Journal of Pediatric Surgery
Volume 38, Issue 1 , Pages 37-44, January 2003

Body temperature and heat production in suckling rat endotoxaemia: Beneficial effects of glutamine☆☆☆★

Department of Paediatric Surgery, Institute of Child Health, London, England

Article Outline

Abstract 

Background/Purpose: Sepsis is an important cause of neonatal mortality. The aim of the study was to investigate the metabolism of endotoxic neonatal rats and the potential beneficial effect of glutamine. Methods: Suckling rats received intraperitoneal saline (control; C), endotoxin (300 μg/g LPS; E), saline+glutamine (2 mmol/g; CG), endotoxin+glutamine (EG), saline+leucine (2 mmol/g; CL) or endotoxin+leucine (EL). Sepsis score (0-8) and rectal temperature were monitored. Hypothermia was defined as rectal temperature less than 32°C. Oxygen consumption (VO2, mL/kg/h), a determinant of heat production, was measured by indirect calorimetry. Data (mean ± SEM) were compared by analysis of variance (ANOVA), paired t test or Fisher's Exact test. Results: Endotoxic (E) rats had significantly lower VO2 than C rats from 90 minutes postinjection to the end of the experiment, 210 minutes (VO2 from 150 to 210 minutes: C 671 ± 45; E 429 ± 36, P < .0004; n = 8; paired t test). VO2 of CL or CG rats was elevated between 90 and 210 minutes compared with control, but significantly (P < .01) only in the L group (C 706 ± 31; CG 871 ± 63; CL 984 ± 31; n = 7-9, ANOVA). VO2 was significantly higher (P < .05) in EG rats than E rats (E 460 ± 29; EG 654 ± 68; n = 9-10). In the EL group, VO2 was raised but was not significantly different from E (E 460 ± 29; EL 637 ± 52; n = 8-10). EG rats were significantly less hypothermic between 90 and 210 minutes (58 of 132 measurements) compared with E (95 of 147; P = .0007, Fisher's Exact test), whereas the EL group were similarly hypothermic (74 of 120) to E (P = .7). Sepsis score was significantly lower in the EG group than both E and EL groups (E 4.9 ± 0.3; EG 3.6 ± 0.3; EL 5.0 ± 0.3; n = 40; P < .01; ANOVA). Conclusions: Neonatal endotoxaemia lowers VO2, heat production, and body temperature. Glutamine and leucine both cause nutrient-induced thermogenesis in control animals and restore VO2 of endotoxic animals. Glutamine additionally increases rectal temperature, reduces incidence of hypothermia, and improves clinical signs of endotoxic rats. This suggests that glutamine may be beneficial for nutrition in neonatal sepsis. J Pediatr Surg 38:37-44. Copyright 2003, Elsevier Science (USA). All rights reserved.

Keywords:  Glutamine, Sepsis, neonate, oxygen consumption, hypothermia, indirect calorimeter, endotoxaemia

 

Sepsis is an important cause of morbidity and mortality in neonates. Between 1% and 5% of live births have an episode of sepsis in the neonatal period, and, of these, there is a mortality rate of 10% to 15%.1 Those at particular risk include neonates who either are premature or low birth weight, or needing mechanical ventilation or total parenteral nutrition, or those who have congenital gastrointestinal anomalies.1 Suitable therapies and support for these patients are needed to prevent initial sepsis leading to organ failure and the subsequent cascade of multiorgan failure.

We have shown previously that mediators of sepsis (hydrogen peroxide and nitric oxide) inhibit mitochondrial metabolism in suckling rat hepatocytes2, 3 but that these effects could be reversed by glutamine through its effects on the synthesis of glutathione, an important intracellular antioxidant.4 Subsequently, we showed that hepatocytes from endotoxaemic rat pups also had decreased mitochondrial metabolism and damaged mitochondrial ultrastructure and that this could similarly be reversed by incubation of hepatocytes in vitro with glutamine.5

Findings in adults have suggested that there are 2 phases in the metabolic response to sepsis, systemic inflammatory response syndrome, surgery, or trauma: a short hypometabolic (ebb) phase followed by a more prolonged hypermetabolic (flow) phase occurs during sepsis.6 Although infants and children with sepsis or systemic inflammatory response syndrome frequently present with hypothermia, it is not known whether there is a short-lived hypometabolism that may contribute to the hypothermia observed in these patients. Studies in infants and children have suggested the this hypermetabolic phase may not occur7, 8, 9 or may be short lived after surgery.10

The aim of this study was to investigate respiratory gas exchange and body temperature in a model of sepsis in suckling rats and to determine whether glutamine has any effect in this model.

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Materials and methods 

Experimental animals 

The study was approved under the United Kingdom Home Office regulations for Animals (Scientific Procedures) Act 1986. A single litter of 10 11- to 13-day-old Wistar rat pups was split into 2 groups of 5, which were allowed to suckle freely with the mother until the start of the experiment. At time zero, each rat pup was given a single intraperitoneal injection consisting of 0.9% saline (control group C), saline plus 300 μg/kg lipopolysaccharide (LPS; Escherichi coli 055:B5; Sigma, Poole, Dorset, England;5 endotoxin group E), saline plus 2 mol/kg L-glutamine (Sigma; glutamine group G), saline plus LPS plus glutamine (endotoxin glutamine group EG), saline plus 2 mol/kg L-leucine (Sigma; leucine group L), saline plus LPS plus leucine (endotoxin glutamine group EL). Hence all animals received 0.024 mL/g body weight. The weight of the animals was measured hourly to assess whether dehydration was occurring (no animals lost more than 5% body weight during the course of the experiment). Rectal temperature was monitored with a digital probe, and hypothermia was defined as rectal temperature less than 32°C.

Endotoxaemia score 

We used a scoring system adapted from our own previous work,5 which itself was based on a system devised for adult rats (Table 1).11

Table 1. Endotoxemia scoring system
Mobility
0The rat pups will not allow themselves to be supine.
2The rat pups can be turned supine for a few seconds.
4The rat pups can be turned supine for more than 5 seconds.
6The rat pups will not turn back over when turned supine.
Power
0The rat pups can dangle from a finger for more than 5 seconds.
1The rat pups can dangle from a finger for less than 5 seconds.
2The rat pups cannot dangle from a finger.
Shivering
0No shivering
1Shivering

NOTE. The score of shivering is additional. If the total score is 8 for mobility and power then shivering is not counted, ie, maximum score of 8 (very ill); minimum score of 0 (no signs of illness).

Indirect calorimetry 

Respiratory gas exchange was measured using an indirect calorimeter (Oxymax; Columbus Instruments, Columbus, OH) consisting of a sealed Perspex chamber with a variable flow though the chamber, connected to an infrared CO2 analyser and an electrochemical O2 sensor. The flow rate or air through the indirect calorimetry chamber was at a rate of 0.3 to 0.5 L per minute, adjusted to give a change in O2 of approximately −0.3% between inflow and outflow from the chamber. The calorimeter was calibrated using oxygen-free N2 (for zero on both the O2 and CO2 sensors) and a mixture of 20.5% O2, 0.5% CO2, 79.0% N2 (BOC Special Gases; Guildford, Surrey, England) to calibrate the O2 and CO2 sensors. Five rat pups belonging to a single experimental group were placed in the calorimeter chamber for a period of 30 minutes at a time. The temperature of the chamber was monitored during indirect calorimetry measurements. Between each period of 30 minutes in the indirect calorimeter chamber, the rats were returned to their mother for a minimum of 30 minutes to allow them to suckle ad libitum. Data were collected every minute and averaged over each 30-minute period; O2 consumed (VO2) and CO2 produced (VCO2) were expressed in milliliters per kilogram per minute. Respiratory quotient was calculated as VCO2/VO2.

Statistical evaluation 

Results were distributed normally and are expressed as mean ± SEM. VO2 and endotoxaemia score were compared by analysis of variance (ANOVA) with Tukey's Multiple Comparison post-hoc test, or by paired t tests in which animals from the same litter were compared. Incidence of hypothermia was compared between groups by Fisher's Exact test. Prism 3.02 and Instat 3.05 (both GraphPad Software, San Diego, CA) were used for statistical comparisons.

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Results 

Effects of endotoxaemia, glutamine, and leucine on rectal temperatures 

The cage temperature was similar (at 23.9 ± 0.1°C) in all groups and did not change during the course of the experiments. The rectal temperature dropped in all 3 groups given intraperitoneal endotoxin (E, EG, EL) at 90 minutes postinjection and remained lower than the control groups (C, CG, CL) throughout the experiment (Fig 1A and B).

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  • Fig. 1. 

    Rectal temperature after injection of rats with (A) saline □, saline plus glutamine ▵, saline plus leucine ▿ or (B) saline plus endotoxin ■, saline plus endotoxin plus glutamine ▴, saline plus endotoxin plus leucine ▾. (C) proportion of rats given endotoxin alone [E], endotoxin plus glutamine [EG], or endotoxin plus leucine [EL] being hypothermic between 90 and 210 minutes. *P < .006 versus E and L groups, Fisher's Exact test.

The rectal temperature of the group given endotoxin and glutamine (EG) recovered, so that at 210 minutes after injection, it was not significantly different from controls and was significantly higher than the endotoxic group (E; P < .01) and the endotoxin plus leucine group (EL; P < .001) groups. This resulted in significantly fewer hypothermic episodes in the endotoxin plus glutamine group (58 of 132) compared with the endotoxin (95 of 147; P = .0007) and the endotoxin plus leucine groups (74 of 120; P = .006; Fig 1C). There was no significant difference between the incidence of hypothermia in the endotoxin plus leucine and the endotoxin groups (P = .07).

Respiratory quotient 

The respiratory quotient (RQ), reflecting the balance of substrate oxidation (0.71 = net fat oxidation, 1.00 = net carbohydrate oxidation), was between 0.78 and 0.71 in all groups throughout the timecourse (Fig 2) suggesting that fat oxidation predominated during the study.

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  • Fig. 2. 

    Respiratory quotient after injection of rats with saline □, saline plus glutamine ▵, saline plus leucine ▿, saline plus endotoxin ■, saline plus endotoxin plus glutamine ▴, or saline plus endotoxin plus leucine ▾. * P < .01 versus control, control plus leucine, and endotoxin plus leucine groups; ** P < .05 versus control plus leucine and endotoxin plus leucine groups, one-way ANOVA with Tukey's post-hoc test.

Endotoxic rats had a slight increase in RQ to 0.76 at 150 and 0.77 at 210 minutes, possibly reflecting a minor shift to carbohydrate oxidation or inhibition of fat oxidation, and control rats injected with leucine had a lower RQ (~0.71) than the other groups.

Oxygen consumption 

Before injection, oxygen consumption (VO2) was 1,062 ± 43 mL/kg/min. In the control group, VO2 dropped slowly during the course of the experiment, reaching 725 ± 110 mL/kg/min at 210 minutes (Fig 3A).

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  • Fig. 3. 

    Oxygen consumption (VO2) of rats injected with (A) saline □, saline plus glutamine ▵, saline plus leucine ▿ or (B) saline plus endotoxin ■, saline plus endotoxin plus glutamine ▴, saline plus endotoxin plus leucine ▾. (C) VO2 averaged from 90 to 210 minutes postinjection with saline [C], saline plus glutamine [SC], saline plus leucine [CL], saline plus endotoxin [E], saline plus endotoxin plus glutamine [EG], or saline plus endotoxin plus leucine [EL]. * P < .01 versus C, ** P < .05 versus C; P < .001 versus CG and CL; †P < .05 versus E and CG; P = < .001 versus CL; ††P < .001 versus CL, one-way ANOVA with Tukey's post-hoc test.

Rats injected with saline plus glutamine or saline plus leucine had a higher VO2 than saline-injected rats at all time-points after injections (Fig 3A). Endotoxin-injected rats had a lower oxygen consumption than control rats (Fig 3B), so that at the end of the experiment there was a great difference (VO2 from 150 to 210 minutes: C 671 ± 45; E 429 ± 36; P < .0004; n = 8 paired t test). VO2 of rats injected with endotoxin and either glutamine or leucine, however, was increased compared with rats injected with endotoxin alone (Fig 3B). When the data were averaged between 90 and 210 minutes, these trends became more apparent (Fig 3C). Oxygen consumption of control rats injected with glutamine or leucine was greater than control rats (significantly so in the leucine group; P < .01), whereas that of endotoxin-injected rats was decreased significantly compared with all 3 control groups (P < .05 v control; P < .001 v control plus leucine and control plus glutamine). Interestingly, endotoxic rats injected with leucine or with glutamine had a higher VO2 than rats injected with endotoxin alone, although this difference was only significant in the glutamine-injected group (P < .05). The VO2 of endotoxic rats injected with leucine or glutamine was not significantly different from that of control animals (although it was still significantly lower than that in animals injected with saline plus leucine or saline plus glutamine).

Carbon dioxide production and energy expenditure 

Because the respiratory quotient was relatively unchanged throughout the time course of the experiment, changes in VCO2 (and in heat production) mirrored those in VO2 (results not shown).

Endotoxaemia score 

After intraperitoneal injection of endotoxin, the endotoxin group and the groups injected with endotoxin plus either glutamine or leucine had an increased sepsis score (scored as in Table 1) over time (Fig 4).

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  • Fig. 4. 

    Endotoxaemia score of rats injected with saline plus endotoxin ■, saline plus endotoxin plus glutamine ▴, saline plus endotoxin plus leucine ▾. *P < .01 versus endotoxin; P < .001 versus endotoxin plus leucine. **P < .001 versus both endotoxin alone and endotoxin plus leucine.

Rats injected with endotoxin plus glutamine, however, showed a decreased sepsis score throughout the timecourse; this was significantly different to the endotoxin or endotoxin plus leucine groups at 150 and 210 minutes.

Relationship between temperature and oxygen consumption 

There was a strong positive correlation between VO2 and rectal temperature in the animals given endotoxin (Fig 5A), endotoxin plus glutamine (Fig 5B), and endotoxin plus leucine (Fig 5C).

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  • Fig. 5. 

    Relationship between VO2 and rectal temperature in rats injected with (A) endotoxin alone (B) endotoxin plus glutamine, and (C) endotoxin plus leucine. VO2 was plotted against the mean rectal temperature of the 5 rats in the metabolic cage. R2 and P values refer to the linear regression line.

The range of measured rectal temperatures in the control groups was small and insufficient to evaluate whether there was a relationship between temperature and VO2.

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Discussion 

Ex vivo studies on tissues isolated from our suckling animal model of peritoneal sepsis have indicated that hepatocyte oxidative metabolism5 and cardiac mitochondrial function are inhibited.12 In the current study, we have shown that this is accompanied by a profound hypometabolism, which may contribute to the hypothermia observed in these rats. The oxygen consumption of saline-injected animals also drops during the course of the experiment; this is probably caused by repeated handling and measurement of rectal temperature of the animals, and both VO2 and temperature of endotoxaemic rats were clearly lower from the control animals. The low rectal temperature of suckling rats is in keeping with the findings of Bertin et al,13 who showed a steady increase in rectal temperature of rats during development and a temperature of 33.5°C in 11-day-old rats. These observed effects of endotoxin on VO2 and temperature are in keeping with those of DeRijk et al14 in adult rats, although other investigators have shown increases in both VO2 and body temperature in adult rat endotoxaemia15; these responses may vary with both dose and serotype of endotoxin.16 Studies in infants and children have not shown a hypometabolic phase of sepsis7, 8, 9; however, there may be a hypometabolism that occurs early in sepsis and consequently has not been observed in these studies.

The respiratory quotient of these rats was low—around 0.75. This is in keeping with findings of other investigators13 and reflects the reliance of suckling rats on fatty acids as an oxidative fuel.17, 18 The respiratory quotient was not corrected for urinary nitrogen output, so it does include a component of protein oxidation. However, because mixed protein oxidation has a respiratory quotient of around 0.835,19 protein oxidation does not appear to be high in any of the experimental groups. Rats at this age feed more or less continually, so to avoid starvation were replaced with their dams for 30 minutes every hour throughout the experiment. At sacrifice and laparotomy, the stomach was found to be distended with milk in all the experimental groups, supporting the lack of starvation during the experiment. However, endotoxaemia is known to cause paralytic ileus in rats,20 so it is possible that endotoxic rats had impaired absorption. There was a slight increase in respiratory quotient in endotoxic rats at the later time-points, possibly reflecting a minor shift in the balance of substrate oxidation.

The ambient temperature throughout the experiments was around 23°C. This is well below the range of thermeoneutrality for rats of this age (~33° to 34°C),21, 22 and to maintain body temperature, rats respond both by facultative thermogenesis,13, 23 as in the human neonate,24 and by behavioural adaptions, ie, huddling.25 Allowing rats to suckle with their dams and measurement of 5 rats together in a metabolic cage minimised uncontrolled heat loss in these animals. Although endotoxaemia could be causing hypothermia in these animals by promoting vasodilation, decreasing huddling behaviour, and increasing heat losses, the strong relationship between rectal temperature and VO2 in endotoxic animals would suggest that thermogenesis itself is involved. Cytokines, prostaglandins, leukotrienes, and the vagus nerve all have been implicated in the reduced thermogenesis observed in endotoxaemia,14, 26, 27, 28, 29 but the physiologic basis is still uncertain.

The nonessential amino acid glutamine is the most abundant amino acid in plasma, having several important physiologic roles.30 During sepsis, endogenous glutamine stores are mobilised, gut glutamine uptake is diminished, and the liver and immune system become its major consumers such that net glutamine utilization exceeds production and glutamine becomes “conditionally essential.”31, 32 The enhanced hepatic glutamine extraction in sepsis has been attributed to increased hepatic gluconeogenesis, ureagenesis, glutathione production, and synthetic and proliferative activities.33, 34 The provision of exogenous glutamine improves nitrogen balance, attenuates skeletal muscle proteolysis,35 and is essential for the immune system to mount an adequate immune response.36 Glutamine is not included routinely in paediatric parenteral nutrition but has been shown to have beneficial effects in premature neonates.37 In neonatal hepatocytes, we have shown that glutamine and its dipeptides reversed the inhibition of oxidative metabolism caused by mediators by providing a substrate for glutathione synthesis.4 Subsequently, we showed that incubation of hepatocytes from endotoxic rats with glutamine restored their mitochondrial function and reversed ultrastructural changes.5 In the current study, we wanted to determine the effect of intraperitoneal glutamine injection on the in vivo metabolism of endotoxic suckling rats. We also injected rats with leucine as a control to determine whether effects we observed were specific to glutamine.

Nutrient-induced thermogenesis (NIT) is an increase in energy expenditure that occurs on feeding, whether orally or intravenously.38 Protein or amino acids have by far the greatest thermogenic effect, and although NIT may, in part, be caused by effects on the sympathetic nervous system,39 the finding that amino acid and glucose-induced NIT persists in tetraplegic patients suggests that other mechanisms, such as the energy dissipated directly by oxidation or nonoxidative disposal of fuels, also are operative.38, 40 In our study, glutamine and leucine administration to control rats led to increased VO2 of control animals, which is probably caused by NIT and supports the assumption that leucine and glutamine are absorbed from the peritoneum.41, 42 Although it is not known which amino acids have a more thermogenic effect, the finding that leucine had a larger effect on VO2 than glutamine suggests that leucine is a more thermogenic amino acid than glutamine. Leucine previously has been suggested to be a strongly thermogenic amino acid,43, 44, 45 and although the effects of glutamine have not been reported and NIT is not simply owing to oxidative usage of amino acids as fuels, it is noteworthy that leucine has a metabolizable heat of combustion approximately twice that of glutamine.19

Endotoxic rat pups also injected with glutamine or leucine had an increased VO2 from about 90 minutes after injection compared with endotoxic rats, suggesting that NIT also is occurring in endotoxic rats, as in septic humans.46 However, unlike control animals, in endotoxic animals, glutamine had a slightly greater thermogenic effect than leucine. This could be related to increased metabolism of glutamine during endotoxaemia.31, 32, 33, 34, 35, 36 Although both glutamine and leucine caused an increase in VO2 of endotoxic animals, only glutamine appeared to have an effect on rectal temperature and was effective in reducing the number of episodes of hypothermia compared with endotoxaemic rats. It is not known whether glutamine directly or indirectly affects thermoregulation, although a recent study suggested that direct effects of glutamine on cerebral thermoregulatory centres are unlikely.47 Glutamine could act indirectly by altering circulating levels of cytokines, or via effects on prostaglandin or leukotriene metabolism,14, 26, 27, 28, 29 but the physiologic basis for the action of glutamine on body temperature during endotoxaemia requires further work.

Our endotoxaemia scoring method is based on previously published proposals11 but is modified to focus on mobility of animals, which has been shown by other investigators to better predict the endotoxaemic state.48 Using our modified scoring system, glutamine was found to decrease endotoxaemia score compared with endotoxaemic rats and endotoxaemic rats injected with leucine. Because both leucine and glutamine appear to cause an increased VO2 in control and endotoxaemic animals, whereas only glutamine was able to reduce both the number of episodes of hypothermia and the endotoxaemia score, it appears that the beneficial effect of glutamine in this model is at least partly independent from an effect on NIT. Glutamine reduces mortality rate to a lethal bacterial challenge49 and has been shown to have various beneficial effects in clinical trials, such as reduced nitrogen loss,35 prevention of mucosal atrophy,50 and preservation of mucosal structure.51 Our results suggest that glutamine may additionally help prevent sepsis-related hypometabolism and hypothermia.

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Acknowledgements 

The authors thank Tommy's the Baby Charity for a grant for an indirect calorimeter.

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Discussion 

J. Hutson (Melbourne, Australia): The behaviour of neonatal rats is very specific with normal rats huddling together for communal warmth. What happened to the position of the rats in the cage when you gave the glutamine? Did they huddle like normal rats, or did they scatter around like the half-dead animals that you showed in the photo?

R.G. Garrett-Cox (response): They were in between the 2 groups, and the huddling itself in the leucine group was difficult to quantify and was not used in the endotoxic score. They were sometimes huddling a bit but not as much as the control animals.

J. Hutson (Melbourne Australia): It strikes me that one of the controls you need is to deliberately make them huddle by putting them together and then measuring the biochemical parameters.

R.G. Garrett-Cox (response): We have approached it slightly differently as we also are looking at data now having given them a heat lamp to keep their temperature up, and this shows a decrease in the endotoxin group and an improvement, but it is smaller than shown here.

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☆ Winner of the Peter Paul Rickham Prize at the 49th Annual Congress of the British Association of Paediatric Surgeons, Cambridge, England, July 23-26, 2002.

☆☆ Supported by the Royal College of Surgeons of England and the Shane McGovern Trust Fund.

★ Address reprint requests to Simon Eaton, PhD, Department of Paediatric Surgery, Institute of Child Health, 30, Guilford St, London WCIN 1EH, England.

PII: S0022-3468(02)63014-3

doi:10.1053/jpsu.2003.50006

Journal of Pediatric Surgery
Volume 38, Issue 1 , Pages 37-44, January 2003

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