Cytochrome P450 activity mirrors nitric oxide levels in postoperative sepsis: predictive indicators of lethal outcome.
BACKGROUND
The development of liver failure significantly influences prognosis during the course of major septic complications. Although the underlying cause for septic liver failure is still unclear, research using animal models has demonstrated that an increased nitric oxide (NO) synthesis compromises detoxification processes in the liver.


METHODS
In the present study, serum NO levels were measured by high-performance liquid chromatography (HPLC) and aminopyrine breath test (ABT) scores, reflecting the in vivo activity of cytochrome P450-dependent liver enzymes, were investigated in 42 patients (23 who survived sepsis [survivors]/19 patients who ultimately died of sepsis [nonsurvivors]) suffering from major septic complications after abdominal surgery. Additionally, TNF-alpha serum levels, serving as indicators for major systemic inflammation, were monitored using enzyme-linked immunosorbent assay (ELISA).


RESULTS
The increased serum NO levels that were found during sepsis correlated with the severity of the septic course. Compared with preoperative values of 42.77 +/- 5.84 mM, nitrite/nitrate levels reached 72.88 +/- 10.16 mM in early sepsis. An increased NO synthesis also was accompanied by a rise in serum TNF-alpha levels. Monitoring of liver function by ABT allowed an early differentiation between transient sepsis and sepsis with a lethal outcome (P=.006). In contrast, cytochrome P450 activity as measured by the ABT was significantly diminished in septic patients (0.45 +/- 0.02 [% dose x kgBW per (mmol CO2)-1] before sepsis onset/0.16 +/- 0.01 [% dose x kgBW per (mmol CO2)-1] in sepsis). Like the NO and TNF-alpha levels, ABT scores showed a difference between transient sepsis and sepsis with a lethal outcome. Serum NO levels were inversely correlated with ABT scores (P=.022) and positively correlated with TNF-alpha levels (P=0.015) in the late phase of sepsis. Serum TNF-alpha levels and ABT scores were inversely correlated in the early (P=.027), as well as in the late (P=.015) phases of sepsis.


CONCLUSIONS
This study supports the hypothesis that septic liver failure is linked to the induction of NO synthesis in major systemic inflammation. Therefore, the ABT provides a clinically useful tool for predicting the outcome in the early stages of sepsis. This may aid in the decision-making process when early surgical intervention is considered.
Novotny
Alexander R
AR
Department of Surgery, Klinikum rechts der Isar, Technishen Universität München, Munich, Germany.
Emmanuel
Klaus
K
Maier
Stefan
S
Westerholt
Alexandra
A
Weighardt
Heike
H
Stadler
Josef
J
Bartels
Holger
H
Schwaiger
Markus
M
Siewert
Jörg-Rüdiger
JR
Holzmann
Bernhard
B
Heidecke
Claus-Dieter
CD
D000368:Aged; D000632:Aminopyrine / Q000493:pharmacokinetics; D015415:Biomarkers / Q000097:blood; D001944:Breath Tests; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D017093:Liver Failure / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood*; D011183:Postoperative Complications / Q000378:metabolism* / Q000401:mortality*; D011237:Predictive Value of Tests; D011379:Prognosis; D018805:Sepsis / Q000378:metabolism* / Q000401:mortality*; D012720:Severity of Illness Index; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D015415:Biomarkers; D002250:Carbon Radioisotopes; D014409:Tumor Necrosis Factor-alpha; D000632:Aminopyrine; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System