Tarek Sharshar

Circulating vasopressin levels in septic shock

OBJECTIVE To assess the frequency of vasopressin deficiency in septic shock. DESIGN Prospective cohort study. SETTING Intensive care unit at Raymond Poincaré University Hospital. PATIENTS A cohort of 44 patients who met the usual criteria for septic shock for < 7 days. A second cohort of 18 septic shock patients were enrolled within the first 8 hrs of disease onset. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS General demographics, severity scores, vital signs, standard biochemical data, and circulating vasopressin levels were systematically obtained at baseline in the two cohorts. Vasopressin deficiency was defined by a normal plasma vasopressin level in the presence of a systolic blood pressure of <100 mm Hg or in the presence of hypernatremia. Baroreflex sensitivity was systematically evaluated in patients of the first cohort when vasopressin deficiency was noted. In the second cohort of patients, plasma levels of vasopressin were obtained at baseline, 6, 24, 48, and 96 hrs after shock onset. In the first population, plasma vasopressin levels were inversely correlated to the delay from shock onset. Fourteen patients had relative vasopressin deficiency: 12 patients had systolic blood pressure <100 mm Hg, with impaired baroreflex sensitivity in four, and three patients had hypernatremia. In the second population, only two patients had relative vasopressin deficiency. The plasma levels of vasopressin significantly decreased over time (p < 10-3). CONCLUSIONS Plasma vasopressin levels are almost always increased at the initial phase of septic shock and decrease afterward. Relative vasopressin deficiency is seen in approximately one-third of late septic shock patients.

Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock

BACKGROUND Results of experimental and clinical studies have shown that septic shock is associated with cardiovascular autonomic failure. Thus, we aimed to investigate the existence of ischaemia and apoptosis within the cerebral autonomic centres that control the cardiovascular system in patients with septic shock. METHODS In a prospective cohort study, we did post-mortem examinations of supraoptic and paraventricular nuclei, cerebral amygdala, locus coeruleus, and medullary autonomic nuclei in 19 patients with septic shock, seven with non-septic shock and five who died suddenly from extracranial injury. Ischaemic and apoptotic neurons and microglial cells, and expression of tumour necrosis factor alpha (TNFalpha) and inducible nitric oxide synthase (iNOS) were scored. FINDINGS Ischaemic, neuronal, and microglial apoptosis scores differed between groups (p=0.0007, p<0.0001, and p=0.0037, respectively) and were higher in patients with septic shock than in those with non-septic shock (p=0.0033, p=0.0005, and p=0.0235, respectively), and extra-cranial injury related deaths (p=0.0027, p=0.0007, and p=0.0045, respectively). There was little microglial activation and glial expression of TNFalpha. The scores for endothelial iNOS expression were different between the three groups (p<0.0001), and were higher in septic shock than in non-septic shock (p=0.0009) and than in extracranial injury related deaths (p=0.0007). Vascular expression of iNOS also correlated (Spearman tau=0.57) with autonomic-centre neuronal apoptosis in the combined septic and non-septic shock group. INTERPRETATION Septic shock is associated with neuronal and glial apoptosis within the autonomic centres, which is strongly associated with endothelial iNOS expression.

Depletion of neurohypophyseal content of vasopressin in septic shock.

OBJECTIVES To assess the mechanisms underlying the inappropriately low plasma vasopressin levels reported in septic shock. DESIGN Prospective case series. SETTING A 26-bed general medical intensive care unit at a university hospital. PATIENTS Septic shock patients. MEASUREMENTS AND MAIN RESULTS In three consecutive patients with septic shock, plasma vasopressin levels, circulating vasopressinase activity, baroreflex sensitivity, and neurohypophyseal vasopressin content were assessed. Plasma vasopressin concentration was unexpectedly within normal range in two patients (1.6 pg/mL and 1.8 pg/mL) and increased in one (16 pg/mL). In all cases, vasopressinase activity was undetectable, baroreflex sensitivity was decreased, and the high signal intensity of the posterior lobe of the pituitary gland on T1-weighted magnetic resonance images was absent. Magnetic resonance imaging and plasma vasopressin levels normalized after recovery from shock in the patient who survived. CONCLUSION These data suggest that in septic shock, inappropriately low plasma levels of vasopressin are at least partly related to a depletion of vasopressin stores in the neurohypophysis.

Intensive care unit-acquired weakness: risk factors and prevention.

Intensive care unit-acquired weakness, the main clinical sign of critical illness neuromyopathy, is an increasingly recognized cause of prolonged mechanical ventilation and delayed return to physical self-sufficiency. Identifying risk factors and developing preventive measures are therefore important goals. Several studies on risk factors for critical illness neuromyopathy including prospective observational studies with a multivariate analysis of potential risk factors were conducted over the last decade. A large body of data is also available from two large prospective randomized trials comparing the effect of strict vs. conventional blood-glucose control on intensive care unit mortality and on secondary outcomes including the occurrence of critical illness neuromyopathy. Five central risk factors and their related potential measures to prevent intensive care unit-acquired weakness can be identified including multiple organ failure, muscle inactivity, hyperglycemia, and use of corticosteroids and neuromuscular blockers. Although strong evidence regarding the efficacy of preventive measures is still lacking, the results of available studies are promising and cast doubt on the widespread belief that the treatment of intensive care unit-acquired weakness is essentially supportive. Early identifying and treating conditions leading to multiple organ failure, especially severe sepsis and septic shock, avoiding unnecessary deep sedation and excessive blood glucose levels, promoting early mobilization, and carefully weighing the risks and benefits of corticosteroids might contribute to reduce the incidence and severity of intensive care unit-acquired weakness.

Cardiac variability in critically ill adults: influence of sepsis.

ObjectiveTo evaluate, in critically ill adults, factors associated with impaired sympathovagal balance. DesignOne-month inception cohort study. SettingTwenty-six-bed medical intensive care unit of a teaching hospital. PatientsCritically ill adults with an expected duration of intensive care unit stay of ≥48 hrs were enrolled. Patients with permanent arrhythmia or cardiac pacing were not included. InterventionsNone. Measurement and Main Results Sympathovagal balance was assessed on the day after intensive care unit admission by the low-frequency/high-frequency ratio obtained from spectral components of heart rate signal: overall variability, low frequency, and high frequency. ResultsForty-one patients, 13 with sepsis and 28 without sepsis, were assessed. Predictors of low-frequency/high-frequency ratio with the automatic interaction detection method were sepsis and age. Binary logit analysis adjusted for age showed that sepsis remained a strong and independent factor of a low-frequency/high-frequency ratio of <1.50, with an odds ratio of 3.63 (95% confidence interval, 1.47–9.01, p = .005). Use of mechanical ventilation, catecholamines, or sedation did not add any information. The use of the low-frequency/high-frequency ratio in diagnosing sepsis may be supported by a likelihood ratio for low frequency/high frequency <1 at 6.47. ConclusionsThis work suggests that impaired cardiac variability and notably sympathovagal balance (i.e., a low-frequency/high-frequency ratio <1.0) may be a diagnostic test for sepsis.

Acquired neuromuscular disorders in critically ill patients: a systematic review

Objective: To summarize the prospective clinical studies of neuromuscular abnormalities in intensive care unit (ICU) patients. Study identification and selection: Studies were identified through MEDLINE, EMBASE, references in primary and review articles, personal files, and contact with authors. Through duplicate independent review, we selected prospective cohort studies evaluating ICU-acquired neuromuscular disorders. Data abstraction: In duplicate, independently, we abstracted key data regarding design features, the population, clinical and laboratory diagnostic tests, and clinical outcomes. Results: We identified eight studies that enrolled 242 patients. Inception cohorts varied; some were mechanically ventilated patients for ≥ 5 days, others were based on a diagnosis of sepsis, organ failure, or severe asthma while others were selected on the basis of exposure to muscle relaxants, or because of participation in muscle biochemistry studies. Weakness was systematically assessed in two of the eight studies, concerning patients with severe asthma, with a reported frequency of 36 and 70 %, respectively. Electrophysiologic and histologic abnormalities consisted of both peripheral nerve and muscle involvement and were frequently reported, even in non-selected ICU patients. In a population of patients mechanically ventilated for more than 5 days, electrophysiologic abnormalities were reported in 76 % of cases. Two studies showed a clinically important increase (5 and 9 days, respectively) in duration of mechanical ventilation and a mortality twice as high in patients with critical illness neuromuscular abnormalities, compared to those without. Conclusions: Prospective studies of ICU-acquired neuromuscular abnormalities include a small number of patients with various electrophysiologic findings but insufficiently reported clinical correlations. Evaluation of risk factors for these disorders and studies examining their contribution to weaning difficulties and long-term disability are needed.

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.

Presence and severity of intensive care unit-acquired paresis at time of awakening are associated with increased intensive care unit and hospital mortality.

Objectives: To assess whether the presence and severity of intensive care unit-acquired paresis are associated with intensive care unit and in-hospital mortality. Design: Prospective, observational study. Setting: Two medical, one surgical, and one medico-surgical intensive care units in two university hospitals and one university-affiliated hospital. Patients: A total of 115 consecutive patients were enrolled after > 7 days of mechanical ventilation. Interventions: None. Measurements and Main Results: The Medical Research Council score (from 0–60) was used to evaluate upper and lower limb strength at time of awakening, identified as the ability to follow five commands. Intensive care unit-acquired paresis was defined as a Medical Research Council score <48. Patients were followed-up until hospital discharge. The primary end point was hospital mortality. At awakening, median Medical Research Council score was 41 (interquartile range, 21–52), and 75 (65%) patients had intensive care unit-acquired paresis. Hospital non-survivors had a significantly lower Medical Research Council score at awakening (21 [11–43]) vs. 41 [28–53]; p = .008) and a significantly higher rate of intensive care unit-acquired paresis (85.1% vs. 58.4%; p = .02) compared to survivors. After multivariate risk adjustment, intensive care unit-acquired paresis was independently associated with higher hospital and intensive care unit mortality (odds ratio for hospital mortality, 2.02; 95% confidence interval, 1.03–8.03; p = .048). Each Medical Research Council point decrease was associated with a significantly higher hospital mortality (odds ratio, 1.03; 95% confidence interval, 1.01–1.05; p = .033). Conclusions: Both the presence and severity of intensive care unit-acquired paresis at the time of awakening are associated with increased intensive care unit and hospital mortality; the mechanisms underlying this association need further study.

Science review: The brain in sepsis--culprit and victim.

On one side, brain dysfunction is a poorly explored complication of sepsis. On the other side, brain dysfunction may actively contribute to the pathogenesis of sepsis. The current review aimed at summarizing the current knowledge about the reciprocal interaction between the immune and central nervous systems during sepsis. The immune-brain cross talk takes part in circumventricular organs that, being free from blood-brain-barrier, interface between brain and bloodstream, in autonomic nuclei including the vagus nerve, and finally through the damaged endothelium. Recent observations have confirmed that sepsis is associated with excessive brain inflammation and neuronal apoptosis which clinical relevance remains to be explored. In parallel, damage within autonomic nervous and neuroendocrine systems may contribute to sepsis induced organ dysfunction.

Understanding brain dysfunction in sepsis

Sepsis often is characterized by an acute brain dysfunction, which is associated with increased morbidity and mortality. Its pathophysiology is highly complex, resulting from both inflammatory and noninflammatory processes, which may induce significant alterations in vulnerable areas of the brain. Important mechanisms include excessive microglial activation, impaired cerebral perfusion, blood–brain-barrier dysfunction, and altered neurotransmission. Systemic insults, such as prolonged inflammation, severe hypoxemia, and persistent hyperglycemia also may contribute to aggravate sepsis-induced brain dysfunction or injury. The diagnosis of brain dysfunction in sepsis relies essentially on neurological examination and neurological tests, such as EEG and neuroimaging. A brain MRI should be considered in case of persistent brain dysfunction after control of sepsis and exclusion of major confounding factors. Recent MRI studies suggest that septic shock can be associated with acute cerebrovascular lesions and white matter abnormalities. Currently, the management of brain dysfunction mainly consists of control of sepsis and prevention of all aggravating factors, including metabolic disturbances, drug overdoses, anticholinergic medications, withdrawal syndromes, and Wernicke’s encephalopathy. Modulation of microglial activation, prevention of blood–brain-barrier alterations, and use of antioxidants represent relevant therapeutic targets that may impact significantly on neurologic outcomes. In the future, investigations in patients with sepsis should be undertaken to reduce the duration of brain dysfunction and to study the impact of this reduction on important health outcomes, including functional and cognitive status in survivors.