Daptomycin Plasma and CSF Levels in Patients with Healthcare-Associated Meningitis.

BACKGROUND: There are currently few data concerning the cerebrospinal fluid (CSF) penetration of daptomycin in patients with healthcare-associated meningitis. This study aims (1) to better characterize the pharmacokinetics of daptomycin in humans during a 7-day intravenous (IV) therapy course, and (2) to study the penetration of daptomycin in the CSF after IV infusion at the dose of 10 mg/kg. RESULTS: In this prospective observational study, we enrolled nine patients with an implanted external ventricular drainage and a diagnosis of a healthcare-associated meningitis. Daptomycin was administered at 10 mg/kg for a maximum of 7 days. The pharmacokinetic of daptomycin was studied using a two-compartment population/pharmacokinetic (POP/PK) model and by means of a nonlinear mixed effects modeling approach. A large inter-individual variability in plasma area under the curve (Range: 574.7-1366.3 h mg/L), paralleled by high-peak plasma concentration (Cmax) (all values > 60 mg/L), was noted. The inter-individual variability of CSF-AUC although significant (range: 1.17-6.81 h mg/L) was narrower than previously reported and with a late occurrence of CSF-Cmax (range: 6.04-9.54 h). The terminal half-life between plasma and CSF was similar. tmax values in CSF did not show a high inter-individual variability, and the fluctuations of predicted CSF concentrations were minimal. The mean value for daptomycin penetration obtained from our model was 0.45%. CONCLUSIONS: Our POP/PK model was able to describe the pharmacokinetics of daptomycin in both plasma and CSF, showing that daptomycin (up to 7 days at 10 mg/kg) has minimal penetration into central nervous system. Furthermore, the observed variability of AUC, tmax and predicted concentration in CSF was lower than what previously reported in the literature. Based on the present findings, it is unlikely that daptomycin could reach CSF concentrations high enough to have clinical efficacy; this should be tested in future studies.

Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy.

Sepsis, or systemic inflammatory response syndrome, is the major cause of critical illness resulting in admission to intensive care units. Sepsis is caused by severe infection and is associated with mortality in 60% of cases. Morbidity due to sepsis is complicated by neuromyopathy, and patients face long-term disability due to muscle weakness, energetic dysfunction, proteolysis and muscle wasting. These processes are triggered by pro-inflammatory cytokines and metabolic imbalances and are aggravated by malnutrition and drugs. Skeletal muscle regeneration depends on stem (satellite) cells. Herein we show that mitochondrial and metabolic alterations underlie the sepsis-induced long-term impairment of satellite cells and lead to inefficient muscle regeneration. Engrafting mesenchymal stem cells improves the septic status by decreasing cytokine levels, restoring mitochondrial and metabolic function in satellite cells, and improving muscle strength. These findings indicate that sepsis affects quiescent muscle stem cells and that mesenchymal stem cells might act as a preventive therapeutic approach for sepsis-related morbidity.

An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults

RATIONALE: Profound muscle weakness during and after critical illness is termed intensive care unit-acquired weakness (ICUAW). OBJECTIVES: To develop diagnostic recommendations for ICUAW. METHODS: A multidisciplinary expert committee generated diagnostic questions. A systematic review was performed, and recommendations were developed using the Grading, Recommendations, Assessment, Development, and Evaluation (GRADE) approach. MEASUREMENT AND MAIN RESULTS: Severe sepsis, difficult ventilator liberation, and prolonged mechanical ventilation are associated with ICUAW. Physical rehabilitation improves outcomes in heterogeneous populations of ICU patients. Because it may not be feasible to provide universal physical rehabilitation, an alternative approach is to identify patients most likely to benefit. Patients with ICUAW may be such a group. Our review identified only one case series of patients with ICUAW who received physical therapy. When compared with a case series of patients with ICUAW who did not receive structured physical therapy, evidence suggested those who receive physical rehabilitation were more frequently discharged home rather than to a rehabilitative facility, although confidence intervals included no difference. Other interventions show promise, but fewer data proving patient benefit existed, thus precluding specific comment. Additionally, prior comorbidity was insufficiently defined to determine its influence on outcome, treatment response, or patient preferences for diagnostic efforts. We recommend controlled clinical trials in patients with ICUAW that compare physical rehabilitation with usual care and further research in understanding risk and patient preferences. CONCLUSIONS: Research that identifies treatments that benefit patients with ICUAW is necessary to determine whether the benefits of diagnostic testing for ICUAW outweigh its burdens.(AU)

The relationship between the intracranial pressure-volume index and cerebral autoregulation.

OBJECTIVE: The pressure-volume index (PVI) can be used to assess the cerebrospinal fluid dynamics and intracranial elastance in critically ill brain injured patients. The dependency of PVI on the state of cerebral autoregulation within the physiologic range of cerebral perfusion pressure (CPP) can be described by mathematical models that account for changes in cerebral blood volume during PVI testing. This relationship has never been verified clinically using direct PVI measurement and independent cerebral autoregulation assessment. DESIGN, SETTING, AND PATIENTS: PVI and cerebral autoregulation were prospectively assessed in a cohort of 19 comatose patients admitted to an academic intensive care unit in Brescia, Italy. INTERVENTION: None. METHODS: PVI was measured injecting a fixed volume of 2 ml of 0.9% sodium chloride solution into the cerebral ventricles through an intraventricular catheter. Cerebral autoregulation was assessed using transcranial Doppler transient hyperaemic response (THR) test. MEASUREMENTS AND RESULTS: Fifty-nine PVI assessments and 59 THR tests were performed. Mean PVI was 20.0 (SD 10.2) millilitres in sessions when autoregulation was intact (THR test >or=1.1) and 31.6 (8.8) millilitres in sessions with defective autoregulation (THR test <1.1) (DeltaPVI = 11.7 ml, 95% CI = 4.7-19.3 ml; P = 0.002). Intracranial pressure, CPP and brain CT findings were not significantly different between the measurements with intact and disturbed autoregulation. CONCLUSIONS: Cerebral autoregulation status can affect PVI estimation despite a normal CPP. PVI measurement may overestimate the tolerance of the intracranial system to volume loads in patients with disturbed cerebral autoregulation.

Thromboembolic prophylaxis in head trauma and multiple-trauma patients.

The association between trauma and venous thromboembolism (VTE) is well recognized. VTE consists mainly of deep venous thrombosis (DVT) and pulmonary embolism, a complication that leads to mortality in nearly 50% of cases. Without thromboprophylaxis, the risk of DVT exceeds 50%, but even with routine use of prophylaxis,one third of patients may develop DVT. Despite these findings, appropriate DVT prophylaxis is often not prescribed in trauma patients, mainly because of fear that VTE prophylaxis increases bleeding in injured tissues. Pharmacological VTE prophylaxis is based on the use of low-molecular weight heparins (LMWH). Once-daily or twice-daily LMWH protocols started within 36 h of trauma and continued throughout the hospital stay, or once-daily LMWH followed by a twice-daily protocol are possible options. Mechanical VTE prophylaxis by graduated compression stockings or intermittent pneumatic compression provides suboptimal protection, and its use is recommended only in combination with LMWH prophylaxis unless active bleeding is not controlled. The routine use of VTE prophylaxis in trauma patients is a standard of care. The use of LMWH, started once primary hemostasis has been accomplished, is safe, efficacious and cost-effective in the majority of trauma patients, including TBI patients.

Critical illness myopathy and neuropathy.

Muscle wasting and paralysis are common complications in Intensive Care Unit (ICU) patients, where critical illness polyneuropathy (CIP) and critical illness myopathy (CIM), alone or in combination (CIP/CIM), are the commonest causes. CIP is an acute axonal sensory-motor polyneuropathy usually suspected in ICU patients who, after a period of days or weeks, cannot be weaned from the ventilator despite the absence of pulmonary or cardiac causes of respiratory failure, or because they suffer from various degrees of limb weakness. CIM is an acute primary myopathy with a continuum of myopathic findings, from myopathies with pure functional impairment and normal histology to myopathies with atrophy and necrosis. The true incidence of CIM is unknown, because neither the diagnosis of CIM nor the differential diagnosis between CIP and CIM in the ICU are easy, and requires specialized neurophysiological methods or biopsy investigations in addition to conventional nerve conduction studies and needle electromyography. When these methods are used, CIM is as frequent as or more frequent than CIP. Failed weaning of patients from the ventilator, inappropriate evaluations of comatose patients and prolonged disability after ICU discharge are common consequences of CIP/CIM. Recent data indicate that CIM has a better prognosis than CIP, and differential diagnosis is therefore important to predict long term outcome in ICU patients. Bioenergetic failure is thought to be a relevant pathophysiological mechanism explaining both CIP/CIM and multi-organ failure. Indeed, CIP/CIM itself should be considered as the failure of the peripheral nervous-muscular system.

The early phase of critical illness is a progressive acidic state due to unmeasured anions.

BACKGROUND AND OBJECTIVE: Stewart's and Fencl's methods have recently been proposed to interpret acid-base disorders where traditional theory has proven inadequate. Our objectives were to evaluate: (1) the occurrence of acid-base disturbances in critically ill patients and their trend over the first 3 intensive care unit days, (2) whether Stewart's theory offers advantages over the traditional theory in the diagnosis of acid-base metabolic disturbances and (3) whether variables derived from Stewart's and Fencl's methods offer advantages over the traditional method to predict patient mortality. METHODS: A prospective cohort study in a general intensive care unit. Blood samples were analysed for arterial blood gases, electrolytes and proteins. PaCO2, pH, bicarbonate, base excess, standard base-excess, sodium, potassium, chloride, phosphorous, calcium, magnesium and lactate were measured. Anion gap, Stewart's and Fencl's variables were calculated. RESULTS: When using Stewart's method, metabolic acidosis and metabolic alkalosis were found in 92.9% and 93.4% of samples, respectively. Corresponding figures obtained with the traditional method were 15% and 18.7%. In 245 (64.5%) samples, Stewart's method revealed that metabolic acidosis and alkalosis were simultaneously present, whereas the traditional method revealed a normal acid-base status. Strong ion gap increased significantly over the first 3 intensive care unit days. Strong ion gap and lactate were independent predictors of 28-day mortality. CONCLUSIONS: Metabolic acidosis by unmeasured anions is a clinically relevant phenomenon, which is correlated with mortality. Progressive metabolic acidosis may be ongoing in the early phase of critical illness despite the absence of acidaemia.

Long-term outcome in patients with critical illness myopathy or neuropathy: the Italian multicentre CRIMYNE study.

BACKGROUND: Critical illness myopathy (CIM) and polyneuropathy (CIP), alone or in combination (CIP/CIM), are frequent complications in patients in the intensive care unit (ICU). There is no evidence that differentiating between CIP and CIM has any impact on patient prognosis. METHODS: 1-year prospective cohort study of patients developing CIP, CIM or combined CIP and CIM during ICU stay. RESULTS: 28 out of 92 (30.4%) patients developed electrophysiological signs of CIP and/or CIM during their ICU stay, which persisted in 18 patients at ICU discharge. At hospital discharge, diagnoses in the 15 survivors were CIM in six cases, CIP in four, combined CIP and CIM in three and undetermined in two uncooperative patients. During the 1-year follow-up of six patients with CIM, one patient died and five recovered completely within 3 (three patients) to 6 (two patients) months. Of three patients with CIP/CIM, one died, one recovered and one with residual CIP remained tetraplegic. Of four patients with CIP, one recovered, two had persisting muscle weakness and one remained tetraparetic. CONCLUSION: CIM has a better prognosis than CIP. Differential diagnosis is important to predict long-term outcome in ICU patients.

Meticillin-resistant Staphylococcus aureus control in an intensive care unit: a 10 year analysis.

Data regarding the efficacy of programmes to control meticillin-resistant Staphylococcus aureus (MRSA) in intensive care units (ICUs) are limited. We performed an observational 'before-and-after' study to evaluate the search-and-destroy (S&D) strategy as compared with S&D and isolation (SDI), to control MRSA in a general ICU. S&D included active surveillance, contact precautions and treatment of carriers; in SDI, isolation or cohorting were added. Three phases were identified: period 1 (p1), 1996-1997, before the introduction of programme; period 2 (p2), 1998-2002, with S&D programme; period 3 (p3), 2003-2005, with SDI in a new ICU. During the 10 years of the study we observed 3978 patients; 667, 1995 and 1316 patients in p1, p2 and p3 respectively. The numbers of MRSA-infected patients were 19 in p1, 23 in p2, and 6 in p3. The infection rate was 3.5, 1.7 and 0.7 cases per 1000 patient-days in p1, p2 and p3, respectively; a significant reduction was observed between p1 vs p2 (P=0.024) and p2 vs p3 (P=0.048), although the latter was not confirmed by a segmented regression analysis. The proportion of ICU-acquired MRSA cases was 80%, 77% and 52% during p1, p2 and p3, respectively (P=0.0001 for trend). The proportion of S. aureus isolates resistant to meticillin was 51%, 32% and 23% during p1, p2 and p3, respectively (P<0.0001 for trend). S&D strategy was effective in significantly reducing MRSA infection, transmission rates and proportion of meticillin resistance in an ICU with endemic MRSA. SDI may further enhance S&D efficacy.

Bi-occipital decompressive craniectomy in refractory post traumatic intracranial hypertension: first report of one case.

Decompressive craniectomy (DC) is considered a 'second tier' therapy to control posttraumatic intracranial hypertension refractory to maximal medical treatment. The authors present a case of refractory intracranial hypertension due to diffuse brain swelling and a large (>25 ml) non-surgically-treatable haematoma of the splenium of the corpus callosum successfully treated with bi-occipital DC and augmentative duraplasty.

Posttraumatic cerebral infarction in patients with moderate or severe head trauma.

OBJECTIVE: To evaluate the frequency, types, and location of posttraumatic cerebral infarction, to assess if secondary cerebral insults were associated with cerebral infarction, and to determine if cerebral infarction affected patients' outcome. METHODS: We based diagnosis of cerebral infarction on review of brain CT scans. We assessed frequency of secondary cerebral insults, including intracranial hypertension, cerebral hypoperfusion, systolic hypo- and hypertension, arterial blood oxygen desaturation, hypocapnia, and hyperthermia, using clinical charts. We used the Glasgow Outcome Scale to evaluate outcome at 6 months after trauma. RESULTS: Of the 89 patients included, a total of 28 cerebral infarctions were found in 17 cases (19.1%). Infarctions were territorial in 23 (82.1%) and watershed in 5 (17.9%) cases. Territorial infarctions were localized to the middle cerebral artery (n = 9, 32.1%), lenticulostriate arteries (n = 6, 21.4%), posterior cerebral artery (n = 3, 10.7%), anterior cerebral artery (n = 3, 10.7%), thalamoperforating arteries (n = 1, 3.6%), and basilar artery (n = 1, 3.6%) territories. Watershed infarctions were in the boundary (n = 4, 14.3%) and terminal (n = 1, 3.6%) zones. Intracranial hypertension was the only independent variable predicting cerebral infarction (odds ratio [OR] 13.3; 95% CI 2.8 to 62.6). At 6 months after trauma, there was a lower proportion of patients with good outcome among patients with cerebral infarction vs patients without (23.5 and 61.1%; p = 0.005). Cerebral infarction was the only independent predictor of 6-month outcome (OR of good outcome 0.19, 95% CI 0.06 to 0.66). CONCLUSIONS: The risk of developing posttraumatic cerebral infarction may be higher in patients with intracranial hypertension than in those without. Patients with posttraumatic cerebral infarction may be at increased risk of residual disability.

An Italian survey of severe head trauma management during extracranial surgery.

BACKGROUND AND OBJECTIVE: Anaesthetic drugs and procedures interfere with secondary brain injury following severe head trauma, yet studies regarding the anaesthetic management of these patients are lacking. We investigated the behaviour of Italian anaesthetists regarding this topic. METHODS: A questionnaire investigating the approach to a patient with severe head trauma requiring an urgent splenectomy for ruptured spleen was sent to 250 Italian anaesthetists. Questions regarded the pre-, intra- and postoperative phases, and concerned the rationale use and availability of specific monitoring systems, and indications for invasive procedures and use of drugs, fluids and blood products. RESULTS: There were 162 (64.8%) responders. Seventy-five percent believed that early tracheal intubation within the emergency room was necessary, while 25% postponed it to the operating room. Basic monitoring was defined as essential by all responders, 147 (90.7%) considered invasive arterial pressure monitoring to be essential. Fifty-seven (84%) anaesthetists working in hospitals without neurosurgical facilities would have transferred the patient after splenectomy. Prophylactic hyperventilation was frequently used (36%). Sixty-eight percent of responders would have preferred in intracranial pressure monitoring inserted before laparotomy, but only 35% actually had this possibility. In case of acute intraoperative arterial hypotension after splenectomy, 54% of the responders advocated the use of blood or blood products to optimize peripheral oxygen transport. CONCLUSIONS: More widespread knowledge of certain areas of severe head trauma management such as early tracheal intubation, avoidance of prophylactic hyperventilation, adequate invasive monitoring, appropriate use of blood products, and timing of transfer to hospitals with neurosurgical facilities is needed.

Antibiotic prophylaxis of early onset pneumonia in critically ill comatose patients. A randomized study.

OBJECTIVE: To evaluate if a 3-day ampicillin-sulbactam prophylaxis can reduce the occurrence of early-onset pneumonia (EOP) in comatose mechanically-ventilated patients. DESIGN: This was a single-centre, prospective, randomised, open study. SETTING: A 10-bed general-neurological ICU in a 2,000-bed university hospital. PATIENTS AND PARTICIPANTS: Comatose mechanically-ventilated patients with traumatic, surgical or medical brain injury. INTERVENTIONS: Patients were randomized to either ampicillin-sulbactam prophylaxis (3 g every 6 h for 3 days) plus standard treatment or standard treatment alone. MEASUREMENTS AND RESULTS: Main outcome was the occurrence of EOP. Secondary outcome measures were occurrence of late-onset pneumonia, percentage of non-pulmonary infections and of emerging multiresistant bacteria, duration of mechanical ventilation and of ICU stay and ICU mortality. Interim analysis at 1 year demonstrated a statistically significant reduction of EOP in the ampicillin-sulbactam group, and the study was interrupted. Overall, 39.5% of the patients developed EOP, 57.9% in the standard treatment group and 21.0% in the ampicillin-sulbactam group (chi-square 5.3971; P =0.022). Relative risk reduction of EOP in patients receiving ampicillin-sulbactam prophylaxis was 64%; the number of patients to be treated to avoid one episode of EOP was three. No differences in other outcome parameters were found; however, the small sample size precluded a definite analysis. CONCLUSIONS: Antibiotic prophylaxis with ampicillin-sulbactam significantly reduced the occurrence of EOP in critically ill comatose mechanically ventilated patients. This result should encourage a large multicenter trial to demonstrate whether ampicillin-sulbactam prophylaxis reduces patient mortality, and whether antibiotic resistance is increased in patients receiving prophylaxis.

The 14-3-3 protein in multiple sclerosis: a marker of disease severity.

CONTEXT: In multiple sclerosis (MS) axonal damage is an early event and is probably to be considered the most relevant cause of permanent and progressive disability. OBJECTIVES: To investigate the value of the increase of 14-3-3 and tau proteins in the cerebrospinal fluid (CSF) as peripheral markers of axonal pathology and predictors of disease evolution. PATIENTS AND METHODS: In the CSF samples obtained from 63 patients with demyelinating diseases (DD), including 20 clinically isolated syndromes (CIS) and 43 clinically defined MS, as well as from 56 controls, we analysed the presence of 14-3-3 reactivity by immunoblot analysis along with the concentration of tau protein by sandwich ELISA. RESULTS: The percentage of DD subjects showing a positive 14-3-3 protein CSF reactivity (38%) was significantly higher than the one previously detected, and was correlated in the MS patients with a more severe clinical phenotype in terms of degree of disability and rate of disease progression, during a 10-month mean clinical follow-up. On the contrary, the levels of the CSF-tau protein were highly variable in DD and control subjects, and the mean CSF-tau concentration was similar in both groups. CONCLUSIONS: The immunoblot analysis of 14-3-3 protein in the CSF could be a useful marker to identify a subgroup of DD patients with high risk of developing severe disability.

Bedside burr hole for intracranial pressure monitoring performed by anaesthetist-intensive care physicians. Extending the practice to the entire ICU team.

BACKGROUND: To evaluate the effects of extending the practice of bedside burr hole for intracranial pressure (ICP) monitoring to the entire ICU team. DESIGN: a 10-year observational cohort study. SETTING: A general-neurologic 12-bed ICU of a University Hospital with 10 full-time specialists in anaesthesia-intensive care. PATIENTS: patients admitted for acute neurologic lesions requiring ICP monitoring. MEASUREMENTS: ICP monitoring was performed by means of intraparenchymal fiberoptic cathe-ters. Rates of successfully performed procedures and complications were compared between 2 study periods: January 1990 - August 1997, in which the procedure was performed by 2 experienced physicians (group 1), and September 1997-July 2000 in which the procedure was extended to the entire team (group 2). RESULTS: Two hundred and seventy patients had 293 catheters positioned (group 1=180; 2=113). The procedure was successfully performed in all cases. Occurrence of complications was similar in the 2 groups: minor surgical wound infections (3.3%; 2.6%); meningitis (0.5%; 0); scalp (3.9%; 2.6%) and dural (5.0%; 6.2%) bleeding; intracranial haematoma (1.1%; 1.8%). Two of these latter (1 for each group) required surgical evacuation. Twelve anaesthetist-intensive care physicians were trained, and they were able to perform burr hole for ICP monitoring without help after 2-3 assisted procedures. CONCLUSIONS: Extending the practice of ICP monitoring to the entire ICU team is safe and feasible. To decide whether or not to implement this technique, one should consider the high costs on one side and prompt availability of ICP monitoring on the other. Haemorrhagic and infectious complications are comparable to those of neurosurgical series.

Normal jugular bulb oxygen saturation.

BACKGROUND: Normal values of the jugular bulb oxygen saturation were obtained in 1942 and in 1963. Correct catheter positioning was not confirmed radiologically. OBJECTIVES: To replicate the measurements during angiographic catheterisation of the jugular bulb. METHODS: Oxygen saturation in the jugular bulb (SjO(2)), inferior petrosal sinus (SipsO(2)), and internal jugular vein was bilaterally measured in 12 patients with Cushing's syndrome undergoing selective bilateral catheterisation of the inferior petrosal sinus. In addition, data from the two old series were reanalysed for comparison. RESULTS: SjO(2) values (44.7%) were significantly lower than in the two old series, particularly concerning the normal lower limit (54.6% and 55.0% respectively). Comparative analysis suggests that contamination with the extracerebral blood of the facial veins and inferior petrosal sinuses was responsible for falsely high SjO(2) values in the two old series. CONCLUSIONS: The normal lower SjO(2) limit is lower than previously recognised. This may have practical implications for treating severe head trauma patients.