A Comparative Analysis of Sepsis Identification Methods in an Electronic Database.

OBJECTIVES: To evaluate the relative validity of criteria for the identification of sepsis in an ICU database. DESIGN: Retrospective cohort study of adult ICU admissions from 2008 to 2012. SETTING: Tertiary teaching hospital in Boston, MA. PATIENTS: Initial admission of all adult patients to noncardiac surgical ICUs. INTERVENTIONS: Comparison of five different algorithms for retrospectively identifying sepsis, including the Sepsis-3 criteria. MEASUREMENTS AND MAIN RESULTS: 11,791 of 23,620 ICU admissions (49.9%) met criteria for the study. Within this subgroup, 59.9% were suspected of infection on ICU admission, 75.2% of admissions had Sequential Organ Failure Assessment greater than or equal to 2, and 49.1% had both suspicion of infection and Sequential Organ Failure Assessment greater than or equal to 2 thereby meeting the Sepsis-3 criteria. The area under the receiver operator characteristic of Sequential Organ Failure Assessment (0.74) for hospital mortality was consistent with previous studies of the Sepsis-3 criteria. The Centers for Disease Control and Prevention, Angus, Martin, Centers for Medicare & Medicaid Services, and explicit coding methods for identifying sepsis revealed respective sepsis incidences of 31.9%, 28.6%, 14.7%, 11.0%, and 9.0%. In-hospital mortality increased with decreasing cohort size, ranging from 30.1% (explicit codes) to 14.5% (Sepsis-3 criteria). Agreement among the criteria was acceptable (Cronbach's alpha, 0.40-0.62). CONCLUSIONS: The new organ dysfunction-based Sepsis-3 criteria have been proposed as a clinical method for identifying sepsis. These criteria identified a larger, less severely ill cohort than that identified by previously used administrative definitions. The Sepsis-3 criteria have several advantages over prior methods, including less susceptibility to coding practices changes, provision of temporal context, and possession of high construct validity. However, the Sepsis-3 criteria also present new challenges, especially when calculated retrospectively. Future studies on sepsis should recognize the differences in outcome incidence among identification methods and contextualize their findings according to the different cohorts identified.

StO2 guided early resuscitation in subjects with severe sepsis or septic shock: a pilot randomised trial.

The scientific community has agreed upon developing accurate monitoring of tissue perfusion and oxygenation to improve the management of subjects with sepsis. This pilot study aimed to investigate the feasibility of targeting tissue oxygen saturation (StO2) in addition to the currently recommended resuscitation goals, central venous pressure, mean arterial pressure and central venous oxygen saturation, in patients with severe sepsis or septic shock. A pilot, single-centre, randomised, non-blinded trial recruited 30 subjects with severe sepsis upon intensive care unit admission at an academic medical centre in France. Subjects were randomly assigned to a 6 h resuscitation strategy following the Surviving Sepsis Campaign guidelines with (experimental) or without (control) StO2. StO2 was measured over several muscles (masseter, deltoid and pectoral or thenar muscles), and a StO2 above 80 % over at least 2 muscles was the therapeutic goal. The primary outcome was evaluated as follows: 7-day mortality or worsening of SOFA score between day 7 and study onset, i.e., DSOFA > 0). Thirty subjects were included in the study over a period of 40 weeks. Fifteen subjects were included in each group. Monitoring of StO2 over three areas was performed in the experimental group. However, measures over the pectoral muscle provided poor results. At study day 7, there were 5/15 (33.3 %) subjects who died or had a DSOFA > 0 in the experimental arm and 4/15 (26.6 %) who died or had a DSOFA > 0 in the control arm (p = 1.00). This pilot study was the first randomised controlled trial using an algorithm derived from the SSC recommendations, which included StO2 as a treatment goal. However, the protocol showed no clear trend for or against targeting StO2.

Masseter tissue oxygen saturation predicts normal central venous oxygen saturation during early goal-directed therapy and predicts mortality in patients with severe sepsis.

OBJECTIVE: This study aimed to investigate, in patients with severe sepsis, the correlation between central venous oxygen saturation and tissue oxygen saturation at different levels. DESIGN: Prospective observational study. SETTING: General intensive care unit at an academic medical center in France. PATIENTS: Thirty-eight patients with underresuscitated severe sepsis and septic shock on intensive care unit admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During early resuscitation according to the 6-hr bundles of the Surviving Sepsis Campaign guidelines, tissue oxygen saturation was recorded every other hour at the level of the thenar, masseter, and deltoid muscles along with central hemodynamics, arterial lactate concentrations, and central venous oxygen saturation. Over the 6-hr resuscitation period, thenar tissue oxygen saturation was consistently higher than masseter tissue oxygen saturation (p = .04) and deltoid tissue oxygen saturation (p = .002), and masseter tissue oxygen saturation was consistently higher than deltoid tissue oxygen saturation (p = .04). Receiver operating characteristic curves analyses showed that masseter tissue oxygen saturation was better predictor of central venous oxygen saturation >70% than thenar tissue oxygen saturation (area under the curve, 0.80; 95% confidence interval 0.71-0.89 vs. 0.67; 95% confidence interval 0.56-0.77; p = .02). The crude 28-day mortality was 36.8%. Receiver operating characteristic curve analysis showed that masseter tissue oxygen saturation (area under the curve 0.87; 0.75-0.98) and deltoid tissue oxygen saturation (area under the curve 0.88; 0.77-0.98) but not thenar tissue oxygen saturation (area under the curve 0.66; 0.46-0.86) or central venous oxygen saturation (area under the curve 0.56; 0.38-0.80) were strong predictors of 28-day mortality. CONCLUSIONS: This study suggested that in the early 6-hr resuscitation period, masseter tissue oxygen saturation accurately identified patients with severe sepsis and central venous oxygen saturation >70%. Both masseter tissue oxygen saturation and deltoid tissue oxygen saturation but not central venous oxygen saturation or thenar tissue oxygen saturation are strong predictors of 28-day mortality.

Dead space and CO2 elimination related to pattern of inspiratory gas delivery in ARDS patients.

INTRODUCTION: The inspiratory flow pattern influences CO2 elimination by affecting the time the tidal volume remains resident in alveoli. This time is expressed in terms of mean distribution time (MDT), which is the time available for distribution and diffusion of inspired tidal gas within resident alveolar gas. In healthy and sick pigs, abrupt cessation of inspiratory flow (that is, high end-inspiratory flow (EIF)), enhances CO2 elimination. The objective was to test the hypothesis that effects of inspiratory gas delivery pattern on CO2 exchange can be comprehensively described from the effects of MDT and EIF in patients with acute respiratory distress syndrome (ARDS). METHODS: In a medical intensive care unit of a university hospital, ARDS patients were studied during sequences of breaths with varying inspiratory flow patterns. Patients were ventilated with a computer-controlled ventilator allowing single breaths to be modified with respect to durations of inspiratory flow and postinspiratory pause (TP), as well as the shape of the inspiratory flow wave. From the single-breath test for CO2, the volume of CO2 eliminated by each tidal breath was derived. RESULTS: A long MDT, caused primarily by a long TP, led to importantly enhanced CO2 elimination. So did a high EIF. Effects of MDT and EIF were comprehensively described with a simple equation. Typically, an efficient and a less-efficient pattern of inspiration could result in ± 10% variation of CO2 elimination, and in individuals, up to 35%. CONCLUSIONS: In ARDS, CO2 elimination is importantly enhanced by an inspiratory flow pattern with long MDT and high EIF. An optimal inspiratory pattern allows a reduction of tidal volume and may be part of lung-protective ventilation.

Dyspnea in mechanically ventilated critically ill patients.

OBJECTIVES: Ensuring the comfort of intensive care unit patients is crucial. Although control of pain has been extensively addressed in this setting, data on dyspnea in mechanically ventilated patients are scant. The objective of this study was to assess the prevalence of dyspnea in mechanically ventilated patients, identify its clinical correlates, and examine its impact on clinical outcomes. DESIGN: Prospective 6-month observational study. SETTING: Two medical intensive care units within university hospitals. PARTICIPANTS: Intubated or tracheotomized patients who were mechanically ventilated for >24 hrs. We enrolled 96 patients (age, 61 ± 18 yrs; Simplified Acute Physiology Score II 43 [interquartile range, 31-60]) as soon as they could answer symptom-related questions. Dyspnea was evaluated on a "yes-no" basis; if yes, it was followed by a visual analog scale and descriptor choice ("air hunger" and/or "respiratory effort"). Pain and anxiety were also assessed by visual analog scales. INTERVENTIONS: Ventilator settings adjustment in dyspneic patients. MEASUREMENTS AND MAIN RESULTS: Forty-five patients (47%) reported dyspnea (respiratory effort in seven cases, air hunger in 15, both in 16, and neither of these in seven). Dyspneic and nondyspneic patients did not differ in terms of age, Simplified Acute Physiology Score II, indication for mechanical ventilation, respiratory rate, clinical examination, chest radiograph, or blood gases. Dyspnea was significantly associated with anxiety (odd ratio [OR], 8.84; 95% confidence interval [CI], 3.26-24.0), assist-control ventilation (OR, 4.77; 95% CI, 1.60-4.3), and heart rate (OR, 1.33 per 10 beats/min; 95% CI, 1.02-1.75). Adjusting ventilator settings improved dyspnea in 35% of patients. Successful extubation within 3 days was significantly less frequent in patients whose dyspnea failed to recede after adjusting ventilator settings (five [17%] vs. 27 [40%]; p = .034). CONCLUSIONS: Dyspnea is frequent, intense, and strongly associated with anxiety in mechanically ventilated patients. It can be sensitive to ventilator settings and seems to be associated with delayed extubation.

Postintensive care unit psychological burden in patients with chronic obstructive pulmonary disease and informal caregivers: A multicenter study.

OBJECTIVE: To determine the prevalence and risk factors of symptoms of anxiety, depression, and posttraumatic stress disorder-related symptoms in patients with chronic obstructive pulmonary disease and their relatives after an intensive care unit stay. DESIGN: Prospective multicenter study. SETTING: Nineteen French intensive care units. SUBJECTS: One hundred twenty-six patients with chronic obstructive pulmonary disease who survived an intensive care unit stay and 102 relatives. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Patients and relatives were interviewed at intensive care unit discharge and 90 days later to assess symptoms of anxiety and depression using Hospital Anxiety and Depression Scale (HADS) and posttraumatic stress disorder-related symptoms using the Impact of Event Scale (IES). At intensive care unit discharge, 90% of patients recollected traumatic psychological events in the intensive care unit. At day 90, we were able to conduct telephone interviews with 53 patients and 47 relatives. Hospital Anxiety and Depression Scale scores indicated symptoms of anxiety and depression in 52% and 45.5% of patients at intensive care unit discharge and in 28.3% and 18.9% on day 90, respectively. Corresponding prevalence in relatives were 72.2% and 25.7% at intensive care unit discharge and 40.4% and 14.9% on day 90, respectively. The Impact of Event Scale indicated posttraumatic stress disorder-related symptoms in 20.7% of patients and 29.8% of relatives on day 90. Peritraumatic dissociation assessed using the Peritraumatic Dissociative Experiences Questionnaire was independently associated with posttraumatic stress disorder-related symptoms in the patients and relatives. Previous intensive care unit experience and recollection of bothersome noise in the intensive care unit predicted posttraumatic stress disorder-related symptoms in the patients. CONCLUSIONS: Psychiatric symptoms were found to be common in a group of 126 patients with chronic obstructive pulmonary disease who survived an intensive care unit stay and their relatives at intensive care unit discharge and 90 days later. Peritraumatic dissociation at intensive care unit discharge was found to independently predict posttraumatic stress disorder-related symptoms in this sample of patients and relatives.

Brainstem responses can predict death and delirium in sedated patients in intensive care unit.

OBJECTIVES: In critically ill patients, the assessment of neurologic function can be difficult because of the use of sedative agents. It is not known whether neurologic signs observed under sedation can predict short-term outcomes. The objective of this study was to assess whether abnormal brainstem responses within the first 24 hrs of sedation are associated with mortality and altered mental status postsedation. DESIGN: Observational prospective study including an initial single-center and a subsequent multicenter study to develop and then validate the prognostic models. SETTING: Three mixed and two medical intensive care units. PATIENTS: Mechanically ventilated intensive care unit patients sedated with midazolam (± sufentanyl). INTERVENTIONS: Neurologic examination including the Glasgow Coma Scale, the Assessment to Intensive Care Environment score, cranial nerve examination, response to noxious stimuli, and the cough reflex was performed. MEASUREMENTS AND MAIN RESULTS: Seventy-two patients were included in the initial group and 72 in a subsequent validation study. Neurologic responses were independent of sedative dose. Twenty-two patients in the development cohort and 21 (29%) in the validation group died within 28 days of inclusion. Adjusted for Simplified Acute Physiology Score II score, absent cough reflex was independently associated with 28-day mortality in the development (adjusted odds ratio [OR], 7.80; 95% confidence interval [CI], 2.00-30.4; p = .003) and validation groups (adjusted OR, 5.44; 95% CI, 1.35-22.0; p = .017). Absent oculocephalic response, adjusted for Simplified Acute Physiology Score II score, was independently associated with altered mental status after the withdrawal of sedation in the development (adjusted OR, 4.54; 95% CI, 1.34-15.4; p = .015) and validation groups (adjusted OR, 6.10; 95% CI, 1.18-25.5; p = .012). CONCLUSIONS: Assessment of brainstem responses is feasible in sedated critically ill patients and loss of selected responses is predictive of mortality and altered mental status.

Extracorporeal CO2 removal in acute exacerbation of COPD unresponsive to non-invasive ventilation.

BACKGROUND: The gold-standard treatment for acute exacerbation of chronic obstructive pulmonary disease (ae-COPD) is non-invasive ventilation (NIV). However, NIV failures may be observed, and invasive mechanical ventilation (IMV) is required. Extracorporeal CO2 removal (ECCO2R) devices can be an alternative to intubation. The aim of the study was to assess ECCO2R effectiveness and safety. METHODS: Patients with consecutive ae-COPD who experienced NIV failure were retrospectively assessed over two periods of time: before and after ECCO2R device implementation in our ICU in 2015 (Xenios AG). RESULTS: Both groups (ECCO2R: n=26, control group: n=25) were comparable at baseline, except for BMI, which was significantly higher in the ECCO2R group (30 kg/m² vs 25 kg/m²). pH and PaCO2 significantly improved in both groups. The mean time on ECCO2R was 5.4 days versus 27 days for IMV in the control group. Four patients required IMV in the ECCO2R group, of whom three received IMV after ECCO2R weaning. Seven major bleeding events were observed with ECCO2R, but only three led to premature discontinuation of ECCO2R. Eight cases of ventilator-associated pneumonia were observed in the control group. Mean time spent in the ICU and mean hospital stay in the ECCO2R and control groups were, respectively, 18 vs 30 days, 29 vs 49 days, and the 90-day mortality rates were 15% vs 28%. CONCLUSIONS: ECCO2R was associated with significant improvement of pH and PaCO2 in patients with ae-COPD failing NIV therapy. It also led to avoiding intubation in 85% of cases, with low complication rates. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT04882410. Date of registration 12 May 2021, retrospectively registered.https://www.clinicaltrials.gov/ct2/show/NCT04882410.

She Has The Blues: An Unusual Case of Copper Sulphate Intoxication.

BACKGROUND: Copper is an essential trace element of the human body. However, it is related to many diseases. Copper intoxication is not common in Western countries, but needs to be rapidly recognised because of its high lethality. CASE PRESENTATION: We report the case of a 40-year-old woman who presented to the emergency department after performing intrarectal administration of a blue powder sent from Cameroon by her family, in the belief that this would help her to get pregnant. Her evolution was complicated by multiorgan failure and the unusual circumstances. The diagnosis was suspected on the basis of the clinical presentation and the colour of the powder, and confirmed by blood dosage and toxicological analysis of the powder. She underwent symptomatic treatment, and the outcome was progressively favourable, apart from persistent chronic renal failure with dependence on dialysis. CONCLUSION: Copper intoxications are rare but severe. Laboratory diagnosis of the condition is not an issue; the difficulty is suspecting it and quickly initiating chelation treatment associated with symptomatic treatments. LEARNING POINTS: Copper sulphate is a rare but severe condition that must be promptly diagnosed. Diagnosis may be based on clinical presentation, characterised by multiple organ failure, and suspected in the case of ingestion of a blue chemical product.In the presence of saturation gap on pulse oximetry, the clinician must consider the possibility of methemoglobinaemia, and look for toxic causes.Treatment of copper sulphate poisoning requires mainly symptomatic treatment and chelation of copper by oral or IV drugs.

Early mechanical ventilation in patients with Guillain-Barré syndrome at high risk of respiratory failure: a randomized trial.

INTRODUCTION: About 30% of patients with Guillain-Barré syndrome become ventilator dependent, of whom roughly 75% develop pneumonia. This trial aimed at assessing the impact of early mechanical ventilation (EMV) on pneumonia occurrence in GBS patients. We hypothesize that EMV will reduce the incidence of pneumonia. METHODS: This was a single centre, open-label, randomized controlled trial performed on two parallel groups. 50 intensive care unit adults admitted for Guillain-Barré syndrome and at risk for acute respiratory failure. Patients were randomized to early mechanical ventilation via face-mask or endotracheal intubation owing to the presence or absence of impaired swallowing (experimental arm), or to conventional care (control arm). The primary outcome was the incidence of pneumonia up to intensive care unit discharge (or 90 days, pending of which occurred first). FINDINGS: Twenty-five patients were randomized in each group. There was no significant difference between groups for the incidence of pneumonia (10/25 (40%) vs 9/25 (36%), P = 1). There was no significant difference between groups for the time to onset of pneumonia (P = 0.50, Gray test). During follow-up, there were 16/25 (64%) mechanically ventilated patients in the control group, and 25/25 (100%) in the experimental arm (P < 000·1). The time on ventilator was non-significantly shorter in the experimental arm (14 [7; 29] versus 21.5 [17.3; 35.5], P = 0.10). There were no significant differences between groups for length of hospital stay, neurological scores, the proportion of patients who needed tracheostomy, in-hospital death, or any serious adverse events. CONCLUSIONS: In the present study including adults with Guillain-Barré syndrome at high risk of respiratory failure, we did not observe a prevention of pneumonia with early mechanical ventilation. TRIAL REGISTRATION: ClinicalTrials.gov under the number NCT00167622. Registered 9 September 2005, https://clinicaltrials.gov/ct2/show/NCT00167622?cond=Guillain-Barre+Syndrome&cntry=FR&draw=2&rank=1.

Continuous Positive Airway Pressure (CPAP) face-mask ventilation is an easy and cheap option to manage a massive influx of patients presenting acute respiratory failure during the SARS-CoV-2 outbreak: A retrospective cohort study.

INTRODUCTION: Because of the COVID-19 pandemic, intensive care units (ICU) can be overwhelmed by the number of hypoxemic patients. MATERIAL AND METHODS: This single centre retrospective observational cohort study took place in a French hospital where the number of patients exceeded the ICU capacity despite an increase from 18 to 32 beds. Because of this, 59 (37%) of the 159 patients requiring ICU care were referred to other hospitals. From 27th March to 23rd April, consecutive patients who had respiratory failure or were unable to maintain an SpO2 > 90%, despite receiving 10-15 l/min of oxygen with a non-rebreather mask, were treated by continuous positive airway pressure (CPAP) unless the ICU physician judged that immediate intubation was indicated. We describe the characteristics, clinical course, and outcomes of these patients. The main outcome under study was CPAP discontinuation. RESULTS: CPAP was initiated in 49 patients and performed out of ICU in 41 (84%). Median age was 65 years (IQR = 54-71) and 36 (73%) were men. Median respiratory rate before CPAP was 36 (30-40) and median SpO2 was 92% (90-95) under 10 to 15 L/min oxygen flow. Median duration of CPAP was 3 days (IQR = 1-5). Reasons for discontinuation of CPAP were: intubation in 25 (51%), improvement in 16 (33%), poor tolerance in 6 (12%) and death in 2 (4%) patients. A decision not to intubate had been taken for 8 patients, including the 2 who died while on CPAP. Two patients underwent less than one hour CPAP for poor tolerance. In the end, 15 (38%) out of 39 evaluable patients recovered with only CPAP whereas 24 (62%) were intubated. CONCLUSIONS: CPAP is feasible in a non-ICU environment in the context of massive influx of patients. In our cohort up to 1/3 of the patients presenting with acute respiratory failure recovered without intubation.

Plasma cortisol levels in Guillain-Barré syndrome.

OBJECTIVE: To assess the relationship between plasma cortisol level and Guillain-Barré syndrome-related complications, notably respiratory failure. One third of patients with Guillain-Barré syndrome develop respiratory failure, which is predicted by few early indicators. Adrenal function has rarely been studied in Guillain-Barré syndrome. DESIGN: Prospective study. SETTING: Intensive care unit in a teaching hospital. PATIENTS: Patients with Guillain-Barré syndrome referred to our unit (n = 102). INTERVENTIONS: Plasma cortisol levels were measured before baseline and 60 mins after corticotrophin test in 93 patients with Guillain-Barré syndrome at admission, 16 (17%) of whom were ventilated within 24 hrs from admission, 17 (18%) ventilated after the 24th hr and 60 (65%) never ventilated. MEASUREMENTS AND MAIN RESULTS: Mean plasma cortisol levels at baseline and 60 mins after corticotrophin test were 22.9 +/- 11.3 ng/mL and 45.4 +/- 16.1 ng/mL. At baseline, the plasma cortisol levels were significantly higher in 17 (18%) patients, who developed respiratory failure at least 24 hrs later (28.5 +/- 12.1 ng/mL vs. 20.4 +/- 9.6 ng/mL; p = .003) and dysautonomia (33.1 +/- 14.3 ng/mL vs. 21.4 +/- 10.2 ng/mL, p = .003). When adjusting on only validated clinical predictors (i.e., delay between onset and admission <7 days, inability to lift head and vital capacity <60%), baseline cortisol level was the only independent risk factor for respiratory failure (odds ratio: 2.45 per 10 ng/mL [1.23-4.88 ng/mL], p = .01). Fifty-nine patients underwent electrophysiological testing. When adjusting on a validated electrophysiological model (i.e., peroneal proximal/distal compound muscle action potential ratio and vital capacity), baseline cortisol level remained an independent predictor (odds ratio: 2.50 per 10 ng/mL [1.14-5.51 ng/mL], p = .02). CONCLUSION: Measurement of baseline plasma cortisol levels can be helpful for early detection of patients with Guillain-Barré syndrome at risk for respiratory failure at least 24 hrs later.

Bench-to-bedside review: Beta-adrenergic modulation in sepsis.

Sepsis, despite recent therapeutic progress, still carries unacceptably high mortality rates. The adrenergic system, a key modulator of organ function and cardiovascular homeostasis, could be an interesting new therapeutic target for septic shock. Beta-adrenergic regulation of the immune function in sepsis is complex and is time dependent. However, beta2 activation as well as beta1 blockade seems to downregulate proinflammatory response by modulating the cytokine production profile. beta1 blockade improves cardiovascular homeostasis in septic animals, by lowering myocardial oxygen consumption without altering organ perfusion, and perhaps by restoring normal cardiovascular variability. Beta-blockers could also be of interest in the systemic catabolic response to sepsis, as they oppose epinephrine which is known to promote hyperglycemia, lipid and protein catabolism. The role of beta-blockers in coagulation is less clear cut. They could have a favorable role in the septic pro-coagulant state, as beta1 blockade may reduce platelet aggregation and normalize the depressed fibrinolytic status induced by adrenergic stimulation. Therefore, beta1 blockade as well as beta2 activation improves sepsis-induced immune, cardiovascular and coagulation dysfunctions. Beta2 blocking, however, seems beneficial in the metabolic field. Enough evidence has been accumulated in the literature to propose beta-adrenergic modulation, beta1 blockade and beta2 activation in particular, as new promising therapeutic targets for septic dyshomeostasis, modulating favorably immune, cardiovascular, metabolic and coagulation systems.

Preclinical septic shock research: why we need an animal ICU.

Animal experiments are widely used in preclinical medical research with the goal of disease modeling and exploration of novel therapeutic approaches. In the context of sepsis and septic shock, the translation into clinical practice has been disappointing. Classical animal models of septic shock usually involve one-sex-one-age animal models, mostly in mice or rats, contrasting with the heterogeneous population of septic shock patients. Many other factors limit the reliability of preclinical models and may contribute to preclinical research failure in critical care, including the host specificity of several pathogens, the fact that laboratory animals are raised in pathogen-free facilities and that organ support techniques are either absent or minimal. Advanced animal models have been developed with the aim of improving the clinical translatability of experimental findings. So-called animal ICUs refer to the preclinical investigation of adult or even aged animals of either sex, using-in case of rats and mice-miniaturized equipment allowing for reproducing an ICU environment at a small animal scale and integrating chronic comorbidities to more closely reflect the clinical conditions studied. Strength and limitations of preclinical animal models designed to decipher the mechanisms involved in septic cardiomyopathy are discussed. This article reviews the current status and the challenges of setting up an animal ICU.

Hydrocortisone effects on cardiovascular variability in septic shock: a spectral analysis approach.

RATIONALE: Septic shock may be associated with a loss in cardiovascular variability and adrenal dysfunction. OBJECTIVES: To investigate the relationship between cardiovascular autonomic modulation and adrenal function during sepsis. MEASUREMENT AND MAIN RESULTS: Seventy-five volunteers with septic shock and six healthy volunteers were prospectively included in the study. Cardiovascular variability was assessed by spectral analysis of heart rate and diastolic blood pressure signals, which included computation of normalized low (LF(nu)) and high frequency (HF(nu)) components. Cardiovascular variability was investigated in patients and healthy volunteers immediately before and 1 hr after a single bolus of 50 mg of hydrocortisone (study phase I); in patients according to adrenal function (study phase II); and in patients with septic shock and adrenal insufficiency, before and 72 hrs after a treatment with 50 mg every 6 hrs of hydrocortisone and 50 microg daily of fludrocortisone or their placebos (study phase III). As compared to healthy volunteers, patients had decreased LF(nu)-HR (.16 +/- .05 vs. .23 +/- .07 p = .01) and LF(nu)-DBP (.18 +/- .11 vs. .28 +/- .02 p = .01) and, after hydrocortisone, they had a greater increase in LF(nu)-DBP (p = .01). As compared to patients with normal adrenal function, those with adrenal failure had decreased LF(nu)-HR (.1 +/- .01 vs. .2 +/- .15 p = .01) and LF(nu)-DBP (.008 +/- .01 vs. .14 +/- .22 p = .0003). In patients with adrenal failure, as compared to placebos, hydrocortisone plus fludrocortisone increased significantly LF(nu)-DBP (p = .02) and low frequency/high volume ratio (p = .009). CONCLUSION: In septic shock, the loss in cardiovascular variability is more marked in patients with adrenal insufficiency and is partly restored by exogenous administration of corticosteroids.

Pattern of inspiratory gas delivery affects CO2 elimination in health and after acute lung injury.

OBJECTIVE: To avoid ventilator induced lung injury, tidal volume should be low in acute lung injury (ALI). Reducing dead space may be useful, for example by using a pattern of inspiration that prolongs the time available for gas distribution and diffusion within the respiratory zone, the mean distribution time (MDT). A study was conducted to investigate how MDT affects CO2 elimination in pigs at health and after ALI. DESIGN AND SETTING: Randomised crossover study in the animal laboratory of Lund University Biomedical Center. SUBJECTS AND INTERVENTION: Healthy pigs and pigs with ALI, caused by surfactant perturbation and lung-damaging ventilation were ventilated with a computer-controlled ventilator. With this device each breath could be tailored with respect to insufflation time and pause time (TI and TP) as well as flow shape (square, increasing or decreasing flow). MEASUREMENTS AND RESULTS: The single-breath test for CO2 allowed analysis of the volume of expired CO2 and the volume of CO2 re-inspired from Y-piece and tubes. With a long MDT caused by long TI or TP, the expired volume of CO2 increased markedly in accordance with the MDT concept in both healthy and ALI pigs. High initial inspiratory flow caused by a short TI or decreasing flow increased the re-inspired volume of CO2. Arterial CO2 increased during a longer period of short MDT and decreased again when MDT was prolonged. CONCLUSIONS: CO2 elimination can be enhanced by a pattern of ventilation that prolongs MDT. Positive effects of prolonged MDT caused by short TI and decreasing flow were attenuated by high initial inspiratory flow.

Effects of inspiratory pause on CO2 elimination and arterial PCO2 in acute lung injury.

A high respiratory rate associated with the use of small tidal volumes, recommended for acute lung injury (ALI), shortens time for gas diffusion in the alveoli. This may decrease CO(2) elimination. We hypothesized that a postinspiratory pause could enhance CO(2) elimination and reduce Pa(CO(2)) by reducing dead space in ALI. In 15 mechanically ventilated patients with ALI and hypercapnia, a 20% postinspiratory pause (Tp20) was applied during a period of 30 min between two ventilation periods without postinspiratory pause (Tp0). Other parameters were kept unchanged. The single breath test for CO(2) was recorded every 5 min to measure tidal CO(2) elimination (VtCO(2)), airway dead space (V(Daw)), and slope of the alveolar plateau. Pa(O(2)), Pa(CO(2)), and physiological and alveolar dead space (V(Dphys), V(Dalv)) were determined at the end of each 30-min period. The postinspiratory pause, 0.7 +/- 0.2 s, induced on average <0.5 cmH(2)O of intrinsic positive end-expiratory pressure (PEEP). During Tp20, VtCO(2) increased immediately by 28 +/- 10% (14 +/- 5 ml per breath compared with 11 +/- 4 for Tp0) and then decreased without reaching the initial value within 30 min. The addition of a postinspiratory pause significantly decreased V(Daw) by 14% and V(Dphys) by 11% with no change in V(Dalv). During Tp20, the slope of the alveolar plateau initially fell to 65 +/- 10% of baseline value and continued to decrease. Tp20 induced a 10 +/- 3% decrease in Pa(CO(2)) at 30 min (from 55 +/- 10 to 49 +/- 9 mmHg, P < 0.001) with no significant variation in Pa(O(2)). Postinspiratory pause has a significant influence on CO(2) elimination when small tidal volumes are used during mechanical ventilation for ALI.

Esmolol indirectly stimulates vagal nerve activity in endotoxemic pigs.

BACKGROUND: There is an increasing interest in beta-blockade as a therapeutic approach to sepsis following consistent experimental findings of attenuation of inflammation and improved survival with beta1 selective antagonist. However, the mechanism of these beneficial effects remains very uncertain. Thus, this study is aimed at investigating the effects of a beta-1 selective blockade on sympathetic/parasympathetic activity in endotoxin-challenged pigs using heart rate variability. The hypothesis is that an adrenergic blockade could promote parasympathetic activity. Indeed, the increase of parasympathetic activity is a mechanism recently described as beneficial in septic states. METHODS: Fifty-one endotoxin-challenged pigs were studied. After 30 min of endotoxin infusion and 30 min of evolution without intervention, the pigs were randomly assigned the placebo or esmolol treatment and were observed for 200 min. Overall heart rate variability was assessed continuously, in the temporal domain by standard deviation of RR intervals (SDNN, ms),and in the frequency domain by spectral powers of low frequency (LF, ms2 × 103/Hz) and high frequency (HF, ms2 × 103/Hz) bands. RESULTS: Variations of power in these frequency bands were interpreted as putative markers of sympathetic (LF) and parasympathetic (HF) activity. In LPS treated animals, Esmolol did not increase SDNN, but instead decreased LF and increased HF power. CONCLUSION: These spectral modifications associated to a beta-blocker treatment after an endotoxemic challenge are interpreted as a significant decrease of sympathetic activity and an indirect increase of vagal autonomic tone.

Correction to: Esmolol indirectly stimulates vagal nerve activity in endotoxemic pigs.

Following publication of the original article [1], the author reported these required corrections to Fig. 5 and Fig. 6.

The hypothalamic pituitary adrenal axis in sepsis.

At the beginning of the 20th century, observations of apoplectic adrenal glands in fatal meningococcemia underlined their key role in host defence against infection. Thirty years later, cortisone was discovered and rapidly proven to have numerous and diversified physiological functions in the host response to stress. Corticosteroids were introduced in the treatment of severe infection as early as in the 1940s. Several 'negative' randomized controlled trials of high-dose of glucocorticoids given for a short period of time in the early course of severe sepsis or acute respiratory distress syndrome raised serious doubts as to the benefit of this treatment. Recently, a link between septic shock and adrenal insufficiency, or systemic inflammation-induced glucocorticoid receptor resistance has been established. This finding prompted renewed interest in a replacement therapy with low doses of corticosteroids during longer periods. We will review the key role of the hypothalamic-pituitary-adrenal axis in the host response to stress.