Quality of Life in Animals as a New Outcome for Surgical Research: G-CSF as a Quality of Life Improving Factor

Abstract

Sepsis is still a major problem in human medicine with a high mortality rate. Nearly all attempts to improve the outcome of septic patients with immune modulators failed. In most of these trials only mechanistic endpoints such as mortality rate, complication rate, cytokine levels and physiological parameters were assessed. Only in a very few trials quality of life had been chosen as primary endpoint. In basic research and especially in animal experiments in the field of sepsis and oncology, only molecular investigations which explain drug and treatment interactions were in the focus of the scientific community. Animal models simulating clinical complexity and investigating outcomes like quality of life were very rare. The aim of this study was to demonstrate alterations in sickness behaviour – the animal equivalent to quality of life in man – in rats as a response to sepsis after prophylaxis with G-CSF and antibiotics. Sickness behaviour was assessed by measurement of core body temperature, food and water intake, locomotor activity and circadian rhythm of these parameters. Complex animal experiments in rats were performed including anaesthesia, antibiotic and cytokine (G-CSF) prophylaxis, volume substitution, laparotomy, contamination and infection with human faecal suspension and postoperative analgesia. In group A (sham) and D (antibiotic + G-CSF) the mortality rate was 0% , but in group B (no prophylaxis) 33% (3/9) and in group C (antibiotic prophylaxis) 11% (1/9) of the animals died. Before infection all rats showed clear circadian patterns of locomotor activity and body temperature with physiologically higher values during the night-time. Immediately after operation and infection temperature increased, water and food intake, locomotor activity decreased and circadian rhythms were lost. Body temperature and water consumption were already normalised at day 2 after infection in all groups. Normal food intake was re-established in group C and D at day 3 while one more day was needed for recovery in Group C. Restoration of locomotor activity occurred in group D at day 5, in group C at day 7. In group B locomotor activity remained suppressed during the whole observation period of 8 days postoperatively. In conclusion, in septic rats sickness behaviour, an equivalent to quality of life in humans, is improved rapidly by a prophylaxis with G-CSF in combination with antibiotics and can be used as a new outcome in preclinical surgical research.

Individual behavioral differences in recovery from abdominal sepsis in rats

“…At first sight, the results from the present study appear not to support the data from the previous telemetric experiments [9,10], when neither open field nor social interaction behavior yielded superior recovery in the G-CSF group. However, the results do not necessarily contradict our previous findings because telemetric data were yielded in the home cage while the present study used external environments.…”

“…Using the technique of radio-telemetry [9,10], we had previously shown that antibiotic prophylaxis, especially when combined with G-CSF, positively altered sickness behavior measured in terms of behavioral activity and circadian rhythms of heart rate and blood pressure in septic rats. At first sight, the results from the present study appear not to support the data from the previous telemetric experiments [9,10], when neither open field nor social interaction behavior yielded superior recovery in the G-CSF group.…”

“…Recently, we showed in clinic modeling randomized trials (CMRTs) in rats that sepsis leads to reduced behavioral activity which can be monitored continuously in the home cage by radio-telemetry [9,10] or in well-established behavioral tests like the open field, elevated plus-maze, and social interaction test [11]. Out of these, the open field test is widely used as a standard screening procedure to measure psychomotor activity and exploration [12,13].…”

Sickness behavior of rats with abdominal sepsis can be improved by antibiotic and G-CSF prophylaxis in clinic modeling randomized trials

“…In previous experiments we had shown that the recovery of food intake is faster in animals with prophylaxis than without [12], thus weight loss in such animals should be less rather than more severe as compared to septic animals without prophylaxis. This discrepancy may be explained by an altered metabolism induced by the prophylaxes.…”

“…A definite trial has to be performed including only the most important treatment groups. Recently, we showed in other CMRTs that sepsis can lead to reduced activity in rats monitored continuously in the home cage by radio-telemetry [11,12].…”