Coagulation Profile after Spontaneous Intracerebral Hemorrhage: A Cohort Study.

BACKGROUND: Intracerebral hemorrhage (ICH) causes death or disability and the incidence increases with age. Knowledge of acute hemostatic function in patients with ICH without anticoagulant and antiplatelet therapy is sparse. Increased knowledge of the coagulation profile in the acute phase of ICH could improve acute treatment and recovery. We investigated coagulation at admission and changes in coagulation during the first 24hours after symptom onset. METHODS: Enrolled were 41 ICH patients without anticoagulant or antiplatelet therapy admitted to Aarhus University Hospital, Denmark. Blood samples were collected at admission, 6, and 24hours after symptom onset. Thromboelastometry (ROTEM), thrombin generation, and thrombin-antithrombin (TAT) complex were analyzed. Clinical outcome was evaluated using the National Institute of Health Stroke Scale, the Modified Rankin Score, and mortality. RESULTS: At admission, compared with healthy individuals, ICH patients had increased maximum clot firmness (EXTEM P < .0001; INTEM P < .0001; FIBTEM P < .0001), increased platelet maximum clot elasticity (P < .0001) in ROTEM, higher peak thrombin (P < .0001) and endogenous thrombin potential (P = .01) in thrombin generation, and elevated TAT complex levels. During 24hours after significantly, while thrombin generation showed decreased peak thrombin (P < .0001) and endogenous thrombin potential (P < .0001). Coagulation test results did not differ between patients when stratified according to clinical outcome. CONCLUSIONS: ICH patients without anticoagulant or antiplatelet therapy demonstrated activated coagulation at admission and within 24hours after symptom onset.

Cortical spreading depolarizations in the postresuscitation period in a cardiac arrest male rat model.

Neurological injury develops over days following cardiac arrest (CA); however, the exact mechanisms remain unknown. After stroke or trauma, the progression of neurological injury is associated with cortical-spreading depolarizations (CSDs). The objective was to investigate whether CA and subsequent resuscitation in rats are associated with 1) the development of spontaneous negative direct current (DC) shifts indicative of CSDs, and 2) changes in artificially induced CSDs in the postresuscitation period. Male Sprague-Dawley rats were randomized into four groups: 1) CA 90, 2) Control 90, 3) CA 360, and 4) Control 360. Following 8 min of asphyxial CA, animals were resuscitated using adrenaline, ventilation, and chest compressions. Animals were observed for 90 or 360 min, respectively, before a 210-min data collection period. Cortical potentials were recorded through burr holes over the right hemisphere. Animals were intubated and monitored with invasive blood pressure, ECG, and arterial blood gas samples throughout the study. Spontaneous DC shifts occurred in only 1 of the 14 CA animals. In control animals, DC shifts were easy to induce, and their shape was highly uniform, consistent with that of classical CSDs. In CA animals, significantly fewer DC shifts could be induced, and their shape was profoundly altered compared with controls. We observed frequent epileptiform discharges and temporal clusters of activity. Spontaneous CSDs were not a consistent finding in CA animals. Instead, spontaneous epileptiform discharges and temporal cluster of activity were observed, while the shapes of induced DC shifts were profoundly altered compared with controls. © 2017 Wiley Periodicals, Inc.

The frequently used intraperitoneal hyponatraemia model induces hypovolaemic hyponatraemia with possible model-dependent brain sodium loss.

NEW FINDINGS: What is the central question of this study? The brain response to acute hyponatraemia is usually studied in rodents by intraperitoneal instillation of hypotonic fluids (i.p. model). The i.p. model is described as 'dilutional' and 'syndrome of inappropriate ADH (SIADH)', but the mechanism has not been explored systematically and might affect the brain response. Therefore, in vivo brain and muscle response were studied in pigs. What is the main finding and its importance? The i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution, not dilution. A large reduction in brain sodium is observed, probably because of the specific mechanism causing the hyponatraemia. This is not accounted for in current understanding of the brain response to acute hyponatraemia. Hyponatraemia is common clinically, and if it develops rapidly, brain oedema evolves, and severe morbidity and even death may occur. Experimentally, acute hyponatraemia is most frequently studied in small animal models, in which the hyponatraemia is produced by intraperitoneal instillation of hypotonic fluids (i.p. model). This hyponatraemia model is described as 'dilutional' or 'syndrome of inappropriate ADH (SIADH)', but seminal studies contradict this interpretation. To confront this issue, we developed an i.p. model in a large animal (the pig) and studied water and electrolyte responses in brain, muscle, plasma and urine. We hypothesized that hyponatraemia was induced by simple water dilution, with no change in organ sodium content. Moderate hypotonic hyponatraemia was induced by a single i.v. dose of desmopressin and intraperitoneal instillation of 2.5% glucose. All animals were anaesthetized and intensively monitored. In vivo brain and muscle water was determined by magnetic resonance imaging and related to the plasma sodium concentration. Muscle water content increased less than expected as a result of pure dilution, and muscle sodium content decreased significantly (by 28%). Sodium was redistributed to the peritoneal fluid, resulting in a significantly reduced plasma volume. This shows that the i.p. model induces hypovolaemic hyponatraemia and not dilutional/SIADH hyponatraemia. Brain oedema evolved, but brain sodium content decreased significantly (by 21%). To conclude, the i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution and not water dilution. The large reduction in brain sodium is probably attributable to the specific mechanism that causes the hyponatraemia. This is not accounted for in the current understanding of the brain response to acute hyponatraemia.

Preserved Cerebral Microcirculation After Cardiac Arrest in a Rat Model.

OBJECTIVE: Recent studies show that sublingual microcirculation is altered in patients resuscitated from CA. The objective of this study was to investigate whether the cerebral microcirculation is disturbed in the early post-resuscitation period. METHODS: Male Sprague-Dawley rats were randomized to either 10 minutes of CA or uninterrupted circulation, and observed to 120 or 360 minutes after ROSC. At 120 and 360 minutes, cerebral microcirculation was evaluated by SDF microscopy through a craniectomy. Plasma samples were analyzed for endothelial adhesion molecules and inflammatory markers, and brains were fixated for histological analysis. RESULTS: Cerebral microcirculation, evaluated by TVD, PVD, PPV, and MFI did not differ between groups (p > 0.16). Plasma samples drawn 360 minutes after ROSC displayed a significant increase in sE-selectin, sL-selectin, sI-CAM1, IL-1ß, IL-6, IL-10, and elastase compared to controls. In the CA animals, sE-selectin and elastase increased between 120 and 360 minutes after resuscitation (p < 0.007). Histological analysis revealed neuronal death in hippocampus layer CA1 360 min after resuscitation. CONCLUSION: When evaluated by SDF, the cerebral microcirculation appears unaffected in the early post-CA period despite hypotension, systemic inflammation, endothelial activation, and neuronal injury.

From spouse to caregiver and back: a grounded theory study of post-intensive care unit spousal caregiving.

AIM: To explore the challenges and caring activities of spouses of intensive care unit survivors during the first year of patient recovery. BACKGROUND: Every year, millions of people globally are discharged from an intensive care unit after critical illness to continue treatment, care and rehabilitation in general hospital wards, rehabilitation facilities and at home. Consequently, millions of spouses become informal caregivers. Little is known, however, about the concrete challenges spouses face in post-intensive care unit everyday life. DESIGN: Explorative, qualitative grounded theory study. METHODS: Participants were spouses of intensive care unit survivors. The study was undertaken in Denmark in 2009-2010. Data consisted of 35 semi-structured dyad interviews at 3 and 12 months post-intensive care unit discharge, two group interviews with patients and two with spouses. FINDINGS: 'Shifting their role from spouse to caregiver and back' was identified as the core category of the study. The role shifts progressed in a dynamic process involving four elements: (1) committing to caregiving; (2) acquiring caregiving skills; (3) negotiating level of caregiving and (4) gradually leaving the caregiver role. Post-ICU caregiving comprised five patient dimensions: observing, assisting, coaching, advocating and managing activities. CONCLUSIONS: Spouses play a vital and multifaceted role in post-intensive care unit recovery. The findings can inform healthcare professionals in their efforts to prepare intensive care unit patients' families for the time following intensive care unit and hospital discharge. Hospital staff, rehabilitation experts and primary care professionals must acknowledge spouses' important contribution from intensive care unit admission throughout recovery.

Small-volume 7.5% NaCl adenosine, lidocaine, and Mg2+ has multiple benefits during hypotensive and blood resuscitation in the pig following severe blood loss: rat to pig translation.

OBJECTIVES: Currently, there is no effective small-volume fluid for traumatic hemorrhagic shock. Our objective was to translate small-volume 7.5% NaCl adenosine, lidocaine, and Mg hypotensive fluid resuscitation from the rat to the pig. DESIGN: Pigs (35-40 kg) were anesthetized and bled to mean arterial pressure of 35-40 mm Hg for 90 minutes, followed by 60 minutes of hypotensive resuscitation and infusion of shed blood. Data were collected continuously. SETTING: University hospital laboratory. SUBJECTS: Female farm-bred pigs. INTERVENTIONS: Pigs were randomly assigned to a single IV bolus of 4 mL/kg 7.5% NaCl + adenosine, lidocaine and Mg (n = 8) or 4 mL/kg 7.5% NaCl (n = 8) at hypotensive resuscitation and 0.9% NaCl ± adenosine and lidocaine at infusion of shed blood. MEASUREMENTS AND MAIN RESULTS: At 60 minutes of hypotensive resuscitation, treatment with 7.5% NaCl + adenosine, lidocaine, and Mg generated significantly higher mean arterial pressure (48 mm Hg [95% CI, 44-52] vs 33 mm Hg [95% CI, 30-36], p < 0.0001), cardiac index (76 mL/min/kg [95% CI, 63-91] vs 47 mL/min/kg [95% CI, 39-57], p = 0.002), and oxygen delivery (7.6 mL O2/min/kg [95% CI, 6.4-9.0] vs 5.2 mL O2/min/kg [95% CI, 4.4-6.2], p = 0.003) when compared with controls. Pigs that received adenosine, lidocaine, and Mg/adenosine and lidocaine also had significantly lower blood lactate (7.1 mM [95% CI, 5.7-8.9] vs 11.3 mM [95% CI, 9.0-14.1], p = 0.004), core body temperature (39.3°C [95% CI, 39.0-39.5] vs 39.7°C [95% CI, 39.4-39.9]), and higher base excess (-5.9 mEq/L [95% CI, -8.0 to -3.8] vs -11.2 mEq/L [95% CI, -13.4 to -9.1]). One control died from cardiovascular collapse. Higher cardiac index in the adenosine, lidocaine, and Mg/adenosine and lidocaine group was due to a two-fold increase in stroke volume. Left ventricular systolic ejection times were significantly higher and inversely related to heart rate in the adenosine, lidocaine, and Mg/adenosine and lidocaine group. Thirty minutes after blood return, whole-body oxygen consumption decreased in pigs that received adenosine, lidocaine, and Mg/adenosine and lidocaine (5.7 mL O2/min/kg [95% CI, 4.7-6.8] to 4.9 mL O2/min/kg [95% CI, 4.2-5.8]), whereas it increased in controls (4.2 mL O2/min/kg [95% CI, 3.5-5.0] to 5.8 mL O2/min/kg [95% CI, 4.9-5.8], p = 0.02). After 180 minutes, pigs in the adenosine, lidocaine, and Mg/adenosine and lidocaine group had three-fold higher urinary output (2.1 mL//kg/hr [95% CI, 1.2-3.8] vs 0.7 mL//kg/hr [95% CI, 0.4-1.2], p = 0.001) and lower plasma creatinine levels. CONCLUSION: Small-volume resuscitation with 7.5% NaCl + adenosine, lidocaine, and Mg/adenosine and lidocaine provided superior cardiovascular, acid-base, metabolic, and renal recoveries following severe hemorrhagic shock in the pig compared with 7.5% NaCl alone.

Adenosine, lidocaine and Mg2+ improves cardiac and pulmonary function, induces reversible hypotension and exerts anti-inflammatory effects in an endotoxemic porcine model.

INTRODUCTION: The combination of Adenosine (A), lidocaine (L) and Mg(2+) (M) (ALM) has demonstrated cardioprotective and resuscitative properties in models of cardiac arrest and hemorrhagic shock. This study evaluates whether ALM also demonstrates organ protective properties in an endotoxemic porcine model. METHODS: Pigs (37 to 42 kg) were randomized into: 1) Control (n = 8) or 2) ALM (n = 8) followed by lipopolysaccharide infusion (1 µg ∙ kg(-1) ∙ h(-1)) for five hours. ALM treatment consisted of 1) a high dose bolus (A (0.82 mg/kg), L (1.76 mg/kg), M (0.92 mg/kg)), 2) one hour continuous infusion (A (300 µg ∙ kg(-1) ∙ min(-1)), L (600 µg ∙ kg(-1) ∙ min(-1)), M (336 µg ∙ kg(-1) ∙ min(-1))) and three hours at a lower dose (A (240 ∙ kg(-1) ∙ min(-1)), L (480 µg ∙ kg(-1) ∙ min(-1)), M (268 µg ∙ kg(-1) ∙ min(-1))); controls received normal saline. Hemodynamic, cardiac, pulmonary, metabolic and renal functions were evaluated. RESULTS: ALM lowered mean arterial pressure (Mean value during infusion period: ALM: 47 (95% confidence interval (CI): 44 to 50) mmHg versus control: 79 (95% CI: 75 to 85) mmHg, P < 0.0001). After cessation of ALM, mean arterial pressure immediately increased (end of study: ALM: 88 (95% CI: 81 to 96) mmHg versus control: 86 (95% CI: 79 to 94) mmHg, P = 0.72). Whole body oxygen consumption was significantly reduced during ALM infusion (ALM: 205 (95% CI: 192 to 217) ml oxygen/min versus control: 231 (95% CI: 219 to 243) ml oxygen/min, P = 0.016). ALM treatment reduced pulmonary injury evaluated by PaO2/FiO2 ratio (ALM: 388 (95% CI: 349 to 427) versus control: 260 (95% CI: 221 to 299), P = 0.0005). ALM infusion led to an increase in heart rate while preserving preload recruitable stroke work. Creatinine clearance was significantly lower during ALM infusion but reversed after cessation of infusion. ALM reduced tumor necrosis factor-α peak levels (ALM 7121 (95% CI: 5069 to 10004) pg/ml versus control 11596 (95% CI: 9083 to 14805) pg/ml, P = 0.02). CONCLUSION: ALM infusion induces a reversible hypotensive and hypometabolic state, attenuates tumor necrosis factor-α levels and improves cardiac and pulmonary function, and led to a transient drop in renal function that was reversed after the treatment was stopped.

Three-year risk of cardiovascular disease among intensive care patients with acute kidney injury: a population-based cohort study.

INTRODUCTION: Acute kidney injury (AKI) is common among intensive care unit (ICU) patients, but follow-up data on subsequent risk of cardiovascular disease remain sparse. We examined the impact of AKI on three-year risk of first-time heart failure, myocardial infarction (MI), and stroke among ICU patients surviving to hospital discharge, and whether this risk is modified by renal recovery before hospital discharge. METHODS: We used population-based medical registries to identify all adult patients admitted to an ICU in Northern Denmark between 2005 and 2010 who survived to hospital discharge and who had no previous or concurrent diagnosis of heart failure, MI, or stroke. AKI was defined according to the creatinine criteria in the Kidney Disease Improving Global Outcomes classification. We computed the three-year cumulative risk of hospitalization with heart failure, MI, and stroke for patients with and without AKI and the hazard ratios (HRs), using a Cox model adjusted for potential confounders. RESULTS: Among 21,556 ICU patients surviving to hospital discharge, 4,792 (22.2%) had an AKI episode. Three-year cumulative risk of heart failure was 2.2% in patients without AKI, 5.0% for AKI stage 1, and 5.0% for stages 2 to 3. The corresponding adjusted HRs were 1.33 (95% confidence interval (CI), 1.06 to 1.66) for patients with AKI stage 1 and 1.45 (95% CI, 1.14 to 1.84) for AKI stages 2 to 3, compared to patients without AKI. The three-year cumulative MI risk was 1.0% for patients without AKI, 1.8% for patients with AKI stage 1 and 2.3% for patients with AKI stages 2 to 3. The adjusted HR for MI was 1.04 (95% CI, 0.71 to 1.51) for patients with AKI stage 1 and 1.51 (95% CI, 1.05 to 2.18) for patients with AKI stages 2 to 3, compared with patients without AKI. We found no association between AKI and stroke. The increased risk of heart failure and MI persisted in patients with renal recovery before discharge, although it was less pronounced than in patients without renal recovery. CONCLUSIONS: ICU patients surviving any stage of AKI are at increased three-year risk of heart failure, but not stroke. Only AKI stages 2 to 3 are associated with increased MI risk.

Intensive care delirium - effect on memories and health-related quality of life - a follow-up study.

AIMS AND OBJECTIVES: To investigate the effects of delirium in the intensive care unit on health-related quality of life, healthcare dependency and memory after discharge and to explore the association between health-related quality of life and memories, patient diaries and intensive care unit follow-up. BACKGROUND: Up to 83% of intensive care unit patients experience delirium. In addition to increased risk of mortality, morbidity and cognitive impairment, the experience itself is unpleasant. A number of studies have focused on memories associated with delirium, but the association between delirium, memories and health-related quality needs further investigation. DESIGN: We used an observational multicentre design with telephone interviews. METHODS: Adult intensive care unit patients (n = 360) were consecutively recruited and interviewed using the intensive care unit-Memory Tool one week after intensive care unit. Interviews were repeated after two and six months and supplemented with Short Form-36 and the Barthel Index. RESULTS: Delirium was detected in 60% of the patients in our study, and delirious patients had significantly fewer factual memories and more memories of delusion than nondelirious patients up to six months postintensive care unit discharge. Delirium, memories and intensive care unit diaries with follow-up did not affect health-related quality of life and healthcare dependency. Memories of delusions might have an impact on patients assessed as nondelirious. CONCLUSIONS: More than half of the patients in intensive care unit experience delirium, which is associated with fewer factual memories and more memories of delusions. Short Form-36 might not be sensitive to delirium-related outcomes. Future research should include the development of better assessment tools to determine the long-term consequences of intensive care unit delirium. RELEVANCE TO CLINICAL PRACTICE: We recommend regular assessment to prevent, detect and treat delirium. We also recommend an intensive care unit follow-up programme providing an opportunity for postintensive care unit patients, particularly previously delirious patients, to discuss their memories and experiences with intensive care unit professionals.

Targeting dexamethasone to macrophages in a porcine endotoxemic model.

OBJECTIVES: Macrophages are important cells in immunity and the main producers of pro-inflammatory cytokines. The main objective was to evaluate if specific delivery of glucocorticoid to the macrophage receptor CD163 is superior to systemic glucocorticoid therapy in dampening the cytokine response to lipopolysaccharide infusion in pigs. DESIGN: Two randomized, placebo-controlled trials. SETTING: University hospital laboratory. SUBJECTS: Female farm-bred pigs (26-31 kg). DESIGN: A humanized antibody that binds to pig and human CD163 was produced, characterized, and conjugated with dexamethasone. In the first study (total n = 12), pigs were randomly assigned to four groups: 1) saline; 2) dexamethasone (1.0 mg/kg); 3) dexamethasone (0.02 mg/kg); and 4) anti-CD163-conjugated dexamethasone (0.02 mg/kg). In the second study (total n = 36), two additional groups were included in addition to the four original groups: 5) anti-CD163-conjugated dexamethasone (0.005 mg/kg); 6) unconjugated anti-CD163. Treatments were given 20 hours prior to infusion of lipopolysaccharide (1 µg × kg × h) for 5 hours. Blood samples were analyzed for cytokines, cortisol, and adrenocorticotropic hormone. RESULTS: In the saline group, lipopolysaccharide increased cytokine and plasma cortisol levels. In both studies, dexamethasone (1 mg/kg) and anti-CD163 dexamethasone (0.02 mg/kg) uniformly attenuated tumor necrosis factor-α peak levels (both p < 0.05) compared with low-dose dexamethasone (0.02 mg/kg). However, dexamethasone 1 mg/kg significantly suppressed plasma cortisol and adrenocorticotropic hormone levels compared with anti-CD163 dexamethasone (0.02 mg/kg; p < 0.05). No significant hemodynamic difference existed between groups. The anti-CD163 dexamethasone drug conjugate exhibited a fast plasma clearance, with a half-life of approximately 5-8 minutes. CONCLUSION: Targeted delivery of dexamethasone to macrophages using a humanized CD163 antibody as carrier exhibits anti-inflammatory effects comparable with 50 times higher concentrations of free dexamethasone and does not inhibit endogenous cortisol production. This antibody-drug complex showing similar affinity and specificity for human CD163 is, therefore, a promising drug candidate in this novel type of anti-inflammatory therapy.

Type 2 diabetes and 1-year mortality in intensive care unit patients.

BACKGROUND: Data on the prognostic impact of diabetes and diabetic complications in intensive care unit (ICU) patients are limited and inconsistent. We, therefore, examined mortality in ICU patients with type 2 diabetes with and without pre-existing heart and kidney diseases compared with nondiabetic patients. DESIGN: We conducted this population-based cohort study in Northern Denmark during 2005-2011. We included all ICU patients aged 40 years or older from the 17 ICUs in the area and identified type 2 diabetes by either a filled prescription for an antidiabetic drug, a previous diagnosis of diabetes, or an elevated glycosylated haemoglobin level. Diabetic patients were disaggregated according to pre-existing diagnoses of heart disease (myocardial infarction or heart failure) and kidney disease. We estimated 1-year mortality by the Kaplan-Meier method and hazard ratios of death (HRs) during follow-up using Cox regression, controlling for confounding factors and stratified by relevant subgroups. RESULTS: Among 45 018 ICU patients, 7219 (16·0%) had type 2 diabetes. Overall, 1-year mortality was 36·0% in ICU patients with type 2 diabetes, rising to 54·6% in patients with pre-existing heart and kidney diseases, compared with 29·1% in nondiabetic patients. Comparing diabetic with nondiabetic patients, the adjusted 0- to 30-day HR was 1·20 (95% confidence interval (CI): 1·13-1·26) and 1·19 (95% CI: 1·10-1·28) during the 31- to 365-day follow-up period. Pre-existing kidney disease further increased the impact of diabetes, while heart disease alone had no such effect. CONCLUSIONS: ICU patients with type 2 diabetes had higher 1-year mortality compared with nondiabetic ICU patients, particularly those with pre-existing kidney disease.

Five-year risk of end-stage renal disease among intensive care patients surviving dialysis-requiring acute kidney injury: a nationwide cohort study.

INTRODUCTION: Dialysis-requiring acute kidney injury (D-AKI) is common among intensive care unit (ICU) patients. However, follow-up data on the risk of end-stage renal disease (ESRD) among these patients remain sparse. We assessed the short-term and long-term risk of ESRD after D-AKI, compared it with the risk in other ICU patients, and examined the risk within subgroups of ICU patients. METHODS: We used population-based medical registries to identify all adult patients admitted to an ICU in Denmark from 2005 through 2010, who survived for 90 days after ICU admission. D-AKI was defined as needing acute dialysis at or after ICU admission. Subsequent ESRD was defined as a need for chronic dialysis for more than 90 days or a kidney transplant. We computed the cumulative ESRD risk for patients with D-AKI and for other ICU patients, taking into account death as a competing risk, and computed hazard ratios (HRs) using a Cox model adjusted for potential confounders. RESULTS: We identified 107,937 patients who survived for 90 days after ICU admission. Of these, 3,062 (2.8%) had an episode of D-AKI following ICU admission. The subsequent risk of ESRD up to 180 days after ICU admission was 8.5% for patients with D-AKI, compared with 0.1% for other ICU patients. This corresponds to an adjusted HR of 105.6 (95% confidence interval (CI): 78.1 to 142.9). Among patients who survived 180 days after ICU admission without developing ESRD (n = 103,996), the 181-day to 5-year ESRD risk was 3.8% for patients with D-AKI, compared with 0.3% for other ICU patients, corresponding to an adjusted HR of 6.2 (95% CI: 4.7 to 8.1). During the latter period, the impact of AKI was most pronounced in the youngest patients, aged 15 to 49 years (adjusted HR = 12.8, 95% CI: 6.5 to 25.4) and among patients without preexisting chronic kidney disease (adjusted HR = 11.9, 95% CI: 8.5 to 16.8). CONCLUSION: D-AKI is an important risk factor for ESRD for up to five years after ICU admission.

Preadmission metformin use and mortality among intensive care patients with diabetes: a cohort study.

INTRODUCTION: Metformin has anti-inflammatory and anti-thrombotic effects that may improve the outcome of critical illness, but clinical data are limited. We examined the impact of preadmission metformin use on mortality among intensive care unit (ICU) patients with type 2 diabetes. METHODS: We conducted this population-based cohort study among all persons admitted to the 17 ICUs in Northern Denmark (population approximately 1.8 million). We focused on all patients with type 2 diabetes who were admitted to the ICUs between January 2005 and December 2011. Through individual-level linkage of population-based medical databases, type 2 diabetes was identified using a previously validated algorithm including hospital diagnoses, filled prescriptions for anti-diabetic drugs, and elevated HbA1c levels. Metformin use was identified by filled prescriptions within 90 days before admission. Covariates included surgery, preadmission morbidity, diabetes duration, and concurrent drug use. We computed 30-day mortality and hazard ratios (HRs) of death using Cox regression adjusted for covariates, both overall and after propensity score matching. RESULTS: We included 7,404 adult type 2 diabetes patients, representing 14.0% of 52,964 adult patients admitted to the ICUs. Among type 2 diabetes patients, 1,073 (14.5%) filled a prescription for metformin as monotherapy within 90 days before admission and 1,335 (18.0%) received metformin in combination with other anti-diabetic drugs. Thirty-day mortality was 17.6% among metformin monotherapy users, 17.9% among metformin combination therapy users, and 25.0% among metformin non-users. The adjusted HRs were 0.80 (95% confidence interval (CI): 0.69, 0.94) for metformin monotherapy users and 0.83 (95% CI: 0.71, 0.95) for metformin combination therapy users, compared to non-users. Propensity-score-matched analyses yielded the same results. The association was evident across most subgroups of medical and surgical ICU patients, but most pronounced in elderly patients and in patients with well-controlled diabetes. Former metformin use was not associated with decreased mortality. CONCLUSIONS: Preadmission metformin use was associated with reduced 30-day mortality among medical and surgical intensive care patients with type 2 diabetes.

Adenocaine and Mg(2+) reduce fluid requirement to maintain hypotensive resuscitation and improve cardiac and renal function in a porcine model of severe hemorrhagic shock*.

OBJECTIVES: Hypotensive resuscitation is gaining clinical acceptance in the treatment of hemorrhagic shock. Our aims were to investigate: 1) the effect of 7.5% NaCl with adenocaine (adenosine and lidocaine, AL) and AL with Mg (ALM) on fluid requirement to maintain a minimum mean arterial pressure of 50 mm Hg, and 2) the effect of a second bolus of 0.9% NaCl with AL during return of shed blood on cardiac and renal function in a porcine model of hemorrhagic shock. DESIGN: Pigs were randomized to: Sham (n = 5), Sham + ALM/AL (n = 5), hemorrhage control (n = 11), or hemorrhage + ALM/AL (n = 9). Hemorrhage animals were bled to a mean arterial pressure of 35 mm Hg. After 90 mins, pigs were fluid resuscitated with Ringers acetate and 20 mL 7.5% NaCl with ALM to maintain a target mean arterial pressure of minimum 50 mm Hg. Shed blood and 0.9% NaCl with AL were infused 30 mins later. Hemorrhage control group was subjected to the same protocol but without ALM/AL. Hemodynamics, cardiodynamics (pressure-volume analysis), oxygen consumption, and kidney function were measured for 6 hrs. SETTING: University hospital laboratory. SUBJECTS: Female farm-bred pigs. RESULTS: Fluid volume infused during hypotensive resuscitation was 40% less in the 7.5% NaCl-/ALM-treated pigs than controls (25 vs. 41 mL/kg, p < .05). ALM was associated with a significant increase in dp/dtmax, end-systolic blood pressure, and systemic vascular resistance. Return of shed blood and 0.9% NaCl/AL reduced whole body oxygen consumption by 27% (p < .05), and significantly improved the end-systolic pressure-volume relationship and preload recruitable stroke work compared to controls. Glomerular filtration rate in the ALM/AL group returned to 83% of baseline compared to 54% in controls (p = .01). CONCLUSION: Resuscitation with 7.5% NaCl ALM increases cardiac function and reduces fluid requirements during hypotensive resuscitation, whereas a second AL infusion during blood resuscitation transiently reduces whole body oxygen consumption and improves cardiac and renal function.

Effects of dietary n-3 and n-6 fatty acids on clinical outcome in a porcine model on post-operative infection.

The present study was performed to evaluate the effects of dietary n-3 and n-6 long-chain PUFA (LC-PUFA) on clinical outcome in a porcine model on early aortic vascular prosthetic graft infection (AVPGI). A total of eighty-four pigs were randomised to a 35 d dietary treatment with 10 % (w/w) fish oil (rich in n-3 LC-PUFA), sunflower oil (rich in n-6 LC-PUFA) or animal fat. After 3 weeks of dietary treatment, the pigs had an aortic vascular prosthetic graft inserted, and it was inoculated with Staphylococcus aureus (106 colony-forming units). Changes in selected plasma and erythrocyte n-3 and n-6 LC-PUFA concentrations and in plasma PGE2 metabolite concentration were determined in the 3-week preoperative period. Clinical signs of infection, i.e. rectal temperature, hindquarter function, general appearance and feed intake, were monitored daily in the 14 d post-operative period, and, finally, daily body-weight gain was determined in both periods. The preoperative changes in plasma and erythrocyte n-3 and n-6 LC-PUFA concentrations reflected the fatty acid compositions of the dietary treatments given, and plasma PGE2 metabolite concentration decreased in the fish oil treatment (P < 0·001). In the post-operative period, feed intake (P = 0·004) and body-weight gain (P = 0·038) were higher in the fish oil treatment compared with the sunflower oil treatment. The dietary treatments did not affect the number of days pigs were showing fever, weakness in the hindquarters or impaired general appearance. In conclusion, preoperative treatment with dietary fish oil compared with sunflower oil improved clinical outcome in pigs with AVPGI by improving feed intake and body-weight gain post-operatively.

One-year mortality among Danish intensive care patients with acute kidney injury: a cohort study.

INTRODUCTION: There are few studies on long-term mortality among intensive care unit (ICU) patients with acute kidney injury (AKI). We assessed the prevalence of AKI at ICU admission, its impact on mortality during one year of follow-up, and whether the influence of AKI varied in subgroups of ICU patients. METHODS: We identified all adults admitted to any ICU in Northern Denmark (approximately 1.15 million inhabitants) from 2005 through 2010 using population-based medical registries. AKI was defined at ICU admission based on the risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) classification, using plasma creatinine changes. We included four severity levels: AKI-risk, AKI-injury, AKI-failure, and without AKI. We estimated cumulative mortality by the Kaplan-Meier method and hazard ratios (HRs) using a Cox model adjusted for potential confounders. We computed estimates for all ICU patients and for subgroups with different comorbidity levels, chronic kidney disease status, surgical status, primary hospital diagnosis, and treatment with mechanical ventilation or with inotropes/vasopressors. RESULTS: We identified 30,762 ICU patients, of which 4,793 (15.6%) had AKI at ICU admission. Thirty-day mortality was 35.5% for the AKI-risk group, 44.2% for the AKI-injury group, and 41.0% for the AKI-failure group, compared with 12.8% for patients without AKI. The corresponding adjusted HRs were 1.96 (95% confidence interval (CI) 1.80-2.13), 2.60 (95% CI 2.38 to 2.85) and 2.41 (95% CI 2.21 to 2.64), compared to patients without AKI. Among patients surviving 30 days (n = 25,539), 31- to 365 day mortality was 20.5% for the AKI-risk group, 23.8% for the AKI-injury group, and 23.2% for the AKI-failure group, compared with 10.7% for patients without AKI, corresponding to adjusted HRs of 1.33 (95% CI 1.17 to 1.51), 1.60 (95% CI 1.37 to1.87), and 1.64 (95% CI 1.42 to 1.90), respectively. The association between AKI and 30-day mortality was evident in subgroups of the ICU population, with associations persisting in most subgroups during the 31- to 365-day follow-up period, although to a lesser extent than for the 30-day period. CONCLUSIONS: AKI at ICU admission is an important prognostic factor for mortality throughout the subsequent year.

Three-year mortality among alcoholic patients after intensive care: a population-based cohort study.

INTRODUCTION: Alcoholic patients comprise a large proportion of patients in intensive care units (ICUs). However, data are limited on the impact of alcoholism on mortality after intensive care. METHODS: We conducted a cohort study among 16,848 first-time ICU patients between 2001 and 2007 to examine 30-day and 3-year mortality among alcoholic patients. Alcoholic patients with and without complications of alcohol misuse (for example, alcoholic liver disease) were identified from previous hospital contacts for alcoholism-related conditions or redemption of a prescription for alcohol deterrents. Data on medication use, demographics, hospital diagnoses, and comorbidity were obtained from medical databases. We computed 30-day and 3-year mortality and mortality rate ratios (MRRs) by using Cox regression analysis, controlling for covariates. RESULTS: In total, 1,229 (7.3%) ICU patients were current alcoholics. Among alcoholic patients without complications of alcoholism (n=785, 4.7% of the cohort), 30-day mortality was 15.9% compared with 19.7% among nonalcoholic patients. Compared with nonalcoholic patients, the adjusted 30-day MRR was 1.04 (95% confidence interval (CI), 0.87 to 1.25). Three-year mortality was 36.2% compared with 40.9% among nonalcoholic patients, corresponding to an adjusted 3-year MRR of 1.16 (95% CI, 1.03 to 1.31). For alcoholic patients with complications (n=444, 2.6% of the cohort), 30-day mortality was 33.6%, and 3-year mortality was 64.5%, corresponding to adjusted MRRs, with nonalcoholics as the comparator, of 1.64 (95% CI, 1.38 to 1.95) and 1.67 (95% CI, 1.48 to 1.90), respectively. CONCLUSIONS: Alcoholic ICU patients with chronic complications of alcoholism have substantially increased 30-day and 3-year mortality. In contrast, alcoholics without complications have no increased 30-day and only slightly increased 3- year mortality.

Preadmission beta-blocker use and 30-day mortality among patients in intensive care: a cohort study.

INTRODUCTION: Beta-blockers have cardioprotective, metabolic and immunomodulating effects that may be beneficial to patients in intensive care. We examined the association between preadmission beta-blocker use and 30-day mortality following intensive care. METHODS: We identified 8,087 patients over age 45 admitted to one of three multidisciplinary intensive care units (ICUs) between 1999 and 2005. Data on the use of beta-blockers and medications, diagnosis, comorbidities, surgery, markers of socioeconomic status, laboratory tests upon ICU admission, and complete follow-up for mortality were obtained from medical databases. We computed probability of death within 30 days following ICU admission for beta-blocker users and non-users, and the odds ratio (OR) of death as a measure of relative risk using conditional logistic regression and also did a propensity score-matched analysis. RESULTS: Inclusion of all 8,087 ICU patients in a logistic regression analysis yielded an adjusted OR of 0.82 (95% confidence interval (CI): 0.71 to 0.94) for beta-blocker users compared with non-users. In the propensity score-matched analysis we matched all 1,556 beta-blocker users (19.2% of the entire cohort) with 1,556 non-users; the 30-day mortality was 25.7% among beta-blocker users and 31.4% among non-users (OR 0.74 (95% CI: 0.63 to 0.87)]. The OR was 0.69 (95% CI: 0.54 to 0.88) for surgical ICU patients and 0.71 (95% CI: 0.51 to 0.98) for medical ICU patients. The OR was 0.99 (95% CI: 0.67 to 1.47) among users of non-selective beta-blockers, and 0.70 (95% CI: 0.58 to 0.83) among users of cardioselective beta-blockers. CONCLUSIONS: Preadmission beta-blocker use is associated with reduced mortality following ICU admission.

Delirium incidents in three Danish intensive care units.

BACKGROUND: Delirium as a result of hospitalization in an intensive care unit (ICU) is defined by a mental state different from the patients' normal state and an acute fluctuating course. Both morbidity and mortality are increased in relation to delirium. The incidence of delirium has been reported from 16% to 87% in international studies primarily in elderly patients. AIMS: The purpose of this study was to evaluate the incidence of delirium in adult intensive care patients in Denmark and to identify correlations between delirium, sedatives, opioid analgesics and age. METHODS: In a prospective follow-up study, 139 adult patients were screened for delirium using the confusion assessment method for the ICU (CAM-ICU) from 48 h after admission to ICU, twice a day until discharged. RESULTS: A total of 41 patients had at least one positive score for delirium, 61 had only negative scores and 37 were too heavily sedated to be scored during the study period. Thus, the incidence of delirium was 40% among patients who were able to be CAM-ICU scored. Patients who were lightly sedated had a 10-fold increased risk of delirium. There was no difference in incidence by age. Patients who received Fentanyl were more at risk of developing delirium compared with patients who received other or no analgesics. Sedative drugs did not influence the incidence. CONCLUSION: In this study delirium occurred in 40% of adult ICU patients of all ages.

Edelman's equation is valid in acute hyponatremia in a porcine model: plasma sodium concentration is determined by external balances of water and cations.

Acute hyponatremia is a serious condition, which poses major challenges. Of particular importance is what determines plasma sodium concentration ([Na(+)]). Edelman introduced an explicit model to describe plasma [Na(+)] in a population as [Na(+)] = alpha.(exchangeable Na(+) + exchangeable K(+))/(total body water) - beta. Evidence for the clinical utility of the model in the individual and in acute hyponatremia is sparse. We, therefore, investigated how the measured plasma [Na(+)] could be predicted in a porcine model of hyponatremia. Plasma [Na(+)] was estimated from in vivo-determined balances of water, Na(+), and K(+), according to Edelman's equation. Acute hyponatremia was induced with desmopressin acetate and infusion of a 2.5% glucose solution in anesthetized pigs. During 480 min, plasma [Na(+)] and osmolality were reduced from 136 (SD 2) to 120 mmol/l (SD 3) and from 284 (SD 4) to 252 mosmol/kgH(2)O (SD 5), respectively. The following interpretations were made. First, Edelman's model, which, besides dilution, takes into account Na(+) and K(+), fits plasma [Na(+)] significantly better than dilution alone. Second, a common value of alpha = 1.33 (SD 0.08) and beta = -13.04 mmol/l (SD 7.68) for all pigs explains well the plasma [Na(+)] in the individual animal. Third, measured exchangeable Na(+) and calculated exchangeable Na(+) + K(+) per weight in the pigs are close to Edelman's findings in humans, whereby the methods are cross-validated. In conclusion, plasma [Na(+)] can be explained in the individual animal by external balances, according to Edelman's construct in acute hyponatremia.