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1.
Acta Anaesthesiol Scand ; 65(6): 834-845, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33583034

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , COVID-19 Drug Treatment , Dexamethasone/administration & dosage , Pandemics , Randomized Controlled Trials as Topic/methods , SARS-CoV-2 , Anti-Inflammatory Agents/adverse effects , COVID-19/complications , Denmark , Dexamethasone/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Hospital Mortality , Humans , Hydrocortisone/therapeutic use , Hypoxia/drug therapy , Hypoxia/etiology , India , Life Support Care/statistics & numerical data , Practice Patterns, Physicians'/statistics & numerical data , Quality of Life , Survival Analysis , Sweden , Switzerland
2.
Acta Anaesthesiol Scand ; 51(8): 1079-84, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17697303

ABSTRACT

AIM: To investigate the effect of different doses of norepinephrine (noradrenaline) on luminal concentrations of L-lactate in the rectum and stomach in patients with fluid-resuscitated septic shock. METHODS: This was a paired cross-over study in which the dose of norepinephrine was titrated to mean arterial blood pressures (MAPs) of 65 and 85 mmHg in random sequence. It was performed in a mixed intensive care unit at a university hospital. Eight patients with fluid-resuscitated septic shock requiring norepinephrine (>0.1 microg/kg/min) were included. Patients were treated with norepinephrine to a MAP of either 65 or 85 mmHg for 2 h. After a 'washout' period of 2 h, the dose of norepinephrine was titrated to the other endpoint of MAP for another 2 h. The concentrations of L-lactate in the rectal and gastric lumen were estimated by 1-h equilibrium dialysis during the second hour of the treatment periods. RESULTS: MAP and central venous oxygen saturation were increased by increasing the dose of norepinephrine [median (range) (microg/kg/min): 0.07 (0.00-0.60) and 0.18 (0.11-1.00) at MAPs of 65 and 85 mmHg, respectively], whereas the metabolic markers were unaffected [luminal concentrations (mmol/l) of L-lactate in the rectum of 1.9 (0.8-6.4) and 1.8 (0.9-5.7) (P =0.94) and in the stomach of 1.1 (0.1-10.0) and 1.3 (0.3-9.7) (P =0.88) at MAPs of 65 and 85 mmHg, respectively]. CONCLUSION: In this small study, luminal concentrations of L-lactate in the rectum and stomach were unaffected by norepinephrine at low to moderate doses. These data suggest that norepinephrine may not increase luminal concentrations of l-lactate in the gut in patients with fluid-resuscitated septic shock.


Subject(s)
Adrenergic alpha-Agonists/administration & dosage , Lactic Acid/analysis , Norepinephrine/administration & dosage , Shock, Septic/metabolism , Adrenergic alpha-Agonists/pharmacology , Aged , Aged, 80 and over , Blood Gas Analysis , Blood Pressure/drug effects , Cardiac Output/drug effects , Cross-Over Studies , Dose-Response Relationship, Drug , Female , Fluid Therapy , Gastric Mucosa/metabolism , Heart Rate/drug effects , Humans , Male , Middle Aged , Norepinephrine/pharmacology , Rectum/metabolism , Statistics, Nonparametric
3.
Acta Anaesthesiol Scand ; 51(8): 1085-92, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17697304

ABSTRACT

BACKGROUND: Increased permeability and increased luminal concentrations of L-lactate have previously been shown in the large bowel in septic patients. To advance these observations, a human model of colorectal barrier failure in sepsis is desirable. Therefore, we assessed the effects of endotoxaemia on markers of permeability, metabolism and inflammation in the large bowel in healthy subjects. METHODS: Twelve healthy male subjects received intravenous endotoxin (2 ng/kg body weight) or saline in a paired cross-over design. Colorectal permeability was assessed after 3, 6, 9 and 12 h by the systemic recovery of luminally instilled (99m)Tc-diethylenetriaminepentaacetate. Luminal concentrations of L-lactate were assessed by equilibrium dialysis. Mucosal biopsies from the large bowel were sampled after 6 and 12 h, and the apoptotic ratio of the epithelium was assessed by terminal deoxynucleotidyl transferase-mediated desoxyuridinetriphosphate nick end-labelling (TUNEL) assay and the expression of inducible nitric oxide synthase (iNOS) mRNA by reverse transcriptase-polymerase chain reaction. RESULTS: Systemic effects of endotoxaemia were observed, including fever, tachycardia and strongly increased plasma values of tumour necrosis factor-alpha. By contrast, the colorectal permeability, luminal lactate concentrations, mucosal infiltration of inflammatory cells, epithelial apoptotic ratio and expression of iNOS were all unaffected by endotoxin. CONCLUSIONS: No effect of a single intravenous dose of endotoxin was observed on markers of large bowel permeability, metabolism and inflammation in healthy subjects. This suggests that this part of the gut is relatively resistant to the systemic inflammation induced by experimental endotoxaemia in humans.


Subject(s)
Endotoxemia/metabolism , Rectum/metabolism , Adult , Apoptosis/genetics , Biomarkers/metabolism , Cross-Over Studies , Endotoxemia/complications , Endotoxins , Humans , Inflammation/metabolism , Intestinal Absorption/physiology , Lactic Acid/analysis , Male , Nitric Oxide Synthase Type II/analysis , Protein C/analysis , Rectum/pathology , Tumor Necrosis Factors/blood
4.
Br J Anaesth ; 95(6): 764-8, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16199418

ABSTRACT

BACKGROUND: Gut ischaemia may contribute to morbidity in patients after cardiopulmonary bypass (CPB), but little is known about the metabolic state of the large bowel in such patients. Therefore we estimated the concentrations of L-lactate and Pco(2) in rectal mucosa in patients undergoing cardiac surgery with or without the use of CPB. METHODS: Patients undergoing coronary artery bypass grafting (CABG) (n=12) or off-pump CABG (n=10) were subjected to equilibrium dialysis of the rectal lumen during the procedure and in the first 4 h afterwards. Dialysate concentrations of L-lactate and Pco(2) were measured using an auto-analyser and compared with values obtained in healthy subjects (n=10). RESULTS: During CPB, a 2- to 3-fold increase in luminal concentrations of L-lactate was observed (CABG vs off-pump CABG, P=0.05; CABG vs healthy subjects, P<0.01). The dialysate concentrations of L-lactate were higher than the mean systemic values (luminal-arterial gradient mean (sd) 0.9 (1.0) mmol litre(-1), P<0.05), and the two values were positively correlated (P<0.05). Luminal L-lactate concentrations remained elevated 4 h after the operation. In contrast, dialysate Pco(2) was equally high in patient and control groups and substantially higher than values observed in arterial blood. CONCLUSIONS: Uncomplicated CPB is associated with moderate but sustained increases in luminal concentrations of L-lactate in the rectum, indicating metabolic dysfunction of the mucosa in the large bowel.


Subject(s)
Cardiopulmonary Bypass , Lactic Acid/metabolism , Rectum/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Carbon Dioxide/blood , Coronary Artery Bypass , Coronary Artery Bypass, Off-Pump , Female , Humans , Intestinal Mucosa/blood supply , Intestinal Mucosa/metabolism , Male , Middle Aged , Monitoring, Intraoperative/methods , Partial Pressure , Rectum/blood supply
5.
Gut ; 54(4): 503-9, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15753535

ABSTRACT

BACKGROUND AND AIMS: Expression of inducible nitric oxide synthase (iNOS) is greatly upregulated in the colonic mucosa of patients with collagenous and ulcerative colitis. As the transcription factor nuclear factor kappaB (NFkappaB) is a major inducer of iNOS gene expression, we compared activation and transcriptional activity of NFkappaB in colonic mucosal biopsies from these patients. PATIENTS: Eight patients with collagenous colitis, six with relapsing ulcerative colitis, and eight with uninflamed bowel were studied. METHODS: NFkappaB DNA binding activity was assessed by electrophoretic mobility shift assay and inhibitor of NFkappaB (IkappaB) kinase (IKK) activity by immunocomplex kinase assay. In vivo recruitment of NFkappaB to the iNOS promoter was determined by chromatin immunoprecipitation analysis and transcriptional activity by NFkappaB gene expression profiling arrays. Cells showing NFkappaB activation were identified by immunohistochemistry. RESULTS: In collagenous and ulcerative colitis, as opposed to uninflamed bowel, IKKbeta activity and strong NFkappaB DNA binding gave rise to activation of identical NFkappaB subunits and recruitment of transcriptionally active p65 to the iNOS promoter. In collagenous colitis, activated NFkappaB was observed only in epithelial cells while up to 10% of lamina propria macrophages showed activation in ulcerative colitis. CONCLUSIONS: In collagenous and ulcerative colitis, colonic mucosal NFkappaB is activated and recruited to the iNOS promoter in vivo via an IKKbeta mediated pathway. As collagenous colitis is not associated with tissue injury, these data challenge the prevailing view that activation of NFkappaB per se mediates tissue injury. Our results suggest that downstream inflammatory reactions leading to tissue damage originate in lamina propria immune cells, as increased NFkappaB activity in collagenous colitis was localised solely in epithelial cells, but present also in macrophages in ulcerative colitis.


Subject(s)
Colitis, Collagenous/metabolism , Colitis, Ulcerative/metabolism , Intestinal Mucosa/metabolism , NF-kappa B/metabolism , DNA-Binding Proteins/metabolism , Epithelial Cells/metabolism , Gene Expression Profiling/methods , Humans , I-kappa B Kinase , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Promoter Regions, Genetic , Protein Serine-Threonine Kinases/metabolism , Transcription, Genetic , Translocation, Genetic
6.
Acta Anaesthesiol Scand ; 48(8): 1054-7, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15315626

ABSTRACT

Terlipressin--a long-acting analogue of vasopressin--has been described to restore blood pressure in patients with catecholamine-resistant septic shock without obvious complications. We administered low-dose terlipressin (a single i.v.-bolus of 0.5 mg) to a patient with severe, hyperdynamic septic shock requiring high dosage of noradrenalin. After terlipressin the dose of noradrenalin could be reduced by 2/3 to obtain the same blood pressure. Two hours after terlipressin, the cardiac index had decreased from 6.2 to 3.3 l min(-1) m(-2) and the concentration of L-lactate in the rectal lumen, as assessed by equilibrium dialysis, increased from 3.6 to 7.2 mmol l(-1). In contrast, the systemic concentration of L-lactate was unaffected around 2.8 mmol l(-1). After 8 h the effect of terlipressin started to decline, and after an additional 12 h the systemic haemodynamics, dose of noradrenalin and concentrations of rectal and systemic L-lactate were the same as prior to the administration of terlipressin. As a strong vasopressor, terlipressin may have further impaired the metabolic dysfunction in the rectal mucosa either directly via vasoconstriction of mucosal vessels or through decreased cardiac output in this patient with noradrenalin-treated septic shock.


Subject(s)
Lactic Acid/metabolism , Lypressin/analogs & derivatives , Lypressin/therapeutic use , Rectum/metabolism , Shock, Septic/metabolism , Vasoconstrictor Agents/therapeutic use , Aged , Cardiac Output/drug effects , Dialysis , Hemodynamics/drug effects , Humans , Male , Norepinephrine/therapeutic use , Rectum/drug effects , Terlipressin
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