Effects of Major and Minor Surgery on Plasma Glutamine and Cytokine Levels Mark
Parry-Billings, DPhil;
Robert J.
Peter J. Morris,
Baigrie, BSc, FRCS; Peter M. Lamont, MD, FRCS; PhD, FRCS; Eric A. Newsholme, DSc
\s=b\ The plasma levels of glutamine and cytokines have been measured frequently in patients before, during, and after elective abdominal aortic aneurysm surgery ("major surgery") or inguinal hernia repair ("minor surgery"). The plasma glutamine level declined rapidly following major surgery and remained markedly below preoperative levels until at least 7 days after surgery. This response of the plasma glutamine level was significantly correlated with the production of interleukin 6 but not with that of interleukin 1, tumor necrosis factor, or interferon gamma. In contrast, following minor surgery, the plasma glutamine level was unchanged and the elaboration of interleukin 6 was attenuated. The decrease in the plasma glutamine level following major surgery may contribute to the state of immunosuppression, which follows major surgery, and the relationship between amino acid and cytokine metabolism is worthy of further study.
(Arch Surg. 1992;127:1237-1240)
a rate by the small and the cells of the immune The role of rates of glutamine utili¬ zation in rapidly dividing cells has been considered previously to be the provision of energy and /or the provision of both nitrogen and carbon for precursors for synthesis of macromolecules, eg, purine and pyrimidine nucleotides for DNA and RNA. However, it has re¬ cently been suggested that a high rate of glutamine utilization has a specific role in providing precision in the control of changes in the rates of purine and pyri¬ midine nucleotide synthesis during cell proliferation.3 Because the rate of utilization of glutamine by these cells depends on the external concentration, mainte¬ nance of the normal physiological concentration would appear to be important for their normal functioning. Indeed, it has been shown that lowering the level of glutamine in culture medium below that normally
is utilized at
very high Glutamine intestine,1 kidneys,2 these high system.3
Accepted for publication January
11, 1992.
Group, Department of Biochemistry, University of Oxford (England) (Drs Parry-Billings and Newsholme), and the Nuffield Department of Surgery, John Radcliffe Hospital, Headington, Oxford (Drs Baigrie, Lamont, and Morris). Reprint requests to the Cellular Nutrition Research Group, Department of Biochemistry, University of Oxford, South Parks Rd, Oxford OX1 3QU, England (Dr Parry-Billings). From the Cellular Nutrition Research
in human plasma decreases the rate of prolifer¬ ation of lymphocytes despite the presence of other amino acids and other fuels such as glucose.4 It is known that surgery increases the rate of utilization of glutamine by the small intestine5 and it would be expected to increase the rate of utilization by cells involved in the immune response to surgery. However, there appears to have been no study of the acute and sequential change in plasma glutamine levels in response to surgical operations of different severity and no studies following
present
major surgery have been done. Cytokines are peptides produced by
cells of the im¬ of both the immune that mediators as act system response and the response of other tissues in the body to injury. Interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor (TNF), and interferon gamma (IFN-7) are considered to be important mediators of the integrated host response. With the exception of IL-6, these cyto¬ kines have rarely been detected in the plasma of injured patients.6 Interleukin 6 may also coordinate the response of other tissues; it is particularly important in stimulat¬ ing the production of acute phase proteins by the liver.7 There have been reports of a rise in the plasma IL-6 level after surgery6 and excessively high postoperative IL-6 levels may be associated with the development of mune
major complications.8 Surgery is known to impair the immune response.9 Al¬ though the mechanism underlying this impairment is not
understood, the net effect is an increased risk of the devel¬ opment of postoperative sepsis. In an attempt to elucidate
possible mechanism for postoperative immunosuppres¬ our study has been carried out to examine the rela¬ tionship between cytokine elaboration and glutamine a
sion,
metabolism.
Consequently, the plasma levels of glutamine, gluta¬ mate, alanine, branched-chain amino acids, IL-1, IL-6, TNF, and IFN-7 were measured in patients before, during, and after inguinal hernia repair (minor surgery) or elective abdominal aortic aneurysm surgery (major surgery). This latter operation has several advantages as an example of major surgery. The age, race, and general health of the pa¬
population is relatively uniform, they undergo a rea¬ surgical insult, they are tumor free, sonably comparable and they have a relatively low risk of sepsis. This permits the impact of major surgery to be evaluated without the tient
Downloaded From: http://archsurg.jamanetwork.com/ by a Oakland University User on 06/13/2015
Table 1.—The Effect of
Major Surgery on
Plasma Amino Acid
Plasma Amino Acid
/L
Patients
0
9
653±21
78±14
308±34
366±23
0.5
9
617±14
105+21
316±41
372±28
1
9
599±27
82±12
312+34
356±24
1.5
9
609±45
86±12
347±48
372±26
2
9
636±41
82±10
408±52+
398±26
2.5
9
430±53t
405±38
3
9
589±39t 573±42+
77±13 83±15
429±61t
415±37
3.5
9
554±46+
87±12
440±73t
429±42
4
9
521 ±40+
76 + 15
380±65
391 ±41
6
9
477±35
76±12
365±58
369±36
No. of
|-1 BCAA Glutamine Glutamate Alanine
8
9
478±26
59+12
392±93
325±16
12
8
529±33
44±12+
385±53
264±13
24
9
542±30
46±9
345±55
306±32+
48
9
455±26§
43±12+
204±29+
368±39 ND
72
6
458±32
25±6
203±33+
120
8
472±19§
39±13+
234±21+
ND
168
7
504±32
54±15
278±24
415±38
•Values are mean±SEM. BCAA denotes branched-chain amino erative values are denoted, tlndicates P
Parry-Billings, DPhil;
Robert J.
Peter J. Morris,
Baigrie, BSc, FRCS; Peter M. Lamont, MD, FRCS; PhD, FRCS; Eric A. Newsholme, DSc
\s=b\ The plasma levels of glutamine and cytokines have been measured frequently in patients before, during, and after elective abdominal aortic aneurysm surgery ("major surgery") or inguinal hernia repair ("minor surgery"). The plasma glutamine level declined rapidly following major surgery and remained markedly below preoperative levels until at least 7 days after surgery. This response of the plasma glutamine level was significantly correlated with the production of interleukin 6 but not with that of interleukin 1, tumor necrosis factor, or interferon gamma. In contrast, following minor surgery, the plasma glutamine level was unchanged and the elaboration of interleukin 6 was attenuated. The decrease in the plasma glutamine level following major surgery may contribute to the state of immunosuppression, which follows major surgery, and the relationship between amino acid and cytokine metabolism is worthy of further study.
(Arch Surg. 1992;127:1237-1240)
a rate by the small and the cells of the immune The role of rates of glutamine utili¬ zation in rapidly dividing cells has been considered previously to be the provision of energy and /or the provision of both nitrogen and carbon for precursors for synthesis of macromolecules, eg, purine and pyrimidine nucleotides for DNA and RNA. However, it has re¬ cently been suggested that a high rate of glutamine utilization has a specific role in providing precision in the control of changes in the rates of purine and pyri¬ midine nucleotide synthesis during cell proliferation.3 Because the rate of utilization of glutamine by these cells depends on the external concentration, mainte¬ nance of the normal physiological concentration would appear to be important for their normal functioning. Indeed, it has been shown that lowering the level of glutamine in culture medium below that normally
is utilized at
very high Glutamine intestine,1 kidneys,2 these high system.3
Accepted for publication January
11, 1992.
Group, Department of Biochemistry, University of Oxford (England) (Drs Parry-Billings and Newsholme), and the Nuffield Department of Surgery, John Radcliffe Hospital, Headington, Oxford (Drs Baigrie, Lamont, and Morris). Reprint requests to the Cellular Nutrition Research Group, Department of Biochemistry, University of Oxford, South Parks Rd, Oxford OX1 3QU, England (Dr Parry-Billings). From the Cellular Nutrition Research
in human plasma decreases the rate of prolifer¬ ation of lymphocytes despite the presence of other amino acids and other fuels such as glucose.4 It is known that surgery increases the rate of utilization of glutamine by the small intestine5 and it would be expected to increase the rate of utilization by cells involved in the immune response to surgery. However, there appears to have been no study of the acute and sequential change in plasma glutamine levels in response to surgical operations of different severity and no studies following
present
major surgery have been done. Cytokines are peptides produced by
cells of the im¬ of both the immune that mediators as act system response and the response of other tissues in the body to injury. Interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor (TNF), and interferon gamma (IFN-7) are considered to be important mediators of the integrated host response. With the exception of IL-6, these cyto¬ kines have rarely been detected in the plasma of injured patients.6 Interleukin 6 may also coordinate the response of other tissues; it is particularly important in stimulat¬ ing the production of acute phase proteins by the liver.7 There have been reports of a rise in the plasma IL-6 level after surgery6 and excessively high postoperative IL-6 levels may be associated with the development of mune
major complications.8 Surgery is known to impair the immune response.9 Al¬ though the mechanism underlying this impairment is not
understood, the net effect is an increased risk of the devel¬ opment of postoperative sepsis. In an attempt to elucidate
possible mechanism for postoperative immunosuppres¬ our study has been carried out to examine the rela¬ tionship between cytokine elaboration and glutamine a
sion,
metabolism.
Consequently, the plasma levels of glutamine, gluta¬ mate, alanine, branched-chain amino acids, IL-1, IL-6, TNF, and IFN-7 were measured in patients before, during, and after inguinal hernia repair (minor surgery) or elective abdominal aortic aneurysm surgery (major surgery). This latter operation has several advantages as an example of major surgery. The age, race, and general health of the pa¬
population is relatively uniform, they undergo a rea¬ surgical insult, they are tumor free, sonably comparable and they have a relatively low risk of sepsis. This permits the impact of major surgery to be evaluated without the tient
Downloaded From: http://archsurg.jamanetwork.com/ by a Oakland University User on 06/13/2015
Table 1.—The Effect of
Major Surgery on
Plasma Amino Acid
Plasma Amino Acid
/L
Patients
0
9
653±21
78±14
308±34
366±23
0.5
9
617±14
105+21
316±41
372±28
1
9
599±27
82±12
312+34
356±24
1.5
9
609±45
86±12
347±48
372±26
2
9
636±41
82±10
408±52+
398±26
2.5
9
430±53t
405±38
3
9
589±39t 573±42+
77±13 83±15
429±61t
415±37
3.5
9
554±46+
87±12
440±73t
429±42
4
9
521 ±40+
76 + 15
380±65
391 ±41
6
9
477±35
76±12
365±58
369±36
No. of
|-1 BCAA Glutamine Glutamate Alanine
8
9
478±26
59+12
392±93
325±16
12
8
529±33
44±12+
385±53
264±13
24
9
542±30
46±9
345±55
306±32+
48
9
455±26§
43±12+
204±29+
368±39 ND
72
6
458±32
25±6
203±33+
120
8
472±19§
39±13+
234±21+
ND
168
7
504±32
54±15
278±24
415±38
•Values are mean±SEM. BCAA denotes branched-chain amino erative values are denoted, tlndicates P
