Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial.

BACKGROUND: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock. METHODS: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116. FINDINGS: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]). INTERPRETATION: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock. FUNDING: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation.

[Septic arthritis].

Septic arthritis (SA) is a rare, but crucial differential diagnosis in any patient with acute arthritis and is associated with high morbidity and mortality. Many chronic diseases predispose for the development of SA and poor prognosis. Reports speak of increasing rates of SA due to multiresistant bacteria, but the development in Denmark is uncertain. Diagnosis is difficult, and absence of positive microbiological findings does not disprove the diagnosis. In addition, evidence supporting one regiment of treatment over another is scarce. Thus, SA requires prompt treatment by orthopaedic specialists.

Hemostasis and endothelial damage during sepsis.

The sepsis syndrome represents a disease continuum, including severe sepsis and septic shock associated with high mortality. One of the main problems in severe sepsis and septic shock, resulting in organ failure and death, are disturbances in the hemostasis due to sepsis-related coagulopathy. Sepsis-related coagulopathy affects not only traditional coagulation factors, but also the platelets and endothelium. Functional testing of the hemostatic system has found application in critical illness. Thrombelastography (TEG) provides an overview of the hemostatic system allowing for an evaluation of interactions between coagulation factors and platelets. Additionally, the role of the endothelium during sepsis can be explored through testing of biomarkers of endothelial damage. The three studies comprising this PhD thesis all investigate important aspects of the disturbed hemostasis during sepsis, including endothelial damage. Together, the specific findings from the three studies improve the existing understanding of sepsis-related coagulopathy, and the possible influences of some of the treatments offered these patients. The first study investigates the occurrence of antimicrobial-induced thrombocytopenia among critically ill patients. In sepsis, thrombocytopenia is a predictor of poor outcome, and reports, of mainly casuistic nature, have previously hypothesized that specific antimicrobial agents could induce in sepsis-related thrombocytopenia. This hypothesis was tested using a randomized designed set-up, encompassing 1147 critically ill patients, and no significant difference in risk of thrombocytopenia was observed among patients receiving large amounts of antimicrobials vs. patients receiving standard-of-care. As a consequence, the risk of antimicrobial-induced thrombocytopenia in the general population of critically ill patients seemingly does not represent a substantial problem and thrombocytopenia during critical illness is most likely due to other factors such as infection severity. In the second study of the thesis, the role of endothelial damage during sepsis was explored. Levels of biomarkers of superficial and profound endothelial damage (syndecan-1 and soluble thrombomodulin (sTM), respectively) were determined in a cohort of 1103 critically ill patients. The results showed that only high levels of sTM were associated with a markedly increased risk of 90-day mortality, as well as multi-organ failure. The finding suggests that profound damage to the endothelium is centrally involved in the pathogenesis of death in sepsis. Thus, the endothelium may be a target for new interventions against sepsis. In the third study, we investigated, using a randomized controlled trial, how mild induced hypothermia (cooling to 32-34°C for 24 hours, MIH) influenced sepsis-related coagulopathy using TEG; functional coagulopathy improved in patients exposed to the intervention compared with the control group. This improvement of coagulopathy parameters during MIH persisted after rewarming. These results not only add to the understanding of the effect of hypothermia on the hemostatic system, but indicate that MIH reduces sepsis-related coagulopathy assessed by TEG. Overall, this thesis emphasizes that the role of the hemostatic system during sepsis is not only complex, but centrally involved in disease severity and prognosis. The endothelium seems to play a central role in the morbidity and mortality of sepsis, which cannot be explained simply by the presences of organ failure. Thus, restoring the broken endothelium and reducing coagulopathy appears to be essential in order to significantly improve sepsis out-comes. MIH could be a promising intervention in sepsis, in part due to the improvement of the coagulopathy. Despite the increased focus on the hemostatic system during sepsis, it seems that continued research on restoring disrupted hemostasis - including endothelial damage - is needed.

Coagulation Status in Hidradenitis Suppurativa: A Danish Population- and Hospital-Based Cross-Sectional Study.

BACKGROUND: Chronic inflammatory diseases other than hidradenitis suppurativa (HS) have been associated with prothrombotic/hypercoagulable status. OBJECTIVE: To investigate a possible association between the chronic inflammatory skin disease HS and prothrombotic/hypercoagulable state. METHODS: We performed a hospital- and population-based cross-sectional study investigating the coagulation status (thrombocytes, mean platelet volume [MPV], international normalized ratio [INR] and activated partial thromboplastin time [APTT]). RESULTS: 32 hospital HS subjects, 430 population HS subjects and 20,780 population non-HS control subjects were identified. The adjusted analyses showed no differences in the levels of thrombocytes, MPV, INR or APTT between the HS groups (hospital HS group, population HS group) when compared to controls (p = 0.089, p = 0.3078; p = 0.5499, p = 0.0659; p = 0.0932; p = 0.3432). CONCLUSION: We did not find an association between HS and prothrombotic/hypercoagulable status. Thus, thrombocytes may not be activated in HS. Furthermore, INR may not be affected in HS, suggesting that intrinsic and vitamin K-dependent coagulation factors appear unaffected.

The potential of antimicrobials to induce thrombocytopenia in critically ill patients: data from a randomized controlled trial.

BACKGROUND: Antimicrobial-induced thrombocytopenia is frequently described in the literature among critically ill patients. Several antimicrobials have been implicated, although experimental evidence to demonstrate causality is limited. We report, using a randomized trial, the potential of antimicrobials to induce thrombocytopenia. METHODS: Randomized trial allocated patients to antimicrobial treatment according to standard- of-care (SOC group) or drug-escalation in case of procalcitonin increases (high-exposure group). Patients were followed until death or day 28. Thrombocytopenia defined as absolute (platelet count ≤ 100 x 109/L) or relative (≥ 20% decrease in platelet count). Analyses were performed in the two randomized groups and as a merged cohort. RESULTS: Of the 1147 patients with platelet data available, 18% had absolute thrombocytopenia within the first 24 hours after admission to intensive care unit and additional 17% developed this complication during follow-up; 57% developed relative thrombocytopenia during follow-up. Absolute and relative thrombocytopenia day 1-4 was associated with increased mortality (HR: 1.67 [95% CI: 1.30 to 2.14]; 1.71 [95% CI: 1.30 to 2.30], P<0.0001, respectively). Patients in the high-exposure group received more antimicrobials including piperacillin/tazobactam, meropenem and ciprofloxacin compared with the SOC group, whereas cefuroxime was used more frequently in the SOC group (p<0.05). Risk of absolute and relative thrombocytopenia (RR: 0.9 [0.7-1.3], p=0.7439; 1.2 [1.0-1.4], p=0.06; respectively), as well as absolute platelet count (daily difference, high-exposure vs. SOC -1.7 [-3.8-0.5], p=0.14) was comparable between groups. In observational analyses, use of ciprofloxacin and piperacillin/tazobactam predicted risk of relative thrombocytopenia (vs. cefuroxime, RR: 2.08 [1.48-2.92]; 1.44 [1.10-1.89], respectively), however only ciprofloxacin were associated with a reduction in absolute platelet count (p=0.0005). CONCLUSION: High exposure to broad-spectrum antimicrobials does not result in a reduction in thrombocytopenia in critically ill patients. However, single use of ciprofloxacin, and less so piperacillin/tazobactam, may contribute to a lower platelet count. TRIAL REGISTRATION: ClinicalTrials.gov NCT00271752 http://clinicaltrials.gov/ct2/show/NCT00271752.

Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial.

OBJECTIVES: To explore whether a strategy of more intensive antibiotic therapy leads to emergence or prolongation of renal failure in intensive care patients. DESIGN: Secondary analysis from a randomised antibiotic strategy trial (the Procalcitonin And Survival Study). The randomised arms were conserved from the primary trial for the main analysis. SETTING: Nine mixed surgical/medical intensive care units across Denmark. PARTICIPANTS: 1200 adult intensive care patients, 18+ years, expected to stay +24 h. EXCLUSION CRITERIA: bilirubin >40 mg/dl, triglycerides >1000 mg/dl, increased risk from blood sampling, pregnant/breast feeding and psychiatric patients. INTERVENTIONS: Patients were randomised to guideline-based therapy ('standard-exposure' arm) or to guideline-based therapy supplemented with antibiotic escalation whenever procalcitonin increased on daily measurements ('high-exposure' arm). MAIN OUTCOME MEASURES: Primary end point: estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). Secondary end points: (1) delta eGFR after starting/stopping a drug and (2) RIFLE criterion Risk 'R', Injury 'I' and Failure 'F'. Analysis was by intention to treat. RESULTS: 28-day mortality was 31.8% and comparable (Jensen et al, Crit Care Med 2011). A total of 3672/7634 (48.1%) study days during follow-up in the high-exposure versus 3016/6949 (43.4%) in the 'standard-exposure arm were spent with eGFR <60 ml/min/1.73 m(2), p<0.001. In a multiple effects model, 3 piperacillin/tazobactam was identified as causing the lowest rate of renal recovery of all antibiotics used: 1.0 ml/min/1.73 m(2)/24 h while exposed to this drug (95% CI 0.7 to 1.3 ml/min/1.73 m(2)/24 h) vs meropenem: 2.9 ml/min/1.73 m(2)/24 h (2.5 to 3.3 ml/min/1.73 m(2)/24 h)); after discontinuing piperacillin/tazobactam, the renal recovery rate increased: 2.7 ml/min/1.73 m(2)/24 h (2.3 to 3.1 ml/min/1.73 m(2) /24 h)). eGFR <60 ml/min/1.73 m(2) in the two groups at entry and at last day of follow-up was 57% versus 55% and 41% versus 39%, respectively. CONCLUSIONS: Piperacillin/tazobactam was identified as a cause of delayed renal recovery in critically ill patients. This nephrotoxicity was not observed when using other beta-lactam antibiotics. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00271752.

[Extreme levels of hyperlipidaemia as a cause of acute pancreatitis]. / Ekstrem hyperlipidaemi ved akut pankreatitis.

Hypertriglyceridaemia is an uncommon cause of acute pancreatitis, accounting for 1-4% of cases. In the case of lipoprotein-lipase mutations, lipid levels may rise to extreme levels during acute pancreatitis. In this case a 29-year-old female was hospitalized several times due to acute pancreatitis. She presented with extreme lipid levels and difficulty in blood testing. While the correlation of acute pancreatitis and hyperlipidaemia is known, awareness of its association with defects in lipid metabolism could, in this case, have furthered diagnostic and prevented repeated hospitalizations.