Sequential changes in in vivo muscle and liver protein synthesis and plasma and tissue glutamine levels in sepsis in the rat.

We have investigated sequential changes in skeletal muscle and hepatic protein synthesis following sepsis, and their relationship to changes in circulating and tissue glutamine concentrations. Male Wistar rats underwent caecal ligation and puncture (CLP) or sham operation, with starvation, and were killed 24, 72 or 96 h later. A group of non-operated animals were killed at the time of surgery. Protein synthesis was determined using a flooding dose of L-[4-(3)H] phenylalanine, and glutamine concentrations were measured by an enzymic fluorimetric assay. Protein synthesis in gastrocnemius muscle fell in all groups. Gastrocnemius total protein content was reduced after CLP and at 72 and 96 h after sham operation. After CLP, protein synthesis was lower at 24 h, and total protein content was lower at 72 and 96 h, than in sham-operated animals. CLP was associated with increased liver protein synthesis at all time points, whereas there was no change after sham operation. Liver protein content did not change after CLP, but was lower at 72 and 96 h after sham operation than in non-operated animals. Plasma glutamine concentrations were reduced at 24 h after sham operation, and at 72 and 96 h after CLP. Muscle glutamine concentrations were reduced in all groups, with the decrease being greater following CLP than after sham operation. In the liver, glutamine concentrations were unchanged after CLP, but increased after sham operation. In rats with sepsis, decreases in muscle protein synthesis and content are associated with markedly reduced muscle glutamine concentrations. Plasma glutamine concentrations are initially maintained, but fall later. In liver, protein synthesis is increased, while glutamine concentrations are preserved. These results support a peripheral-to-splanchnic glutamine flux in sepsis.

In rats with sepsis, the acute fall in IGF-I is associated with an increase in circulating growth hormone-binding protein levels.

OBJECTIVE: Growth hormone (GH) given to reverse muscle catabolism in critical illness increased mortality, illustrating the need for better understanding of the pathophysiology of the GH axis. We describe the relationship between changes in plasma insulin-like growth factor-I (IGF-I) and growth hormone-binding protein (GHBP) levels and hepatic growth hormone-binding in rats with sepsis. DESIGN: Randomised, controlled study. SETTING: University research laboratory. SUBJECTS: One hundred and eleven male Wistar rats. INTERVENTION: Three groups of rats underwent caecal ligation and puncture (CLP) and three groups laparotomy only (LAP). Survivors were killed at 24, 72, and 96 h. All animals were starved during the study. Twelve rats were killed at the start of the experiment (baseline) and twelve (allowed food) at 96 h. MEASUREMENTS AND RESULTS: Plasma levels of IGF-I and GHBP and binding of 125I-labelled human GH in liver homogenates were measured. IGF-I fell significantly following both CLP and LAP; at 24 h, IGF-I levels were lower after CLP than LAP (950 +/- 74 vs 1,522 +/- 60 microg/l, P = < 0.001). GHBP increased at 24 h following both CLP and LAP (45.6 +/- 1.87 and 47.7 +/- 3.01 vs 38.7 +/- 1.98 ng/ml at baseline, P = < 0.05). In LAP animals GHBP fell to below baseline by 72 h, and significantly so by 96 h (33.5 +/- 1.43, P = < 0.05), whereas GHBP remained elevated 72 h following CLP, returning to baseline by 96 h. The density of GH-binding sites in liver tended to increase, following both CLP and LAP at both 24 and 96 h, but these changes failed to achieve statistical significance. CONCLUSION: Reduced IGF-I levels in sepsis in the rat are associated with elevations in GHBP and a trend to increased hepatic GH binding. This suggests that in sepsis 'GH resistance' is not associated with reduced GH receptor numbers.

Oxygenator exhaust capnography as an index of arterial carbon dioxide tension during cardiopulmonary bypass using a membrane oxygenator.

We have studied the relationship between the partial pressure of carbon dioxide in oxygenator exhaust gas (PECO2) and arterial carbon dioxide tension (PaCO2) during hypothermic cardiopulmonary bypass with non-pulsatile flow and a membrane oxygenator. A total of 172 paired measurements were made in 32 patients, 5 min after starting cardiopulmonary bypass and then at 15-min intervals. Additional measurements were made at 34 degrees C during rewarming. The degree of agreement between paired measurements (PaCO2 and PECO2) at each time was calculated. Mean difference (d) was 0.9 kPa (SD 0.99 kPa). Results were analysed further during stable hypothermia (n = 30, d = 1.88, SD = 0.69), rewarming at 34 degrees C (n = 22, d = 0, SD = 0.84), rewarming at normothermia (n = 48, d = 0.15, SD = 0.69) and with (n = 78, d = 0.62, SD = 0.99) or without (n = 91, d = 1.07, SD = 0.9) carbon dioxide being added to the oxygenator gas. The difference between the two measurements varied in relation to nasopharyngeal temperature if PaCO2 was not corrected for temperature (r2 = 0.343, P = < 0.001). However, if PaCO2 was corrected for temperature, the difference between PaCO2 and PECO2 was not related to temperature, and there was no relationship with either pump blood flow or oxygenator gas flow. We found that measurement of carbon dioxide partial pressure in exhaust gases from a membrane oxygenator during cardiopulmonary bypass was not a useful method for estimating PaCO2.

alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role.

Clonidine has proved to be a clinically useful adjunct in clinical anaesthetic practice as well as in chronic pain therapy because it has both anaesthetic and analgesic-sparing activity. The more selective alpha-2 adrenoceptor agonists, dexmedetomidine and mivazerol, may also have a role in providing haemodynamic stability in patients who are at risk of peri-operative ischaemia. The side-effects of hypotension and bradycardia have limited the routine use of alpha-2 adrenoceptor agonists. Investigations into the molecular pharmacology of alpha-2 adrenoceptors have elucidated their role in the control of wakefulness, blood pressure and antinociception. We discuss the pharmacology of alpha-2 adrenoceptors and their therapeutic role in this review. The alpha-2 adrenoceptor agonists are agonists at imidazoline receptors which are involved in central blood pressure control. Selective imidazoline agonists are now available for clinical use as antihypertensive agents and their pharmacology is discussed.

Anaesthetic organ toxicity: is it really a problem?

The hepatotoxicity of halothane is now well known, but only became apparent after several years of use. The nephrotoxicity of methoxyflurane was not realized immediately, but once identified, led to its withdrawal from use. Therefore, when new agents that appear to offer significant advantages over established drugs become available, exhaustive testing and monitoring is necessary to ensure their safety. Sevoflurane, recently available in the UK and the USA but used for some time in Japan, has been subjected to considerable scrutiny.

Prolonged neurogenic weakness in patients requiring mechanical ventilation for acute airflow limitation.

We describe three patients who required mechanical ventilation for severe acute exacerbations of obstructive airways disease. When treatment with sedatives and muscle relaxants was withdrawn, they exhibited profound generalized weakness and consequently required prolonged ventilation despite resolution of the airway obstruction. Clinical features were variable, but none of the patients developed failure of other organs and infection was confined to the lungs. All had electrophysiologic evidence of a predominantly motor axonal syndrome. One patient in whom sensory action potentials were abnormal may represent an unusually severe case of critical illness neuropathy occurring in the absence of systemic sepsis and multiple organ failure. In the other two cases, this diagnosis is made less likely by the complete absence of sensory involvement and in these patients the lesion appeared to be either in the most distal portion of the motor neuron or at the neuromuscular junction. In all three patients, resolution was slow but eventually complete. The etiology of the condition is not clear, but it seems to be distinct from the acute myopathy previously described in asthmatics who had received mechanical ventilation. It is important to recognize this phenomenon to avoid erroneous conclusions about the likelihood of the patient recovering from ventilator dependence. A prolonged weaning period is to be expected in such cases.