Lower vs Higher Oxygenation Target and Days Alive Without Life Support in COVID-19: The HOT-COVID Randomized Clinical Trial.

Importance: Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial. Objective: To assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized clinical trial including 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023. Interventions: Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days. Results: Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adverse events or in number of days alive and out of hospital. Conclusion and Relevance: In adult ICU patients with COVID-19 and severe hypoxemia, targeting a Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg. Trial Registration: ClinicalTrials.gov Identifier: NCT04425031.

Long-term mortality and health-related quality of life of lower versus higher oxygenation targets in ICU patients with severe hypoxaemia.

PURPOSE: We assessed outcomes after 1 year of lower versus higher oxygenation targets in intensive care unit (ICU) patients with severe hypoxaemia. METHODS: Pre-planned analyses evaluating 1-year mortality and health-related quality-of-life (HRQoL) outcomes in the previously published Handling Oxygenation Targets in the ICU trial which randomised 2928 adults with acute hypoxaemia to targets of arterial oxygen of 8 kPa or 12 kPa throughout the ICU stay up to 90 days. One-year all-cause mortality was assessed in the intention-to-treat population. HRQoL was assessed using EuroQol 5 dimensions 5 levels (EQ-5D-5L) questionnaire and EQ visual analogue scale score (EQ-VAS), and analyses were conducted in both survivors only and the intention-to-treat population with assignment of the worst scores to deceased patients. RESULTS: We obtained 1-year vital status for 2887/2928 (98.6%), and HRQoL for 2600/2928 (88.8%) of the trial population. One year after randomisation, 707/1442 patients (49%) in the lower oxygenation group vs. 704/1445 (48.7%) in the higher oxygenation group had died (adjusted risk ratio 1.00; 95% confidence interval 0.93-1.08, p = 0.92). In total, 1189/1476 (80.4%) 1-year survivors participated in HRQoL interviews: median EQ-VAS scores were 65 (interquartile range 50-80) in the lower oxygenation group versus 67 (50-80) in the higher oxygenation group (p = 0.98). None of the five EQ-5D-5L dimensions differed between groups. CONCLUSION: Among adult ICU patients with severe hypoxaemia, a lower oxygenation target (8 kPa) did not improve survival or HRQoL at 1 year as compared to a higher oxygenation target (12 kPa).

Waking Up in Pain: a prospective unselected cohort study of pain in 3702 patients immediately after surgery in the Danish Realm.

BACKGROUND: Acute and persistent pain after surgery is well described. However, no large-scale studies on immediate postoperative pain in the operating room (OR) exist, hindering potential areas of research to improve clinical outcomes. Thus, we aimed to describe the occurrence and severity of immediate postoperative pain in a large, unselected cohort. METHODS: This was a prospective cohort study, encompassing all procedures in 31 public hospitals in the Danish Realm, during a 5-day period including the weekend. Data on procedures and anesthesia were collected and the main outcome was occurrence of moderate or severe pain in the OR. Secondary outcomes included pain, sedation and nausea in the OR or during the first 15 min in the postanesthesia care unit (PACU) including relevant risk factors. Descriptive and logistic regression statistics were used. RESULTS: A total of 3675 procedures were included for analysis (87% inclusion rate). Moderate or severe pain occurred in 7.4% (95% CI 6.5% to 8.3%) of cases in the OR immediately after awakening, rising to 20.2% in the OR and/or PACU. Large intraprocedure and interprocedure variations occurred (0.0%-37.5%), and in 20% of cases with epidural-general anesthesia patients experienced moderate or severe pain. Independent risk factors were female sex, younger age, preoperative pain, daily opioid use and major surgical procedures. CONCLUSION: Moderate or severe pain in the immediate postoperative phase occurred in 20% of all cases with procedure and anesthesiological technique variations, suggesting a need for identification of relevant procedure-specific risk factors and development of preventive treatments. TRIAL REGISTRATION NUMBER: RoPR ID 43191.

Handling oxygenation targets in ICU patients with COVID-19-Protocol and statistical analysis plan in the HOT-COVID trial.

BACKGROUND: Coronavirus disease (COVID-19) primarily affects the lungs and lower airways and may present as hypoxaemic respiratory failure requiring admission to an intensive care unit (ICU) for supportive treatment. Here, supplemental oxygen remains essential for COVID-19 patient management, but the optimal dosage is not defined. We hypothesize that targeting an arterial partial pressure of oxygen of 8 kPa throughout ICU admission is superior to targeting 12 kPa. METHODS: The Handling Oxygenation Targets in ICU patients with COVID-19 (HOT-COVID) trial, is an investigator-initiated, pragmatic, multicentre, randomized, parallel-group trial comparing a lower oxygenation target versus a higher oxygenation target in adult ICU patients with COVID-19. The primary outcome is days alive without life-support (use of mechanical ventilation, renal replacement therapy or vasoactive therapy) at day 90. Secondary outcomes are 90-day and 1-year mortality, serious adverse events in the ICU and days alive and out of hospital in the 90-day period, health-related quality-of-life at 1 year, and health economic analyses. One-year follow-up of cognitive and pulmonary function is planned in a subgroup of Danish patients. We will include 780 patients to detect or reject an absolute increase in days alive without life-support of 7 days with an α of 5% and a ß of 20%. An interim analysis is planned after 90-day follow-up of 390 patients. CONCLUSIONS: The HOT-COVID trial will provide patient-important data on the effect of two oxygenation targets in ICU patients with COVID-19 and hypoxia. This protocol paper describes the background, design and statistical analysis plan for the trial.

Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure.

BACKGROUND: Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher target. METHODS: In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days. RESULTS: At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24). CONCLUSIONS: Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days. (Funded by the Innovation Fund Denmark and others; HOT-ICU ClinicalTrials.gov number, NCT03174002.).

Telemedicine-based physician consultation results in more patients treated and released by ambulance personnel.

OBJECTIVE: We examined whether teleconsultation from ambulances to a physician at an emergency medical communication center (EMCC) would increase the proportion of patients with nonurgent conditions being treated and released on site. METHODS: This research was a before-after pilot study. In the intervention period, the EMCC was manned 24/7 with physicians experienced in emergency care. Eligible participants included all patients with nonurgent conditions receiving an ambulance after a medical emergency call. Ambulance personnel assessed patients and subsequently performed a telephone consultation from the ambulance with the physician. The primary outcome was the proportion of patients treated and released on site. Secondary outcomes were the number of hospital admissions, mortality, and patient satisfaction. The intervention period was compared with a corresponding control period from the previous year. RESULTS: We observed an increase in the proportion of patients treated and released in the intervention period in 2014 compared with the control period in 2013, up from 21% (n=137) to 29% (n=221) (odds ratio=1.46; 95% confidence interval=1.14-1.89, P=0.002). The follow-up rate was 100%. There was no observable increase in hospital admissions or mortality among patients treated and released from 2013 to 2014. A telephone survey of patients treated and released showed that 98.4% (95% confidence interval=91.3-99.9) were very satisfied or satisfied with their treatment. CONCLUSION: Teleconsultation between a physician at the EMCC and ambulance personnel and noncritically ill 1-1-2 patients results in an increased rate of patients treated and released with high satisfaction. The approach does not seem to compromise patient safety.

Prehospital triage of patients suffering severe dyspnoea using N-terminal pro-brain natriuretic peptide, the PreBNP trial: a randomised controlled clinical trial.

PURPOSE: The purpose of this study was to examine whether the addition of brain natriuretic peptide measurement to the routine diagnostic work-up by prehospital critical care team physicians improves triage in patients with severe dyspnoea. METHODS: Prehospital critical care team physicians randomly assigned patients older than 18 years with severe dyspnoea to routine diagnostic work-up or diagnostic work-up with incorporated point-of-care N-terminal pro-brain natriuretic peptide (NT-proBNP) measurement. The primary endpoint was the proportion of patients with dyspnoea of primary cardiac origin triaged directly to a department of cardiology. RESULTS: A total of 747 patients were randomly assigned and 711 patients consented to participate, 350 were randomly assigned to the NT-proBNP group and 361 to the routine work-up group. NT-proBNP was measured in 90% (315/350) of patients in the NT-proBNP group and in 19% (70/361) of patients in the routine work-up group. There was no difference in the proportion of patients with dyspnoea of primary cardiac origin triaged directly to a department of cardiology between the NT-proBNP group and the routine work-up group (75% vs. 69%, P=0.22) in the intention-to-treat analysis. Sensitivity analysis according to the de facto diagnostics performed showed results consistent with this. No differences in hospital length of stay, intensive care unit admission rates or mortality between the NT-proBNP group and the routine work-up group were observed. CONCLUSION: Routine supplementary point-of-care measurement of NT-proBNP in patients with severe dyspnoea did not improve triage of patients with dyspnoea primarily caused by heart disease. ClinicalTrials.gov identifier NCT02050282.

Timing of focused cardiac ultrasound during advanced life support - A prospective clinical study.

INTRODUCTION: Focused cardiac ultrasound can potentially identify reversible causes of cardiac arrest during advanced life support (ALS), but data on the timing of image acquisition are lacking. This study aimed to compare the quality of images obtained during rhythm analysis, bag-mask ventilations, and chest compressions. METHODS: Adult patients in cardiac arrest were prospectively included during 23 months at a Danish community hospital. Physicians who had completed basic ultrasound training performed subcostal focused cardiac ultrasound during rhythm analysis, bag-mask ventilations, and chest compressions. Image quality was categorised as either useful for interpretation or not. Two echocardiography experts rated images useful for interpretation if all the following characteristics could be determined: 1) right ventricle larger than left ventricle, 2) pericardial fluid, and 3) collapsing ventricles. RESULTS: Images were obtained from 60 of 114 patients undergoing ALS. A higher proportion of the images obtained during rhythm analysis and bag-mask ventilations were useful for interpretation when compared with chest compressions (rhythm analysis vs chest compressions: OR 2.2 (95%CI 1.3-3.8), P = 0.005; bag mask ventilations vs chest compressions: OR 2.0 (95%CI 1.1-3.7), P = 0.03). There was no difference between images obtained during rhythm analysis and bag-mask ventilations (OR 1.1 (95%CI 0.6-2.0), P = 0.74). CONCLUSION: The quality of focused cardiac ultrasound images obtained during rhythm analysis and bag-mask ventilations was superior to that of images obtained during chest compressions. There was no difference in the quality of images obtained during rhythm analysis and bag-mask ventilations. Bag-mask ventilations may constitute an overlooked opportunity for image acquisition during ALS.

A novel protocol for dispatcher assisted CPR improves CPR quality and motivation among rescuers-A randomized controlled simulation study.

BACKGROUND: Emergency dispatchers use protocols to instruct bystanders in cardiopulmonary resuscitation (CPR). Studies changing one element in the dispatcher's protocol report improved CPR quality. Whether several changes interact is unknown and the effect of combining multiple changes previously reported to improve CPR quality into one protocol remains to be investigated. We hypothesize that a novel dispatch protocol, combining multiple beneficial elements improves CPR quality compared with a standard protocol. METHODS: A novel dispatch protocol was designed including wording on chest compressions, using a metronome, regular encouragements and a 10-s rest each minute. In a simulated cardiac arrest scenario, laypersons were randomized to perform single-rescuer CPR guided with the novel or the standard protocol. PRIMARY OUTCOME: a composite endpoint of time to first compression, hand position, compression depth and rate and hands-off time (maximum score: 22 points). Afterwards participants answered a questionnaire evaluating the dispatcher assistance. RESULTS: The novel protocol (n=61) improved CPR quality score compared with the standard protocol (n=64) (mean (SD): 18.6 (1.4)) points vs. 17.5 (1.7) points, p<0.001. The novel protocol resulted in deeper chest compressions (mean (SD): 58 (12)mm vs. 52 (13)mm, p=0.02) and improved rate of correct hand position (61% vs. 36%, p=0.01) compared with the standard protocol. In both protocols hands-off time was short. The novel protocol improved motivation among rescuers compared with the standard protocol (p=0.002). CONCLUSIONS: Participants guided with a standard dispatch protocol performed high quality CPR. A novel bundle of care protocol improved CPR quality score and motivation among rescuers.

[Fatal reaction to wasp sting in a patient allergic to wasp venom]. / Fatal udgang efter hvepsestik hos allergiker.

A 68-year-old man suffered from anaphylaxis and cardiac arrest following wasp sting. He was resuscitated and taken to hospital where he later died from anoxic brain injury. Previously he had had an anaphylactic reaction to wasp venom but did not carry his auto-adrenaline-injector. Patients with anaphylaxis due to insect venom must be referred to allergological investigations. Furthermore, they should be educated in recognition and handling of anaphylaxis and they should be provided with a management plan and an auto-adrenaline-injector along with a thorough instruction on the appropriate use.

[Unilateral volume fluctuating expansion of mamma synchronously to respiration is a symptom of pneumothorax].

Women with breast implants constitute a growing proportion of the female population in Denmark. Thoracic trauma can result in a different pathology and clinical presentation compared with women without breast implants. This case report illustrates an atypical manifestation of pneumothorax in a breast augmented woman who suffered thoracic trauma with communication between the thorax cavity and the space around the implant.

[Cardiac arrest during anaesthesia in a young adult with occult cardiomyopathy]. / Hjertestop under anæstesi hos ung patient med uerkendt kardiomyopati.

Severe heart failure is a significant risk factor in anaesthesia. We present a case of circulatory collapse and cardiac arrest during routine anaesthesia of a younger man, caused by occult dilated cardiomyopathy. We propose preoperative focus assessed transthoracic echocardiography as useful in detecting cardiopulmonary pathology.

Normalisation of insulin-like growth factor-I does not improve insulin action in cirrhosis.

BACKGROUND & AIMS: Cirrhosis of the liver is characterised by insulin resistance and low levels of insulin-like growth factor I (IGF-I). Lack of IGF-I may contribute to this insulin resistance, as IGF-I increases insulin sensitivity. This study aimed to determine the effects of normalisation of IGF-I on insulin action in cirrhosis. METHODS: This article is a randomised sequence-crossover placebo controlled study. Eight patients with cirrhosis and eight controls were studied following treatment with IGF-I (50 µg/kg twice daily) or saline. Insulin action, glucose utilisation and endogenous glucose production were measured during the euglycaemic hyperinsulinaemic clamp. RESULTS: The patients with cirrhosis had normal fasting glucose level, but increased levels of insulin (P < 0.05) and C-peptide (P < 0.05). Insulin resistance resulted from a defect in glycogen synthesis, whereas insulin-mediated suppression of glucose production was unaltered. In cirrhosis, IGF-I treatment normalised free (from 0.07 ± 0.01 to 0.26 ± 0.05 µg/L) and total IGF-I (from 73 ± 6 to 250 ± 39 µg/L), whereas in controls, the IGF-I level increased into the upper physiological range (free IGF-I from 0.23 ± 0.02 to 0.61 ± 0.06 µg/L; total IGF-I from 200 ± 19 to 500 ± 50 µg/L) (all P-values < 0.05). In cirrhosis, IGF-I treatment did not change fasting glucose, insulin or C-peptide levels (P > 0.05). In the controls, insulin and C-peptide levels decreased (P < 0.05). IGF-I treatment did not improve insulin sensitivity in cirrhosis. CONCLUSIONS: Because normalisation of IGF-I levels did not affect insulin sensitivity lack of IGF-I is unlikely to result in insulin resistance in cirrhosis. IGF-I supplementation is therefore unlikely to improve insulin action in patients with cirrhosis.

Effects of insulin-like growth factor-I administration on in vivo regulation of urea synthesis in normal subjects and patients with cirrhosis.

BACKGROUND: The anabolic effects of insulin-like growth factor-I (IGF-I) may involve a decrease of hepatic nitrogen (N) clearance, but this has never been studied in humans. Patients with cirrhosis have low levels of IGF-I and might benefit from IGF-I therapy. Conversely, a possible decrease in hepatic N clearance by IGF-I could increase the risk of hepatic encephalopathy. AIMS: To examine the effects of 1-week IGF-I administration on the functional hepatic N clearance (FHNC), viz. the linear slope of the relationship between blood-α-amino-N concentration and urea-N synthesis rate as controlled by an infusion of alanine. METHODS: A randomized sequence-crossover placebo-controlled study. Eight healthy volunteers and eight patients with alcoholic cirrhosis received injections of saline or IGF-I twice daily (50 µg/kg) for 7 days. RESULTS: IGF-I levels at baseline were lower in the patients than those in the controls. The IGF-I treatment normalized patient levels and caused an increase in the controls to supra-physiological levels. FHNC was lower in patients compared with healthy subjects (23.0 vs 36.5 L/h, P=0.03). IGF-I treatment reduced FHNC by 30% in healthy subjects (from 36.5 to 25.7 L/h, P = 0.02), whereas no effect was found in the patients. CONCLUSION: IGF-I downregulates urea synthesis in normal subjects. This may be part of the explanation behind the anabolic effects of IGF-I. The normalization of IGF-I in cirrhosis patients without an effect on urea synthesis implies that the patients were resistant to IGF-I with regard to reduction of hepatic amino-N elimination. IGF-I treatment of cirrhosis patients evidently carries no risk of N accumulation.

Increased energy expenditure and glucose oxidation during acute nontraumatic skin pain in humans.

BACKGROUND AND OBJECTIVE: Tissue injury is accompanied by pain and results in increased energy expenditure, which may promote catabolism. The extent to which pain contributes to this sequence of events is not known. METHODS: In a cross-over design, 10 healthy volunteers were examined on three occasions; first, during self-controlled nontraumatic electrical painful stimulus to the abdominal skin, maintaining an intensity of 8 on the visual analogue scale (0-10). Next, the electrical stimulus was reproduced during local analgesia and, finally, there was a control session without stimulus. Indirect calorimetry and blood and urine sampling was done in order to calculate energy expenditure and substrate utilization. RESULTS: During pain stimulus, energy expenditure increased acutely and reversibly by 62% (95% confidence interval, 43-83), which was abolished by local analgesia. Energy expenditure paralleled both heart rate and blood catecholamine levels. The energy expenditure increase was fuelled by all energy sources, with the largest increase in glucose utilization. CONCLUSION: The pain-related increase in energy expenditure was possibly mediated by adrenergic activity and was probably to a large extent due to increased muscle tone. These effects may be enhanced by cortical events related to the pain. The increase in glucose consumption favours catabolism. Our findings emphasize the clinical importance of pain management.

Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats.

OBJECTIVES: Growth hormone (GH) reduces the catabolic side effects of steroid treatment via effects on the amino-nitrogen metabolism. Ipamorelin is a synthetic peptide with GH releasing properties. We wished to study the metabolic effects of Ipamorelin and GH on selected hepatic measures of alpha-amino-nitrogen conversion during steroid-induced catabolism. DESIGN: Five groups of rats were included: (1) free-fed controls (2) pair-fed controls (3) prednisolone (delcortol, 4 mg x kg(-1) x day(-1)) (4) prednisolone and GH (1 mg x kg(-1) x day(-1)) (5) prednisolone and Ipamorelin (0.5 mg x kg(-1) x day(-1)). After seven days the hepatic capacity of urea-N synthesis (CUNS) was determined in parallel with measurements of liver mRNA levels of urea cycle enzymes, whole-body N-balance, and N-contents of various organs. RESULTS: Compared to pair-fed controls, prednisolone increased CUNS (p<0.01) as well as the expression of urea cycle genes (p<0.01), and decreased N-balance (p<0.01) as well as organ N-contents (p<0.05). Compared to prednisolone treated animals, co-administration of GH reduced CUNS by 33% (p<0.01), normalized urea cycle gene expression, improved N-balance 2.5-fold, and normalized or improved organ N-contents. In prednisolone treated rats Ipamorelin reduced CUNS by 20% (p<0.05), decreased the expression of urea cycle enzymes, neutralised N-balance, and normalized or improved organ N-contents. CONCLUSION: Accelerated nitrogen wasting in the liver and other organs caused by prednisolone treatment was counteracted by treatment with either GH or its secretagogue Ipamorelin, though at the doses given less efficiently by the latter. This functional study of animals confirms that the GH secretagogue exerts GH related metabolic effects and may be useful in the treatment of steroid-induced catabolism.

Cirrhosis and endotoxin decrease urea synthesis in rats.

AIM: In patients with cirrhosis, endotoxemia is frequent and the vitally important capacity for urea synthesis is impaired. The patients' mortality of infection is markedly increased, which could be related to adverse metabolic effects of endotoxins. The effects of endotoxins on in vivo urea synthesis and on urea cycle genes during cirrhosis are unknown. METHODS: We examined the effects of a low dose of 0.5 mg/kg ip lipopolysaccharide (LPS) on the basal urea nitrogen synthesis rate (UNSR), the capacity of urea nitrogen synthesis (CUNS), liver tissue mRNA levels of urea cycle enzyme genes, and on the metabolic liver function measured by the galactose elimination capacity (GEC) in rats with cirrhosis induced by bile duct ligation and in control animals. RESULTS: LPS and cirrhosis + LPS decreased UNSR by 40% (P < 0.05). Cirrhosis and LPS each tended to decrease CUNS and cirrhosis + LPS decreased CUNS by 40% (P < 0.05). Cirrhosis and LPS each decreased the mRNA level of the gene for the flux-generating urea cycle enzyme carbamoyl phosphate synthetase (CPS) and the mRNA for the rate-limiting urea cycle enzyme arginine succinate synthetase (ASS) (P < 0.05). Cirrhosis + LPS left the mRNA level of CPS unchanged and decreased that of ASS (P < 0.05). The GEC did not differ among the study groups. CONCLUSION: Endotoxemia in rats with experimental cirrhosis markedly impaired the ability of the animals' livers to synthesize urea, suggesting a pathophysiological mechanism underlying the severe consequences of endotoxemia in human cirrhosis.

Opposite effects on regulation of urea synthesis by early and late uraemia in rats.

BACKGROUND & AIMS: Acute and chronic kidney failure lead to catabolism with loss of lean body mass. Up-regulation of hepatic urea synthesis may play a role for the loss of body nitrogen and for the level of uraemia. The aims were to investigate the effects of early and late experimental renal failure on the regulation of hepatic urea synthesis and the expression of urea cycle enzyme genes in the liver. METHODS: We examined the in vivo capacity of urea nitrogen synthesis, mRNA levels of urea cycle enzyme genes, and N-balances 6 days and 21 days after 5/6th partial nephrectomy in rats, and compared these data with pair- and free-fed control animals. RESULTS: Compared with pair-fed animals, early uraemia halved the in vivo urea synthesis capacity and decreased urea gene expressions (P<0.05). In contrast, late uraemia up-regulated in vivo urea synthesis and expression of all urea genes (P<0.05), save that of the flux-generating enzyme carbamoyl phosphate synthetase. The N-balance in rats with early uraemia was markedly negative (P<0.05) and near zero in late uraemia. CONCLUSIONS: Early uraemia down-regulated urea synthesis, so hepatic ureagenesis was not in itself involved in the negative N-balance. In contrast, late uraemia up-regulated urea synthesis, which probably contributed towards the reduced N-balance of this condition. These time-dependent, opposite effects on the uraemia-induced regulation of urea synthesis in vivo were not related to food restriction and probably mostly reflected regulation on gene level.

Synthesis of acute phase proteins in rats with cirrhosis exposed to lipopolysaccharide.

BACKGROUND: In patients with cirrhosis, infection is frequent and a leading cause of death. This is secondary to various immunologic abnormalities in both the innate and the adaptive immune system. However, it remains unclear whether cirrhosis affects the inflammatory systemic component of the innate immunity, 'the acute phase response', mostly effectuated by the liver itself. We hypothesized that rats with cirrhosis raise a reduced acute phase response induced by lipopolysaccharide (LPS). RESULTS: We examined the acute phase response induced by intraperitoneal injection of a low dose of LPS, in sham operated control animals and in rats with liver cirrhosis induced by bile duct ligation (BDL). We measured the serum concentrations of the most important acute phase proteins and their liver tissue gene expressions, assessed by mRNA levels. The BDL-model itself increased the serum concentration of alpha1-acid glycoprotein (alpha1AGP) and haptoglobin. LPS was lethal to 25% of the cirrhotic animals and to none of the controls. Twenty-four hours after LPS, the serum concentration of alpha1AGP and haptoglobin, the mRNA level of these acute phase proteins and of alpha2-macroglobulin and thiostatin rose to the same level in the animals with cirrhosis and in controls. CONCLUSION: In rats with experimental cirrhosis LPS caused high mortality. In the survivors, the cirrhotic liver still synthesized acute phase proteins as the normal liver, indicating a normal hepatic contribution to this part of the acute phase response.

Effect of lipopolysaccharide on in vivo and genetic regulation of rat urea synthesis.

BACKGROUND: The acute phase response causes a negative nitrogen balance. It is unknown whether this involves regulation of hepatic urea synthesis. METHODS: We examined the in vivo capacity of urea nitrogen synthesis (CUNS), mRNA levels of urea cycle enzyme genes and galactose elimination capacity (GEC) during moderate and severe acute phase response induced by low- and high-dose lipopolysaccharide (LPS) in rats. RESULTS: Low-dose LPS doubled CUNS (P<0.05), decreased the mRNA level of the rate-limiting urea cycle enzyme (arginino succinate synthetase (ASS) by 26% (P<0.05) and did not change GEC. High-dose LPS did not change CUNS, decreased the mRNA level of the flux-generating enzyme carbamoyl phosphate synthetase (CPS) by 11% (P<0.05) and the rate-limiting urea cycle enzyme (ASS) by 27% (P<0.05) and almost halved GEC (P<0.05). CONCLUSION: The moderate acute phase response up-regulated in vivo urea synthesis but had the opposite effect on gene level. The severe acute phase response decreased the functional liver mass that attenuated the increase in urea synthesis.