Andrea Polito

Sepsis-associated encephalopathy and its differential diagnosis.

Sepsis is often complicated by an acute and reversible deterioration of mental status, which is associated with increased mortality and is consistent with delirium but can also be revealed by a focal neurologic sign. Sepsis-associated encephalopathy is accompanied by abnormalities of electroencephalogram and somatosensory-evoked potentials, increased in biomarkers of brain injury (i.e., neuron-specific enolase, S-100 &bgr;-protein) and, frequently, by neuroradiological abnormalities, notably leukoencephalopathy. Its mechanism is highly complex, resulting from both inflammatory and noninflammatory processes that affect all brain cells and induce blood-brain barrier breakdown, dysfunction of intracellular metabolism, brain cell death, and brain injuries. Its diagnosis relies essentially on neurologic examination that can lead one to perform specific neurologic tests. Electroencephalography is required in the presence of seizure; neuroimaging in the presence of seizure, focal neurologic signs or suspicion of cerebral infection; and both when encephalopathy remains unexplained. In practice, cerebrospinal fluid analysis should be performed if there is any doubt of meningitis. Hepatic, uremic, or respiratory encephalopathy, metabolic disturbances, drug overdose, withdrawal of sedatives or opioids, alcohol withdrawal delirium, and Wernicke’s encephalopathy are the main differential diagnoses of sepsis-associated encephalopathy. Patient management is based mainly on controlling infection, organ system failure, and metabolic homeostasis, at the same time avoiding neurotoxic drugs.

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.

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.

Pattern of Brain Injury in the Acute Setting of Human Septic Shock

BackgroundSepsis-associated brain dysfunction has been linked to white matter lesions (leukoencephalopathy) and ischemic stroke. Our objective was to assess the prevalence of brain lesions in septic shock patients requiring magnetic resonance imaging (MRI) for an acute neurologic change.MethodSeventy-one septic shock patients were included in a prospective observational study. Patients underwent daily neurological examination. Brain MRI was obtained in patients who developed focal neurological deficit, seizure, coma, or delirium. Electroencephalogy was performed in case of coma, delirium, or seizure. Leukoencephalopathy was graded and considered present when white matter lesions were either confluent or diffuse. Patient outcome was evaluated at 6 months with the Glasgow Outcome Scale (GOS).ResultsWe included 71 patients with median age of 65 years (56 to 76) and SAPS II at admission of 49 (38 to 60). MRI was indicated on focal neurological sign in 13 (18%), seizure in 7 (10%), coma in 33 (46%), and delirium in 35 (49%). MRI was normal in 37 patients (52%) and showed cerebral infarcts in 21 (29%), leukoencephalopathy in 15 (21%), and mixed lesions in 6 (8%). EEG malignant pattern was more frequent in patients with ischemic stroke or leukoencephalopathy. Ischemic stroke was independently associated with disseminated intravascular coagulation (DIC), focal neurologic signs, increased mortality, and worse GOS at 6 months.ConclusionsBrain MRI in septic shock patients who developed acute brain dysfunction can reveal leukoencephalopathy and ischemic stroke, which is associated with DIC and increased mortality.

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.

The implications and management of septic acute kidney injury.

Sepsis is the most common and severe cause of morbidity and mortality among critically ill patients. Multiple organ dysfunction syndrome often complicates sepsis, leading to a worse prognosis that is proportional to the severity and number of damaged organs. Acute kidney injury (AKI) also complicates sepsis, with a linear relationship between the severity of kidney damage and sepsis prognosis. The management of sepsis and septic AKI involves intensive proactive preventive measures, medical and extracorporeal treatment of established sepsis, support of failing organs and rehabilitation of the residual effects left by this devastating syndrome. Unfortunately, although some innovations in the clinical management of sepsis are now available, their beneficial effects on renal function are still uncertain. The aim of this Review is to provide an update on the current state of interventions in sepsis-related AKI. Prevention, pharmacological support and extracorporeal blood purification for septic AKI will be reviewed and discussed.

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

Rational: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 (LFnu) and high frequency (HFnu) 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 &mgr;g daily of fludrocortisone or their placebos (study phase III). As compared to healthy volunteers, patients had decreased LFnu-HR (.16 ± .05 vs. .23 ± .07 p = .01) and LFnu-DBP (.18 ± .11 vs. .28 ± .02 p = .01) and, after hydrocortisone, they had a greater increase in LFnu-DBP (p = .01). As compared to patients with normal adrenal function, those with adrenal failure had decreased LFnu-HR (.1 ± .01 vs. .2 ± .15 p = .01) and LFnu-DBP (.008 ± .01 vs. .14 ± .22 p = .0003). In patients with adrenal failure, as compared to placebos, hydrocortisone plus fludrocortisone increased significantly LFnu-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.

Impact of hyperglycemia on neuropathological alterations during critical illness

CONTEXT Although preventing excessive hyperglycemia during critical illness may provide clinical neuroprotection, it remains debated whether normoglycemia is without risk for the brain. OBJECTIVE To address this question, we compared the neuropathological alterations in microglia, astrocytes, and neurons, with uncontrolled hyperglycemia, moderately controlled hyperglycemia, and normoglycemia during human critical illness. We further investigated the time course in an animal model. DESIGN AND SETTING We analyzed brain specimens from patients who died in the intensive care unit and from critically ill rabbits randomized to hyper- or normoglycemia. PATIENTS/OTHER PARTICIPANTS: We compared 10 critically ill patients randomized to normoglycemia (104 ±9 mg/dl) or moderate hyperglycemia (173 ±32 mg/dl), and five patients with uncontrolled hyperglycemia (254 ±83 mg/dl) with 16 controls (out of hospital sudden deaths). Critically ill rabbits were randomized to hyperglycemia (315 ±32 mg/dl) or normoglycemia (85 ±13 mg/dl) and studied after 3 and 7 d. INTERVENTIONS Insulin was infused to control blood glucose. MAIN OUTCOME MEASURES AND RESULTS Patients with uncontrolled hyperglycemia showed 3.7-6-fold increased microglial activation, 54-95% reduced number and activation of astrocytes, more than 9-fold increased neuronal and glial apoptosis, and a 1.5-2-fold increase in damaged neurons in hippocampus and frontal cortex (all P ≤ 0.05). Most of these abnormalities were attenuated with moderate hyperglycemia and virtually absent with normoglycemia. Frontal cortex of hyperglycemic rabbits that had been critically ill for 3 d only revealed microglial activation, followed after 7 d by astrocyte and neuronal abnormalities similar to those observed in patients, all prevented by normoglycemia. CONCLUSIONS Preventing hyperglycemia with insulin during critical illness reduced neuropathological abnormalities, with microglial activation being the earliest preventable event. Whether these pathological findings associate with neurological outcome remains unknown.

Hormonal status in protracted critical illness and in-hospital mortality

IntroductionThe aim of this study was to determine the relationship between hormonal status and mortality in patients with protracted critical illness.MethodsWe conducted a prospective observational study in four medical and surgical intensive care units (ICUs). ICU patients who regained consciousness after 7 days of mechanical ventilation were included. Plasma levels of insulin-like growth factor 1 (IGF-1), prolactin, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and cortisol were measured on the first day patients were awake and cooperative (day 1). Mean blood glucose from admission to day 1 was calculated.ResultsWe studied 102 patients: 65 men and 37 women (29 of the women were postmenopausal). Twenty-four patients (24%) died in the hospital. The IGF-1 levels were higher and the cortisol levels were lower in survivors. Mean blood glucose was lower in women who survived, and DHEA and DHEAS were higher in men who survived.ConclusionsThese results suggest that, on the basis of sex, some endocrine or metabolic markers measured in the postacute phase of critical illness might have a prognostic value.

Osmoregulation of vasopressin secretion is altered in the postacute phase of septic shock.

Objective:To determine whether septic shock patients have an abnormal reponse to increasing osmolarity. Design:Prospective interventional study. Setting:Intensive care unit at Raymond Poincaré and Etampes Hospitals. Patients:Normonatremic patients at >72 hrs from septic shock onset. Intervention:Osmotic challenge consisting of infusing 500 mL of hypertonic saline solution (with cumulative amount of sodium not exceeding 24 g) over 120 mins. Measurements and Main Results:Plasma arginine vasopressin levels were measured 15 mins before the test and then four times every 30 mins. A slope of the relation between arginine vasopressin and plasma sodium levels of <0.5 pg/mEq defined nonresponders. Among the 33 included patients, 17 (52%) were nonresponders. During osmotic challenge, variations throughout the test in plasma sodium levels, blood pressure, and central venous pressure were comparable between the two groups. Arginine vasopressin increased from 4.8 pg/mL [3.3–6.4 pg/mL] to 14.4 pg/mL [11.2–23.3 pg/mL] in responders but only from 2.8 pg/mL [2.3–4.0 pg/mL] to 4.0 pg/mL [3.1–5.3 pg/mL] in nonresponders (p < .0001). Responders had a higher plasma arginine vasopressin levels at baseline and a more severe hematosis alteration. Nonresponders had more frequently bacteremia and liver dysfunction, been referred from the ward and undergone surgery. Critical illness severity, hemodynamic alteration, hydroelectrolytic disturbances, treatment, and outcome did not differ between the two groups. Conclusion:Osmoregulation is dramatically altered in half of patients with prolonged septic shock.