Treatment of sepsis with activated protein C.
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Anticoagulants↗
Biomedical subjects
C J Hinds
Publications and source records attributed to C J Hinds.
A cell wall component from pathogenic and non-pathogenic gram-positive bacteria (peptidoglycan) synergises with endotoxin to cause the release of tumour necrosis factor-alpha, nitric oxide production, shock, and multiple organ injury/dysfunction in the rat.
The incidence of sepsis and septic shock due to gram-positive organisms has increased dramatically over the last two decades. Interestingly, many patients with sepsis/septic shock have both gram-positive and gram-negative bacteria present in the bloodstream and these polymicrobial or "mixed" infections often have a higher mortality than infection due to a single organism. The reason for this observation is unclear. The aim of this study was to investigate whether cell wall fragments from gram-positive and gram-negative bacteria could synergise to cause the release of cytokines, shock, and organ injury/ dysfunction in vivo. Male Wistar rats were anaesthetised and received an intravenous bolus of vehicle (saline), lipopolysaccharide (LPS) from Escherichia coli (0.1 mg/kg), peptidoglycan (Pep G) from Staphylococcus aureus (S10 mg/kg), co-administration of LPS (0.1 mg/kg) and PepG from S. aureus (10 mg/kg), LPS (10 mg/kg), PepG from Bacillus subtilis, or co-administration of LPS and PepG from B. subtilis. Blood pressure and heart rate were monitored for 6 h before plasma samples were taken for the measurement of TNF-alpha, total nitrite, and biochemical indices of organ injury. Peptidoglycan from both pathogenic (S. aureus) and non-pathogenic (B. subtilis) gram-positive bacteria synergised with endotoxin to cause formation of TNF-alpha, nitrite, shock, and organ injury. Synergism between PepG and LPS may partly explain the high mortality associated with mixed bacterial infections, as well as the deleterious effects of translocation of bacteria, or their cell wall components from the gut lumen in patients with sepsis.
Animals↗
Differential expression of suppressors of cytokine signalling genes in response to nutrition and growth hormone in the septic rat.
GH treatment during critical illness and sepsis may increase mortality. A family of negative regulators of cytokine signalling, the suppressors of cytokine signalling (SOCS), have been characterised. SOCS provide a mechanism for cross-talk between the cytokine receptors, including GH. Here, we have investigated the impact of nutrition and GH treatment on GH receptor, SOCS1, SOCS-2, SOCS-3 and cytokine-inducible SH2-containing protein (CIS) hepatic mRNA expression in a rat model of sepsis, caecal ligation and puncture (CLP). Four groups of rats were studied: control (food given ad libitum, n=7), CLP only (n=8), CLP and total parenteral nutrition (TPN) (n=9), and CLP, TPN and GH (n=10). CLP rats underwent surgery and 18 h later received saline or TPN or TPN+GH for 6 h before they were killed. Serum IGF-I levels were lower in all CLP groups (P<0.001). The combination of TPN and GH treatment increased IGF-I levels compared with the saline-treated CLP rats (P<0.01), but IGF-I levels remained lower than control animals (P<0.001). GH receptor and GH-binding protein expression in liver was reduced in animals subjected to CLP and was unaffected by nutrition or GH treatment. Hepatic SOCS-1 was detectable in normal rats, induced in all CLP animals but was unaffected by nutrition and GH. Hepatic SOCS-2 expression was difficult to detect in normal and CLP rats but was greatly induced in CLP rats treated with GH. Hepatic SOCS-3 expression was only just detectable in the control group but was elevated in all CLP groups and unaffected by nutrition and GH. Hepatic CIS expression was difficult to detect in normal rats, was not induced by CLP but was induced by both nutrition and GH. In conclusion, CLP induced low IGF-I levels associated with increased expression of SOCS-1 and SOCS-3, both of which are known to inhibit GH receptor signalling. GH induced SOCS-2 and CIS in the CLP rat despite resistance with respect to IGF-I generation, and parenteral feeding induced CIS in the CLP rat. Thus, there is potential for a complex interaction between GH and cytokine signalling at the level of SOCS expression whereby the inflammatory response may alter GH signalling and GH may influence the inflammatory response.
Adaptor Proteins, Signal Transducing↗
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.
Animals↗
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.
Animals↗
Increased mortality associated with growth hormone treatment in critically ill adults.
BACKGROUND: The administration of growth hormone can attenuate the catabolic response to injury, surgery, and sepsis. However, the effect of high doses of growth hormone on the length of stay in intensive care and in the hospital, the duration of mechanical ventilation, and the outcome in critically ill adults who are hospitalized for long periods is not known. METHODS: We carried out two prospective, multicenter, double-blind, randomized, placebo-controlled trials in parallel involving 247 Finnish patients and 285 patients in other European countries who had been in an intensive care unit for 5 to 7 days and who were expected to require intensive care for at least 10 days. The patients had had cardiac surgery, abdominal surgery, multiple trauma, or acute respiratory failure. The patients received either growth hormone (mean [+/-SD] daily dose, 0.10 +/- 0.02 mg per kilogram of body weight) or placebo until discharge from intensive care or for a maximum of 21 days. RESULTS: The in-hospital mortality rate was higher in the patients who received growth hormone than in those who did not (P<0.001 for both studies). In the Finnish study, the mortality rate was 39 percent in the growth hormone group, as compared with 20 percent in the placebo group. The respective rates in the multinational study were 44 percent and 18 percent. The relative risk of death for patients receiving growth hormone was 1.9 (95 percent confidence interval, 1.3 to 2.9) in the Finnish study and 2.4 (95 percent confidence interval, 1.6 to 3.5) in the multinational study. Among the survivors, the length of stay in intensive care and in the hospital and the duration of mechanical ventilation were prolonged in the growth hormone group. CONCLUSIONS: In patients with prolonged critical illness, high doses of growth hormone are associated with increased morbidity and mortality.
Adolescent↗
ABC of intensive care: circulatory support.
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Blood Pressure↗
Identification of a cAMP response element within the glucose- 6-phosphatase hydrolytic subunit gene promoter which is involved in the transcriptional regulation by cAMP and glucocorticoids in H4IIE hepatoma cells.
The expression of a luciferase reporter gene under the control of the human glucose 6-phosphatase gene promoter was stimulated by both dexamethasone and dibutyryl cAMP in H4IIE hepatoma cells. A cis-active element located between nucleotides -161 and -152 in the glucose 6-phosphatase gene promoter was identified and found to be necessary for both basal reporter-gene expression and induction of expression by both dibutyryl cAMP and dexamethasone. Nucleotides -161 to -152 were functionally replaced by the consensus sequence for a cAMP response element. An antibody against the cAMP response element-binding protein caused a supershift in gel-electrophoretic-mobility-shift assays using an oligonucleotide probe representing the glucose 6-phosphatase gene promoter from nucleotides -161 to -152. These results strongly indicate that in H4IIE cells the glucose 6-phosphatase gene-promoter sequence from -161 to -152 is a cAMP response element which is important for the regulation of transcription of the glucose 6-phosphatase gene by both cAMP and glucocorticoids.
Base Sequence↗
Reversible tetraplegia due to polyneuropathy in a diabetic patient with hyperosmolar non-ketotic coma.
Critical illness polyneuromypathy has not previously been reported as a complication of diabetic coma. We describe a patient with hyperosmolar non-ketotic coma (HONK) complicating gram-negative sepsis in whom persistent coma and profound tetraplegia caused considerable concern. Although, initially, it was feared that the patient had suffered a central neurological complication such as stroke or cerebral oedema, a diagnosis of critical illness motor syndrome (CIMS) was subsequently confirmed neurophysiologically. Profound limb weakness associated with HONK is not necessarily due to a catastrophic cerebral event, rather it may be a result of CIMS, which has an excellent prognosis for full neurological recovery.
Aged↗
Administration of growth hormone to catabolic patients.
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Critical Illness↗
Dissociation of pituitary-adrenal and catecholamine activation after induced cardiac arrest and defibrillation.
To avoid factors which confound attempts to characterize the neuroendocrine response to cardiac arrest, we studied the pituitary-adrenocortical and catecholamine responses to induced ventricular fibrillation (VF) and direct current cardioversion in 10 patients undergoing testing of 'implanted cardioverter defibrillator' devices under sedation. Plasma concentrations of epinephrine were increased 5 min after VF (from a mean basal of 0.39 (S.E.M. 0.09) to a peak of 0.632 (0.212) nmol litre-1; P < 0.05) but were unchanged at other times. Plasma concentrations of norepinephrine did not change at any time. Plasma concentrations of cortisol increased significantly at 10 min (from a mean of 367 (SEM 62) to 539 (64) nmol litre-1; P < 0.001) and remained increased 30 min after VF (470 (74) nmol litre-1; P < 0.05) but had returned towards baseline at 60 min, whereas plasma prolactin concentrations were increased at 5 min (from a mean of 224 (SEM 54) to 320 (63) mu. litre-1; P < 0.01) and remained increased until the end of the sampling period at 60 min (288 (65) mu. litre-1; P < 0.05). Concentrations of adrenocorticotrophic hormone (ACTH) (n = 5) tended to increase but this was not statistically significant. We conclude that a short period of cardiac arrest in lightly sedated humans activated the pituitary-adrenocortical axis but did not appear to stimulate catecholamine secretion. These findings raise questions about the nature and mechanisms of the neuroendocrine response to cardiac arrest.
Adrenocorticotropic Hormone↗
Ranitidine reduced clinically important gastrointestinal bleeding in patients who required mechanical ventilation.
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Anti-Ulcer Agents↗
Manipulating the metabolic response to injury.
In this short review we will concentrate on just one of the features of the metabolic response to injury (classified as accidental trauma, injury or sepsis) which are collectively known as the 'flow' phase. These include an increase in energy expenditure (hypermetabolism), changes in substrate utilisation (insulin resistance) and the focus of this chapter muscle wasting or catabolism. It is recognised that the three features are interrelated, for example insulin is believed to be an important factor in controlling amino acid flux in skeletal muscle and increasing environmental temperature which may reduce flow phase hypermetabolism has been shown to reduce postoperative nitrogen excretion (a marker of protein catabolism). However, we will concentrate on muscle wasting and refer the reader to other reviews on insulin resistance and metabolic rate.
Glutamine↗
Intensive care for patients with medical complications of haematological malignancy: is it worth it?
Appropriately aggressive treatment of haematological malignancies can be complicated by a variety of life threatening events. Usually such acute events are, at least theoretically, potentially reversible and in view of the much improved prognosis of the underlying malignancy it is now generally considered to be appropriate to offer intensive care to selected cases, provided there is a reasonable prospect of cure or at least worthwhile palliation. A few remain concerned, however, and question whether the provision of intensive care for such patients is worthwhile. Hospital mortality rates of between 69-80% have been reported for patients admitted to intensive care with medical complications of haematological malignancy and this rises to 80-90% in those with respiratory failure. Overall mortality rates are generally even higher (87-95%) in those who have received a bone marrow transplant (BMT). The median duration of survival following discharge from hospital is in the region of 12-23 months, but a few survive much longer, a number must be presumed cured and their quality of life is good. These disappointing short- and long-term survival rates are achieved at considerable cost and, as is the case in many other categories of critically ill patients, expense and utilisation of resources is much higher in non-survivors than in survivors. Factors associated with a poor short-term outcome include the need for mechanical ventilation, hypotension, the administration of inotropes or vasopressors, an increasing number of failed organs, relapsed or unresponsive malignancy and persistent neutropenia. A poor prognosis may also be associated with increasing age, time on the ventilator and time in intensive care. BMT recipients have a particularly poor prognosis, especially when they require mechanical ventilation, and survival is unprecedented when ventilated BMT recipients either receive vasopressors or develop hepatic and renal insufficiency. It has not been possible to identify any features of the acute illness which influence the duration of long-term survival: this seems to depend solely on the progress of the underlying malignancy, something which is often difficult to predict before or during intensive care. In our view patients with life threatening complications of haematological malignancy should be offered intensive care unless or until it is clear that there is no prospect of recovery from the acute illness or that the underlying malignancy cannot be controlled.
Bone Marrow Transplantation↗
Patterns of neurophysiological abnormality in prolonged critical illness.
OBJECTIVE: To describe the various patterns of neurophysiological abnormalities which may complicate prolonged critical illness and identify possible aetiological factors. DESIGN: Prospective case series of neurophysiological studies, severity of illness scores, organ failures, drug therapy and hospital outcome. Some patients also had muscle biopsies. SETTING: General intensive care unit (ICU) in a University Hospital. PATIENTS: Forty-four patients requiring intensive care unit stay of more than 7 days. The median age was 60 (range 27-84 years), APACHE II score 19 (range 8-33), organ failures 3 (range 1-6), and mortality was 23%. RESULTS: Seven patients had normal neurophysiology (group I), 4 had a predominantly sensory axonal neuropathy (group II), 11 had motor syndromes characterised by markedly reduced compound muscle action potentials and sensory action potentials in the normal range (group III) and 19 had combinations of motor and sensory abnormalities (group IV). Three patients had abnormal studies but could not be classified into the above groups (group V). All patients had normal nerve conduction velocities. Electromyography revealed evidence of denervation in five patients in group III and five in group IV. There was no obvious relationship between the pattern of neurophysiological abnormality and the APACHE II score, organ failure score, the presence of sepsis or the administration of muscle relaxants and steroids. A wide range of histological abnormalities was seen in the 24 patients who had a muscle biopsy; there was no clear relationship between these changes and the neurophysiological abnormalities, although histologically normal muscle was only found in patients with normal neurophysiology. Only three of the eight patients from group III in whom muscle biopsy was performed had histological changes compatible with myopathy. CONCLUSIONS: Neurophysiological abnormalities complicating critical illness can be broadly divided into three types -- sensory abnormalities alone, a pure motor syndrome and a mixed motor and sensory disturbance. The motor syndrome could be explained by an abnormality in the most distal portion of the motor axon, at the neuromuscular junction or the motor end plate and, in some cases, by inexcitable muscle membranes or extreme loss of muscle bulk. The mixed motor and sensory disturbance which is characteristic of 'critical illness polyneuropathy' could be explained by a combination of the pure motor syndrome and the mild sensory neuropathy. More precise identification of the various neurophysiological abnormalities and aetiological factors may lead to further insights into the causes of neuromuscular weakness in the critically ill and ultimately to measures for their prevention and treatment.
Adult↗
Selective inhibition of the activity of inducible nitric oxide synthase prevents the circulatory failure, but not the organ injury/dysfunction, caused by endotoxin.
Inhibitors of nitric oxide synthase (NOS) attenuate the circulatory failure caused by endotoxin, but the role of NO in the development of multiple organ dysfunction and the relative contribution of NO produced by endothelial NOS and inducible NOS (iNOS) to organ injury remains unclear. Here we report for the first time that 1400W, a novel and highly selective inhibitor of iNOS activity, attenuates the delayed hypotension as well as the rise in the plasma levels of nitrite/nitrate caused by endotoxin in the rat. Inhibition of iNOS activity with 1400W administered either before or 2 h after endotoxin injection did not, however, attenuate the hepatocellular injury, renal dysfunction, or pancreatic injury in this model. Similarly, administration of another selective inhibitor of iNOS activity, L-NIL, 2 h after endotoxin injection abolished the rise in nitrite/nitrate and attenuated the delayed hypotension caused by endotoxin, but failed to ameliorate organ injury. Thus, selective inhibition of iNOS activity with 1400W attenuates the circulatory failure induced by endotoxin in the rat, but fails to influence the degree of organ injury/dysfunction.
Amidines↗
Effects of inhibitors of poly(ADP-ribose) synthetase activity on hypotension and multiple organ dysfunction caused by endotoxin.
The nuclear enzyme poly(ADP-ribose) synthetase (PARS) is activated by DNA strand breakage, caused, for example by nitric oxide (NO), peroxynitrite, or oxygen-derived free radicals. Activation of PARS can cause intracellular energy depletion and cell death in vitro and may play a role in the circulatory and organ failure caused by endotoxin (LPS). Here we investigate the effects of various chemically distinct inhibitors of PARS activity (3-aminobenzamide, nicotinamide, 1,5-dihydroxyisoquinoline) on circulatory failure and organ dysfunction caused by LPS in the rat. Administration of endotoxin caused circulatory failure, acute renal dysfunction, hepatocellular injury and dysfunction, pancreatic injury, elevation of plasma lactate levels, and overproduction of NO. None of the PARS inhibitors used reduced the circulatory failure, the renal dysfunction, rise in lactate, or the overproduction of NO caused by LPS. Although 1,5-dihydroxyisoquinoline (ISO) attenuated the rises in the serum levels of bilirubin, alanine aminotransferase (ALT) (indicators of liver injury/dysfunction), and lipase (indicator of pancreatic injury); a similar effect was also observed with the vehicle for ISO, dimethyl sulfoxide (DMSO), which is a well known scavenger of hydroxyl radicals. Thus, the beneficial effects of ISO are unlikely to be due to inhibition of PARS activity, but may be due to the scavenging of free radicals by its vehicle DMSO. Activation of PARS does not contribute to the circulatory failure, renal dysfunction, lactic acidosis, or the overproduction of NO and is unlikely to contribute to the liver injury/dysfunction caused by endotoxic shock in the rat.
Animals↗
Liver microsomal transport of glucose-6-phosphate, glucose, and phosphate in type 1 glycogen storage disease.
The transport of glucose-6-phosphate (G6P), glucose, and orthophosphate into liver microsomes, isolated from six patients with various subtypes of type 1 glycogen storage disease (GSD), was measured using a light-scattering method. We found that G6P, glucose, and phosphate could all cross the microsomal membrane, in four cases of type 1a GSD. In contrast, liver microsomal transport of G6P and phosphate was deficient in the GSD 1b and 1c patients, respectively. These results support the involvement of multiple proteins (and genes) in GSD type 1. The results obtained with the light-scattering method are in accordance with conventional kinetic analysis of the microsomal glucose-6-phosphatase system. Therefore, this technique could be used to directly diagnose type 1b and 1c GSD.
Adult↗