35][36][37].

Many of the studies that failed to find a treatment effect have had design limitations such as no control group or no placebo control, short duration, small sample size, concomitant use of non-study dietary supplements containing vitamin C, and varying or inadequately described methods for measuring BP; or they were post-hoc analyses where change in BP was not a primary endpoint of the trial. On the other hand, some studies have found significant reductions in BP as a result of treatment with vitamin C [38][39][40][41].

The DASH study [3] is the major intervention trial of nutritional factors, and our results are comparable in magnitude to those of DASH. Among all participants in the DASH study, the DASH diet lowered mean systolic BP by 5.5 mmHg, and lowered mean diastolic BP by 3.0 mmHg. In the present study, the difference between the mean BP in the first and fourth quartiles of ascorbic acid concentration was 4.7 mmHg systolic, and 6.1 mmHg diastolic BP. This suggests the possibility that if the ascorbic acid concentration of those in the lower one-fourth of the distribution could be increased to the ascorbic acid concentration of those in the top one-fourth of the distribution, an effect comparable to that of the DASH diet could be achieved. The present study was not an intervention study and such an intervention effect is only a hypothesis, but one which would seem to merit follow-up.

The ranges of plasma ascorbic acid seen in our sample are very consistent with those found in the United States. We Year 10 Plasma Ascorbic Acid Quartile

Year 10 Systolic Blood Pressure (mmHg) Unadjusted Adjusted women in the same age group, 18-21 years. The mean plasma ascorbic acid concentrations in the four quartiles were 0.43 mg/dL, 0.84 mg/dL, 1.14 mg/dL, and 1.59 mg/ dL (24.1, 47.8, 64.8, 90.1 μmol/L). (Block, unpublished data.) In our sample those means were 0.59, 1.03, 1.36 and 1.83 mg/dL. Thus, in the present sample the first three quartiles were similar although slightly higher than those seen in representative national data. The lower two quartiles represent ascorbic acid concentrations most likely obtained from fruits, vegetables and fortified foods such as cereals. A diet rich in fruits and vegetables can produce a concentration similar to that seen in the third quartile. The concentration in the fourth quartile represents a level in which supplements containing vitamin C have made a substantial contribution.

There is substantial biologic rationale for a causal role of ascorbic acid in maintaining normal BP. Numerous oxidative mechanisms appear to be involved in the pathogenesis of hypertension [6,7,42]. One well-studied oxidative stress biomarker is F 2 -isoprostane, a vasoactive product of lipid peroxidation [43]; we have shown in a randomized trial that supplementation with vitamin C, but not with vitamin E, significantly reduces F 2 -isoprostane [44]. Similarly inflammation, consistently associated with increased risk of cardiovascular disease, is associated with impaired endothelium-dependent vasodilation and hypertension [45]. Bautista found a progressive increase in blood pressure with increases in high-sensitivity C-reactive protein (hsCRP), a sensitive marker of inflammation [45]. We showed, in a randomized trial, that vitamin C but not vitamin E significantly lowered hsCRP, to an extent equivalent to that seen with statins [46]. Thus, vitamin C may have a beneficial effect on BP by mitigating the adverse effects of inflammation and oxidative stress. Specific functions of vitamin C have also been shown. These include effects on smooth muscle contractility of peripheral blood vessels and improvement of vasomotor dysfunction [47], prevention of nitric oxide inhibition of release of endothelium-derived relaxing factor [48], and prevention of free radical inhibition of prostacyclin synthetase. Ascorbic acid may also influence BP by maintain- Unadjusted Adjusted ing the normal production and biological activity of nitric oxide through enhanced recycling of tetrahydrobiopterin, a cofactor that stabilizes and sustains the activity of endothelial nitric oxide synthase [49][50][51][52].

An important limitation of this study is the fact that the results depicted in Figures 1 and 2 are cross-sectional and therefore causality cannot be inferred. Also, the data represented in Figure 3 are limited by the fact that there were no plasma ascorbic acid measurements for the 9th annual visit, and therefore the association with change in BP, while longitudinal, is not truly prospective. In interpreting our findings it is important to consider the fact that dietary variables are often correlated with one another and may be correlated with lifestyle variables. Therefore, it is possible that plasma ascorbic acid concentration is simply a marker for another variable that influences BP. However, the association persisted even after controlling for BMI, race, education, and intake of fat, sodium and antioxidants. We also evaluated the effect of controlling for other potential confounders including smoking, alcohol consumption, television or video watching, and intake of total energy, calcium, and potassium, and none diminished the strength of the association.

Nevertheless, while we cannot confidently infer causality, our findings point to the important possibility that vitamin C may influence BP even among healthy young adults. This finding is of importance because lowering BP or attenuating increases in BP in young adults may lead to lower BP in older adults, which in turn may reduce the risk of age-associated vascular events. Therefore, our findings suggest that further study of the relationship between vitamin C and BP in this young-adult population is warranted.

Conclusion

This is the first study to report on the relationship between plasma ascorbic acid concentration and BP in a cohort of young, normotensive women, aged 18-21 years. Plasma

Change in blood pressure between visit 9 and visit 10, by quartiles of plasma ascorbic acid at visit 10, NHLBI Growth and Health Study, Richmond, CA cohort, 1996-1997 (tests for linear trend: systolic BP p = 0.005; diastolic BP p < 0.0001; adjusted for race, BMI, education, dietary fat, dietary sodium) ascorbic acid concentration was found to be inversely associated with BP and with change in BP over the previous year. These inverse relationships were observed in a sample where two-thirds of participants were Black, a population that suffers disproportionately from elevated BP and its sequelae. Lowering BP or attenuating increases in BP in healthy young adults may lead to lower BP in older adults and reduced risk of age-associated vascular events. This study suggests that vitamin C may be an important factor in BP regulation even among health young adults, and that further study is warranted.

Quartile 1: 0.59 mg/dL (SD 0.18 mg/dL); Quartile 2: 1.03 mg/dL (SD 0.10 mg/dL); Quartile 3: 1.36 mg/dL (SD 0.10 mg/dL); and Quartile 4: 1.83 mg/dL (SD 0.34 mg/dL). (Means in SI units: 33.51 μmol/L, 58.50 μmol/L, 77.25 μmol/L, 103.94 μmol/L for quartiles 1 through 4, respectively.)

examined data from the National Health and Nutrition Examination Survey (NHANES) 2003-2004, among Systolic blood pressure by quartiles of plasma ascorbic acid, NHLBI Growth and Health Study, Richmond, CA cohort, 1996-1997 (tests for linear trend: unadjusted p = 0.0001; adjusted for race, BMI, education, dietary fat, dietary sodium, p = 0.005) Figure 1 Systolic blood pressure by quartiles of plasma ascorbic acid, NHLBI Growth and Health Study, Richmond, CA cohort, 1996-1997 (tests for linear trend: unadjusted p = 0.0001; adjusted for race, BMI, education, dietary fat, dietary sodium, p = 0.005). Plasma ascorbic acid concentrations by quartile: Q1, 0.59 mg/dL (SD 0.18); Q2, 1.03 mg/dL (SD 0.10); Q3, 1.36 mg/dL (SD 0.10); Q4, 1.83 mg/dL (SD 0.34). (SI units: 33.51 μmol/L, 58.50 μmol/L, 77.25 μmol/L, 103.94 μmol/L)

Figure 3
3Change in blood pressure between visit 9 and visit 10, by quartiles of plasma ascorbic acid at visit 10, NHLBI Growth and Health Study, Richmond, CA cohort, 1996-1997 (tests for linear trend: systolic BP p = 0.005; diastolic BP p < 0.0001; adjusted for race, BMI, education, dietary fat, dietary sodium). Plasma ascorbic acid concentrations by quartile: Q1, 0.59 mg/dL (SD 0.18); Q2, 1.03 mg/dL (SD 0.10); Q3, 1.36 mg/dL (SD 0.10); Q4, 1.83 mg/dL (SD 0.34). (SI units: 33.51 μmol/L, 58.50 μmol/L, 77.25 μmol/L, 103.94 μmol/L)

Table 1 :
1Characteristics of 242 young-adult women in the Richmond, CA cohort of the NHLBI Growth and Health Study, 1996-1997.All
(n = 242)

Blacks
(n = 155)

Whites
(n = 87)

Mean
SD
Mean
SD
Mean
SD
p*

Systolic BP (mmHg)
109.8
10.3
111.1
10.8
107.4
9.0
0.007
Diastolic BP (mmHg)
66.9
9.0
67.4
9.0
66.1
9.0
0.31
Plasma vitamin C (mg/dL)  †
1 . 2
0 . 5
1 . 2
0 . 4
1 . 2
0 . 6
0 . 3 4
Age (yr)
19.1
0.6
19.2
0.7
19.1
0.6
0.28
Weight (kg)
70.9
19.3
71.2
19.3
70.4
19.3
0.74
BMI (kg/m 2 )
26.1
6.7
26.4
6.6
25.7
6.9
0.40
Television or video watching
(hr/wk)

32.0
24.1
39.3
23.9
19.0
18.4 < 0.0001

Household income ($)  ‡
20,000-29,999
10,000-19,999
30,000-39,999
< 0.0001
Total energy intake (kcal/d)
1919.6
787.2
1985.8
827.7
1809.9
706.4
0.11
Total fat intake (gm/d)
74.1
36.8
79.3
36.2
65.5
36.2
0.006
Dietary vitamin C intake (mg/d)**
Mean (median, 25 th 75 th %ile)

121.7
(79.3)

176.6
(38.9, 128.2)

128.1
(80.0)

203.4
(43.4, 126.1)

111.1
(63.5)

120.3
(31.0, 136.5)

0.43

* P-values pertain to comparison between Blacks and Whites.
 † Multiply by 56.8 to convert to SI units, μmol/L
 ‡ Household income values are the categories in which the median fell.
** Values in parentheses represent median (in the Means column) and 25 th /75 th percentiles (in the Standard Deviations column)

tests for linear trend: unadjusted p = 0.0001; adjusted for race, BMI, education, dietary fat, dietary sodium, p = 0.0002). Plasma ascorbic acid concentrations by quartile: Q1, 0.59 mg/dL (SD 0.18); Q2, 1.03 mg/dL (SD 0.10); Q3, 1.36 mg/dL (SD 0.10); Q4, 1.83 mg/dL (SD 0.34). (SI units: 33.51 μmol/L, 58.50 μmol/L, 77.25 μmol/L, 103.94 μmol/L)Diastolic blood pressure by quartiles of plasma ascorbic acid, NHLBI Growth and Health Study, Richmond, CA cohort, 1996-
1997 (tests for linear trend: unadjusted p = 0.0001; adjusted for race, BMI, education, dietary fat, dietary sodium, p = 0.0002)
Figure 2
Diastolic blood pressure by quartiles of plasma ascorbic acid, NHLBI Growth and Health Study, Richmond, CA cohort, 1996-
1997 (Diastolic Blood Pressure

70.1

67.9

66.2

69.8

68.3

65.9

63.4 63.7

60

62

64

66

68

70

72

Quartile 1
Quartile 2
Quartile 3
Quartile 4

Year 10 Plasma Ascorbic Acid Quartile

Year 10 Diastolic Blood
Pressure (mmHg)

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AcknowledgementsThe study was supported by grants NO-HC-55023-26 and UO1-HL48941-44 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda Maryland. Data collection and analysis was supported by National Institute of Environmental Health Sciences grant P30 ES01896.AbbreviationsBP: blood pressurel CI: confidence interval; DASH: Dietary Approaches to Stop Hypertension; NHLBI: National Heart, Lung, and Blood Institute; BMI: body mass indexCompeting interestsThe authors declare that they have no competing interests.Authors' contributionsGB and CDJ participated in data analysis and manuscript development. EPN conducted laboratory analyses and participated in manuscript editing. MH participated in data analysis and manuscript editing. PBC participated in the design of the study and manuscript editing. All authors have read and approved the final manuscript.
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Osseous manifestations of non-Hodgkin's lymphoma in Human Immunodeficiency Virus (HIV) infection and Acquired Immunodeficiency Syndrome (AIDS)

DrR Magagula
Mbchb ( Medunsa
M N Rasool
P K Ramdial
Y Singh
A Ramburan
Mmed Sci
PhDAnat Path

Registrar in Orthopaedic Surgery
University of KwaZulu-Natal
Durban

Acting Head of Department
Orthopaedic Surgery
University of KwaZulu-Natal
Durban

Head of Department
Anatomical Pathology
Inkosi Albert Luthuli Central Hospital
Durban

Anatomical Pathologist
Inkosi Albert Luthuli Central Hospital
Durban

Medical Scientist
Inkosi Albert Luthuli Central Hospital
Durban

Department of Orthopaedics Surgery Inkosi Albert Luthuli Central Hospital
800 Vusi Mzimela Road 4091 Cato Manor

Osseous manifestations of non-Hodgkin's lymphoma in Human Immunodeficiency Virus (HIV) infection and Acquired Immunodeficiency Syndrome (AIDS)
37B5DA2932D5597DDDDFDB48807ABF7310.17159/2309-8309/2015/v14n3a1bone lymphomanon-Hodgkin'sHIVAIDS
Background: Lymphoma is the second most common Acquired Human Immunodeficiency Syndrome (AIDS)associated neoplasm, the commonest being Kaposi sarcoma.The diagnosis and treatment of bone lymphoma still remains a challenge in our environment.Materials and methods:This is a retrospective chart review of 105 patients who were diagnosed histopathologically with lymphoma involving the bone over a period of 11 years in six local hospitals.Results: Forty-five (42.9%) patients with bone lesions and who were positive for Human Immunodeficiency Virus (HIV) formed the cohort.Clinical manifestations varied from swelling and pain in all patients to pathological fractures (n = 5, 11.1%) and paraplegia (n = 11, 24.4%) due to cord compression.Common sites included the spine, pelvis, femur, humerus, ribs, tibia and mandible.Treatment included chemotherapy and radiation, splinting or surgical fixation of pathological fractures and decompression of the spine with or without fusion.Conclusion:Bone lymphoma should be considered in any HIV-positive patient presenting with unexplained swelling and pain.The radiological picture may mimic bone infections like chronic pyogenic osteomyelitis, tuberculosis and fungal infections, other systemic disorders like Paget's disease, blood-related tumours such as leukaemia and other primary and metastatic bone neoplasms.

Introduction

Lymphoma, commonly associated with congenital and acquired immune deficiency, is the second most common neoplasm associated with HIV and AIDS, and non-Hodgkin's lymphoma (NHL) is an AIDS-defining condition according to the World Health Organisation (WHO). 1,2With more than six million South Africans infected with HIV and 60 per cent of them already receiving highly active antiretroviral therapy (HAART), HIV-associated morbidity and mortality have decreased significantly. 3However, the incidence of AIDS-related lymphoma has not decreased as much and remains a major therapeutic problem. 3 Skeletal manifestations of this entity in patients with HIV infection are rarely reported in the literature.Any bone, except small bones of hands and feet, can be involved and radiological manifestations are variable making diagnosis difficult and sometimes missed. 4This is a retrospective review of clinical records and radiographs of patients who were HIV-positive and diagnosed with lymphoma affecting bone either as primary or secondary involvement.The aim is to highlight the spectrum of bone lesions in NHL and increase awareness of its occurrence in patients with HIV infection.

Materials and methods

The medical records of all patients who were diagnosed histopathologically with lymphoma involving the musculoskeletal system seen from September 2002 to December 2013 in six local hospitals were reviewed retrospectively.The clinical data recorded included clinical presentation, age, gender, HIV status, antiretroviral treatment, laboratory analysis and CD-4 count.Work-up of these patients included blood analysis (full blood count and differential, erythrocyte sedimentation rate, C-reactive protein, liver enzymes and calcium, magnesium and phosphate).Imaging included computerised tomograph of the chest, ultrasound of the abdomen and bone scan.The radiological patterns of bone lymphoma were assessed on plain radiographs mainly, and on magnetic resonance scans (MRI) when the spine was involved.Open biopsy of the most accessible lesion was performed to confirm the diagnosis.All HIV patients who presented with lymphoma involving bone either as primary or secondary lesions were included.The patients were classified according to the World Health Organisation (WHO) into four groups: 1 1.Lymphoma with a single bone site with or without regional lymph node involvement

Results

In a period of 11 years, 105 patients were diagnosed histologically with lymphoma involving bone.Of these 45 (42.9%) were confirmed HIV-positive and had lymphoma.Their ages ranged from 5 to 60 years (mean 24.4) (Figure 1).

There was no significant male:female difference.All patients presented with constitutional symptoms, pain and swelling, pathological fractures (n = 6, 13.3%, two of which were in one patient) and paraplegia (n = 11, 24.4%) (Table I).The spine was by far the most commonly involved area (n = 23, 51.1%) (Table II).The thoracic (n = 12, 52.2%) region was most often involved, followed by the lumbar (n = 8, 34.8%) and cervical spine (n = 3, 13.0%).

Other sites included the pelvis, femur, ribs, humerus, tibia and mandible.Fifty-eight per cent (n = 26) of the patients presented with secondary bone lymphoma and forty-two per cent (n = 19) were primary.The majority of the patients had anaemia of chronic illness (haemoglobin ranged from 6.5 g/dL to 13.5 g/dL, mean 9.04), were malnourished and presented with raised erythrocyte sedimentation rate (ESR) (ranged from 17 mm/hr to 143 mm/hr, mean 65).The absolute CD4 count in 77.8% (n = 35) of the patients was below 200 (Table III).All patients had large B-cell non-Hodgkin's lymphoma, with CD10 immunopositivity.Imaging investigations revealed a subtle or 'near normal' pattern (n = 7, 15.5%), lytic destructive (n = 18, 40%), sclerotic (n = 12, 26.7%), mixed lytic and sclerotic (n = 8, 17.8%).Pathological fractures were present in five (50%) long bones and the periosteal reaction was mostly nonspecific.In the appendicular skeleton the lesions were monostotic (n = 11, 84.6%) and polyostotic (n = 2, 14.3%) and in the axial skeleton they were single level (n = 7, 31.8%) and multi-level (n = 15, 68.2%) vertebral involvement (Figures 2-6).

Lymphoma is an AIDS-defining condition according to the World Health Organisation

Treatment was multidisciplinary and included orthopaedics, neurosurgery and haematology/oncology.

All patients received CHOP regimen chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone) except for four (8.9%) patients who died of pneumonia after biopsy while awaiting histology results and referral to oncology.Nine patients (20%) did not complete the minimum of six cycles of chemotherapy because they became very debilitated and abandoned therapy and demised after 3 months.Twenty patients (44.5%) received a combination of chemotherapy and radiotherapy.

Most long bone pathological fractures were treated surgically in adults [plating of the humerus (n = 1, 16.6%) and intermedullary nailing of the femur (n = 2, 33.3%)] and immobilised in a plaster in children (n = 2, 33.3%).One femoral (16.6%) nail was later removed and an external fixator applied after development of deep infection post-operatively and the patient demised 2 months later due to septicaemia.Two patients (33.3%) with pathological fractures of the femur and humerus were treated with skeletal traction and backslab immobilisation, respectively, because they were not fit for surgery.They demised of complications 4 weeks later.

Patients who presented with cord compression were treated by surgical decompression with or without spinal fusion (decompression alone, n = 8, 34.8% and decompression and fusion n = 6, 26.1%).Within the first 18 months of treatment a total of 28 (62.2%)patients had demised.Currently five (11.1%) patients have been disease-free for 2 years, seven (15.6%) have had recurrence, and five (11.1%) are lost to follow-up.The minimum follow-up was 6 months (range: 6 months to 2 years; mean: 12 months).

Discussion

Reports on bone lymphoma in HIV-positive patients are rare in the literature, with the exception of a few case reports. 5,6Lymphoma is a haematopoietic neoplasm composed of malignant lymphoid cells affecting different parts of the body.The most common areas of involvement include lymph nodes, spleen, central nervous system, bone marrow and gastrointestinal tract.Malignant lymphomas are classified as Hodgkin's lymphoma (the pathognomonic feature being the presence of Reed-Sternberg cells) and non-Hodgkin's lymphoma. 1,2,7

Treatment was multidisciplinary and included orthopaedics, neurosurgery and haematology/oncology

The current World Health Organisation (WHO) classification of non-Hodgkin's lymphoma (NHL) is based mainly on the B-cell and T-cell origins of the neoplasm. 1In HIV infection the majority of these lymphomas are highgrade B-cell lymphoma: Burkitt lymphoma, diffuse large B-cell lymphoma and diffuse large B-cell lymphoma with immunoblastic features. 7,8In our series all patients had diffuse large B-cell NHL.0][11][12][13] The low incidence of PBL underpins the controversies associated with definition, management strategies and prediction of outcome. 11The common sites of bone involvement include the ribs, pelvis, sternum, clavicle, femur, humerus and vertebrae. 1,7It is therefore unusual to find lymphoma involving the small bones of the hands and feet. 1 NHL is present in about 1% to 3% of HIV-seropositive patients at the time of initial diagnosis of HIV infection. 2he HIV is not involved in the malignant transformation of B cells since no HIV sequences have been detected in the lymphoma cells. 14However, the HIV infection induces the production of a variety of cytokines and growth factors that play an important role in the activation and differentiation of B cells. 14,15In AIDS-associated Burkitt lymphoma (BL), which accounts for 30 per cent of all cases of AIDSassociated lymphomas, the molecular lesions involve activation of myelocytomatosis cancer oncogene (cMYC) and inactivation of tumour suppressor protein (P53). 10,14,16

Figure 2. AP view of the pelvis (arrow) showing a large lytic area with destruction of the left ilium in a 27-yearold woman with secondary NHL Figure 3a and b. Conventional radiographs of an 11year-old girl who presented with severe pain in the left arm and leg and inability to mobilise for 1 month. She was diagnosed with secondary NHL with multiple skeletal involvement and deposits on both

In our series all patients had diffuse large B-cell NHL

With AIDS-associated large B-cell lymphoma (LBL) the molecular alterations involve deregulation of the BCL-6 proto-oncogene. 14][18] Radiological features are quite variable and somewhat non-specific. 1,4The lytic destructive pattern (Figure 2) is the most common radiological presentation. 5,17This pattern may be described as 'permeative', 'moth-eaten' or 'geographic' with well-defined margins. 2,7The blastic sclerotic pattern is more common in secondary bone lymphoma. 4Often the lesion is a mixture of sclerotic and lytic patterns. 1Subtle or 'near-normal' radiographic pattern may need magnetic resonance imaging (MRI) or bone scintigraphy to assess the pathology. 4The process is often poorly demarcated with a large area of transition from normal bone. 1 In long bones the diaphysis tends to be preferentially involved; however, the metaphysis may also be involved (Figures 3 and 5).Cortical break may be accompanied by a large soft tissue mass.Periosteal reaction is unusual and non-specific.Lesions can be solitary or polyostotic. 1In the spine, bone lymphoma is characterised by involvement of both vertebral bodies and posterior elements. 17There is usually a large extradural mass with canal stenosis and cord compression (Figure 6).All the above radiological patterns were observed in this study.CT scan may be more sensitive than conventional radiography for cortical breakthrough, but its main role is ruling out the presence of nodal disease or other soft tissue involvement in the chest and abdomen. 4MRI is useful to assess the extent of bone marrow and soft tissue involvement as well as the status of the spinal cord.Bone marrow shows low signal intensity on T1-weighted sequences and high signal intensity on T2-weighted images. 4,19Bone scintigraphy always shows an increased uptake and is useful for demonstrating multifocal bone involvement. 4,7one lymphoma can resemble various conditions which can make the diagnosis difficult and delayed. 1 Some of these conditions include bone infections (chronic pyogenic osteomyelitis, tuberculosis, fungal), systemic conditions like Paget's disease, primary bone malignancies (e.g.osteosarcoma, Ewing sarcoma, leukaemias) and metastatic deposits like in prostatic cancer.Definitive diagnosis is established on biopsy. 3,4,8ymphoma in HIV is more widespread and presents with extensive organ involvement than in the HIVnegative population. 7Traditional treatment modalities include chemotherapy alone or in combination with irradiation therapy. 13The CHOP regimen is considered the minimum standard of care. 20The patient receives six to eight cycles every three weeks as an outpatient.Antiretroviral therapy is an important part of management.Response is assessed by plain radiographs (Figure 4) and PET scan.

NHL is present in about 1% to 3% of HIV-seropositive patients at the time of initial diagnosis of HIV infection

The outcome for NHL in the setting of HIV continues to improve as insights into the pathology and treatment advance. 21,22Awareness of clinical manifestations and the various patterns of bone involvement in HIV/AIDS is important in making the diagnosis.

Conclusion

Bone lymphoma should be considered in any HIVpositive patient presenting with unexplained swelling and pain.Despite the concerted drive to control HIV disease, lymphoma is still one of the most common HIV-related malignancies. 3,21The mortality rate in our study was 62.2% (n = 28), probably owing to patients being referred late from peripheral hospitals and bone lesions are not suspected early.Some of the poor prognostic factors observed in this study included low absolute CD4 count and number of extra-nodal sites involved.

The authors did not receive payments directly or indirectly from a third party in support of any aspect of this work.Conflict of interest: none.

Figure 1 .
1
Figure 1.Piegraph shows the age distribution in years of 45 patients with HIV-associated bone lymphoma

Figure 4 .
4
Figure 3a and b.Conventional radiographs of an 11year-old girl who presented with severe pain in the left arm and leg and inability to mobilise for 1 month.She was diagnosed with secondary NHL with multiple skeletal involvement and deposits on both sides of the diaphragm.a b

Figure 5 Figure 6 .
56
Figure 5. AP radiograph showing a pathological fracture (arrow) of the humeral diaphysis in a 38year-old male patient with primary bone NHL

Table I : Clinical features of patients with bone lymphoma and HIV
ISymptomsPatientsLoss of weight, malaise, loss of appetite45Pain45Swelling9Weakness5Pathological fracture (long bones)6*Paraplegia (vertebral)11*One patient had two pathological fractures

Table II : Anatomical locations of lesions and the types of lymphoma
IISitesNumber of bones involvedPercentage of total (%)Primary bone lymphomaSecondary involvementVertebrae2351.1815Ribs613.306Humerus48.831Pelvis36.612Femur36.621Mandible36.630Tibia24.420Clavicle12.201

Table III : Absolute CD4 count and antiretroviral therapy at the time of diagnosis of lymphoma
IIICD4 countNumber of patientsHAART Yes No<5096350-10015123100-2001147200-300312300-400422400-500101>500211
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Nutrition Journal Energy expenditure of acutely ill hospitalised patients

Salah Gariballa firstname.lastname@example.com
Sheffield Institute for Nutritional Studies on Ageing
The University of Sheffield
Northern General Hospital
S5 7AUSheffieldUK

Department of Internal Medicine
Faculty of Medicine and Health Sciences
Emirates University
PO Box 17666Al AinUnited Arab

Sarah Forster email@example.com
Sheffield Institute for Nutritional Studies on Ageing
The University of Sheffield
Northern General Hospital
S5 7AUSheffieldUK

Human Nutrition Unit
The University of Sheffied
S5 7AUSheffieldUK

Nutrition Journal Energy expenditure of acutely ill hospitalised patients
10.1186/1475-2891-5-9BioMed Central Page 1 of 5 (page number not for citation purposes) Research * Corresponding author
Objective: To measure energy expenditure of acutely ill elderly patients in hospital and following discharge in the community.Design: Sixty-three consecutive hospitalised acutely ill elderly patients were recruited. Eight patients were studied to assess the reliability of the Delta Tract Machine as a measure of energy expenditure; 35 patients had their energy expenditure studied in hospital on two occasions and 20 patients had their energy expenditure measured in hospital and at 6 weeks in the community Results: Men had higher basal energy expenditure (BMR) values compared to women however the difference was not statistically significant [Men, mean (SD) 1405 (321) Kcal, women 1238 (322) kcal; mean difference (95% CI) 166 kcal (-17 to 531), p = 0.075]. After adjusting for age, gender and body mass index both medication and C-reactive protein (CRP), concentrations showed significant correlation with measured energy expenditure in hospital, (r = -0.36, "p < 0.05"; r = -0.29, "p < 0.05" respectively). However, in a multivariate analysis for all 63 subjects combined CRP explained most of the variance in BMR in hospital. The Harris Benedict equation predicted within ± 10% measured BMR in only 47% of individuals in hospital.Conclusion:Tissue inflammation and medications were associated with change in measured energy expenditure in acutely ill patients.

Introduction

Increasing numbers of older people worldwide has created a need for additional knowledge of age-related changes relevant to nutrition, which has importance in the treatment and prevention of disease and in maintaining good health and quality of life in an ageing population [1,2]. Ill health frequently has an adverse effect on nutritional status of older people. For most, these effects are limited to the time of acute illness and the temporary nutritional disadvantage is overcome depending on the body reserve once the customary pattern of eating is resumed [2]. But if episodes of ill health occur repeatedly or become prolonged, as is the case in older people nutritional status may decline progressively [2][3][4].

Assessing the energy needs of acutely ill elderly patients is vitally important in order to prevent energy and nutrient deficiencies. To date the energy requirements of elderly patients are not clear due to difficulties of measurement of energy intake from self recorded diaries and/or dietary interviews [2]. Measurement of energy expenditure in elderly patients is one important way of establishing esti-mates of energy requirements in both health and disease [5]. However, there is a lack of relevant studies and most prediction equations used to calculate energy expenditure in acutely ill elderly patients are based on young individuals [2]. Furthermore presence of chronic diseases, disabilities, drug intake and heterogeneity of physical activity and body composition make it difficult to obtain accurate data on energy expenditure in the elderly population [5,6].

The aim of this study was therefore to measure the energy expenditure of acutely ill elderly patient in hospital and following discharge in the community.

Subjects & methods

Patients

The study was conducted over an 8 months period at a 650-bed Associate Teaching Hospital in South Yorkshire. The integrated medical unit has 168 beds on 7 wards admitting unselected patients on the basis of need. Sixtythree hospitalised acutely ill elderly patients were recruited. Eight patients were recruited to assess the reliability of the Delta Tract Machine for measuring energy expenditure in acutely ill elderly patients; 35 patients had their energy expenditure studied during their hospital stay on two occasions; 20 patients had their energy expenditure measured both in hospital and 6 weeks later in the community. Patients suffering from severe medical or psychiatric illness, morbid obesity, moderate to severe dementia or difficulty with swallowing were excluded. The Local Health Ethical Committee approved the study and all patients or their carers gave written informed consent. All patients had demographic and medical data collected including current diagnosis, history of chronic illnesses, smoking, alcohol and drug intake

Measurements of basal metabolic rate (BMR) [indirect calorimetry] [7]

Basal metabolic rate (BMR) which reflects the energy requirements for maintenance of the intracellular environment and the mechanical processes such as respiration and cardiac function was measured using the Delta tract machine (Helsinki, Finland). This method of indirect calorimetry uses a plastic ventilated hood, which delivers a known quantity of gases to the subject, and a sample line which feeds back to the main machine, this then measures the amount of oxygen and carbon dioxide in the expired air; and calculates respiratory quotient, and energy expenditure. Reliability was ensured by calibrating the machine immediately before each measurement using a reference gas mixture comprised of 5% carbon dioxide and 95% oxygen. Each individual measurement lasted for 40 minutes and was taken in the morning, around 8.00 am with the patient lying in the bed and after overnight fast (from midnight only water was allowed).

Measurements of Resting Metabolic Rate (RMR)

Thermogenesis encompasses a wide variety of phenomena which include energy expenditure and heat generation associated with feeding, body temperature maintenance and thermogenic response to various specific stimuli such as smoking, caffeine, and drugs. Over the course of the day this builds up and is currently thought to account for about 10% of total energy expenditure. In order to take account of the thermic effect of diet on the energy expenditure of the non-fasting sedentary hospitalized subjects, ten percent of measured BMR was added for dietary induced thermo genesis.

Measurements of Total Energy Expenditure (TEE)

Physical activity accounts for 20-40 % of total daily expenditure in most individuals. However there is a wide variation in the energy cost of any activity both within and between individuals. For subjects in the community the BMR measurement was multiplied by 1.3 to take account of physical activity plus 10% of BMR for the thermic effect of food.

Quantification of the Delta Tract Machine measurement error

We performed a set of replicate readings, obtained by measuring BMR of 8 elderly patients (5 male), of mean age (SD) 75 years [8], on two consecutive days after adjusting for meal times (after 4 hours), medications and severity of illness (CRP).

As the difference between the observed value, with measurement error, and the subject's true value will be at most two standard deviations or within twice the coefficient of variation with probability 0.95. The precision for the BMR data for this study were as follows: BMR within two standard deviations (BMR 2 × 113 = 226 kcal, or within twice the coefficient of variation (BMR 2 × 5.9 % = 11.8%).

Other measurements

Each patient's nutritional status was determined from anthropometric and biochemical data. Weight was measured with a portable mechanical chair scale to 0.1 kg in a hospital gown. Height was inferred from demispan (using the following equation: Men 1.2 × Demispan + 72; Women 1.2 × Demispan + 67) to determine body mass index (BMI) = [weight (kg) ÷ {height (m)} 2 ]. Mid-upper arm circumference (MUAC) was measured by a flexible tape measure at the level of the midpoint between acromion and olecranon, with the elbow flexed at 90°. Triceps skin fold thickness (TSF) was taken at the same level over the triceps with the arm hanging relaxed at the side. TSF was measured using Harpenden Skin fold callipers accurate to 0.2 mm (Practical Metrology Sussex UK) and the mean of three measures was recorded. C-reactive protein (CRP) concentration, a marker of acute inflammation (severity of illness) was measured by a modified latex-enhanced immuno-turbidimetric assay (normal range < 6 mg/L). The inter-assay coefficient of variation was 3.9%.

Data analysis

Repeated measures analysis of variance (ANOVA) test was used to test within and between subject differences and p value < 0.05 was considered significant. Differences between groups at baseline were adjusted for history of drug intake, severity of acute illness (CRP), smoking and alcohol consumption and chronic illness. Mann-u-Whitney test, Partial and Spearman's rank correlation were also used. Forward stepwise multiple regression analysis was performed to determine the predictive importance of baseline variables (age, gender, body weight, body mass index, drugs, and CRP concentration) for measured energy expenditure. Adjusted and change in R 2 values are presented.

Results

Energy expenditure measurements were obtained for 8 patients on two consecutive days following acute admission; for 35 patients within 72 hours of admission and 5 days later in hospital; and for 20 patients in hospital and 6 weeks later following discharge in the community. Underlying diagnoses were ischaemic heart disease (23), stroke (8), falls (6), syncope (4), heart failure (3), cheat infection (2), back pain (1), and miscellaneous (16).

Baseline clinical characteristics, anthropometeric and energy expenditure data for each patient group are presented in table 1.

CRP concentration, drugs and male gender showed significant positive correlation with measured energy expenditure in hospital. Men had higher BMR values compared to women however the difference was not statistically significant [Men, mean (SD) 1405 (321) Kcal, women 1238 (322) kcal; mean difference (95% CI) 166 kcal (-17 to 531), p = 0.075]. After adjusting for age, gender, body mass index both Drugs and CRP concentrations showed significant correlation with measured energy expenditure in hospital (r = 0.36, p value < 0.039; r = 0.29, p value < 0.042 respectively). However, in a multivariate analysis for all 63 subjects combined CRPs a measure of tissue inflammation explained most of the variance in baseline measured energy expenditure in hospital.

Although calculated energy expenditure using Harris-Benedict equation approximates measured energy expenditure during acute illness (figure 1), the equation predicted within ± 10% measured BMR in only 47% of individuals.

Discussion

The main findings of this study were that CRP concentration a marker of severity of acute illness and drugs mainly vasoactive ones, aspirin and analgesics showed a significant and independent association with measured energy expenditure in hospital. The Harris Benedict equation predicted within ± 10% measured BMR in only 47% of individuals in hospital.

Studies of elderly people in hospitals are in agreement that food intakes are less than those reported for free-living elderly people [2,8,9]. The reasons for this are likely to be the combined effects of poor food intake as well as the extra energy cost of the metabolic disturbances associated with illness or disability. Measurement of energy expenditure is therefore important in establishing the energy requirements of older people during acute illness. The information obtained will be clinically important in maintaining adequate supply of nutrients in order to replete energy stores and lean tissues especially for those with low nutritional reserves. The main determinants of energy expenditure in man are body size, body composition, physical activity, age, gender, diet, genetic factors, hormonal and psychological state, pharmacological agents and disease process [10]. With advancing age undernutrition, chronic diseases and drug intake become more common. During acute illness a series of metabolic events are activated that leads to a state of negative nitrogen balance and significant loss of lean body mass. This process is mediated by inflammatory cytokines and is characterised by marked anorexia and net whole body protein breakdown [11]. Basal metabolism may consequently increase by up to 10% for each 1°C rise in body temperature [2,11].

We have found in this study that CRP concentration a marker of severity of acute illness and drugs were associated with a significant increase in energy expenditure. The hypermetabolic state of acute illness and the accompanying neuroendocrine changes strongly influence energy, protein and other nutrients metabolism. For example, gluconeogenesis and glycogenolysis, enhanced lipolytic activity and catabolism of muscle protein are characteristics metabolic responses to catabolic stress associated with acute illness [6]. These changes in metabolism particularly if combined with pre-existing undernutrition which is very common in elderly patients will lead to poor clinical outcome including poor physical function, increased risk of infection and length of hospital stay. Besides the effect of acute illness many drugs commonly used in the elderly may influence energy expenditure such as aspirin, betablockers, anti hypertensive and other vasoactive drugs. Drugs can produce either an increase or decrease in BMR.

For example, Dempsey et al. [12], have shown that in critically ill patients as the dosage of sedatives increased, energy expenditure decreased with some individuals reaching only 60% of predicted energy expenditure on the high doses of sedatives.

Although we have adjusted for physical activity for community patients (Physical Activity taken as an increase of 30% of RMR), we have not done so for the hospitalised cohort because of the sedentary nature of these patients.

We have attempted to measure physical activity in the community using a proxy questionnaire (Yale Physical Activity Survey [YPAS]). However, we abandoned using YPAS scores, because we found the accuracy of physical activity reporting as assessed by this proxy measure to be a problem among patients. Many researchers have found physical activity, the most variable component of daily energy expenditure. It comprises as little as 15% of daily energy expenditure in sedentary older people and up to 50% of daily energy output in highly active older people [10]. Furthermore very few studies to date have measured the accuracy of available methods for measurement of physical activity at all ages but particularly in the elderly. Physical activity still remains an important determinant of energy. Accurate methods for assessment of physical activity in the elderly are therefore needed [10].

Although our aim was to recruit acutely ill patients judging by the CRP concentrations many of our subjects were only minimally stressed. Given the nature of the study very sick patients were less likely to give consent to take part in the study. It is also well known that BMR varies through out the day and also considerably from day to day especially during the early phase of acute illness. Another potential weakness was that many subjects did admit to food and or caffeine consumption 2-4 hours prior to energy expenditure measurement.

Little is known so far about energy expenditure and requirements of acutely ill elderly patients. This group of patients is at risk of negative energy balance, which may lead to undernutrition, because of hypermetabolism associated with acute illness. However, research to date provides no evidence that positive energy balance during critical/acute illness prevent protein-energy undernutrition. It is indeed the case that in clinical practice the timing and the amount of nutritional support in these patients especially those who are critically ill is less clear, because of lack of evidence.

There is however, an urgent need for research, which help the understanding of the metabolic response to tissue inflammation and injury associated with acute illness in elderly patients. This will help provide guidance on optimal timing, route and composition of nutritional therapy Measured (mBMR) and estimated (eBMR) energy expendi-ture in hospital Figure 1 Measured (mBMR) and estimated (eBMR) energy expenditure in hospital relative to a patient's metabolic stress, age and specific illness and therefore improve their outcome.

In conclusion this study showed that acute inflammation and medications during acute illness might affect energy expenditure of hospitalised older people.

Further studies on the impact of acute illness on the timing, macronutrient balance and energy provision of nutritional support of older people is long overdue.

Table 1 :
1Patients baseline characteristics and BMR, RMR and TEE at baseline 5 days and in the community respectively [mean (SD)]Variable
Baseline (n-55)
Day 5 (n = 32)
Six weeks in the community (n = 17)

Age
76 (9)
Gender, female (%)
8 (40%)
Chronic disease/patient
1.5
Drug/patient+
2.1
2.1
Body weight (kg)
70 (13)
72 (12)
BMI (kg/m 2 )
26.3 (5.5)
26.4 (5.5)
MUAC (cm)
29.3 (2.9)
29.7 (1.9)
TSF (mm)
19 (7.8)
16.3 (4.4)
Thyroid stimulating hormone (normal 0.38-4.7 mµ/L)
1.6 (0.75)
3.3 (6.9)
C-reactive proteins * (normal <6 mg/L)
22 (28)
12 (18)
5 (7)
Energy Expenditure [BMR] * (Kcal/day)
1403 (346)
1317 (446)
1159 (445)

* P value for difference between hospital and community values < 0.05 + Diuretics, ACE inhibitors, β-blockers, Calcium channel blockers, statins,
aspirin warfarin, clopidogrel, analgesics, benzidiazepines, antidepressants and oral hyopglycaemics

Table 2 :
2Multiple regression analysis of age, gender, body weight, drug intake and CRPs with measured resting energy expenditure as the dependent variable.Variable/independent
predictor

R square
R square
change

P value

(n = 63)

Age
.004
.004
.679
Gender
.055
.051
.133
Drugs
.118
.062
.093
Body weight
.124
.006
.594
CRP
.209
.086
.044*

*P value < 0.05

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. Nutrition Journal. 59Nutrition Journal 2006, 5:9

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