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.

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.

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.

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.

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.

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.

Acute neuromuscular respiratory failure after ICU discharge. Report of five patients.

OBJECTIVE: To describe a syndrome of acute neuromuscular respiratory failure (NM-ARF) caused by ICU-acquired acute myopathy and neuropathy. DESIGN: Case series. SETTING: General Regional University Hospital in Brescia, Italy. PATIENTS: Five adult patients with NM-ARF after prolonged ICU stay and successful weaning from the ventilator and ICU discharge. INTERVENTIONS: None. MEASUREMENTS: Clinical signs of NM-ARF, electroneurography and electromyography (ENMG) of peripheral nerves and muscles, and functional assessment of respiratory muscles. RESULTS: NM-ARF was diagnosed at the time of (one case), or 1-3 days after, ICU discharge. Limb weakness alarmed the physicians, while the signs of the NM-ARF were initially undetected. In the first observed case the acute respiratory failure was near fatal, and necessitated ICU readmission, while in the other cases 2 weeks of aggressive chest physiotherapy permitted resolution of the respiratory failure. History, clinical course and ENMG indicated the diagnosis of critical illness myopathy and neuropathy (CRIMYNE). Three patients recovered fully, while two had persisting evidence of axonal polyneuropathy several months after the onset. CONCLUSIONS: Critically ill patients with prolonged ICU stay, sepsis and MOF are at great risk of developing CRIMYNE, which in turn may be responsible for NM-ARF. This latter complication may arise after resolution of the respiratory and cardiac dysfunctions and successful weaning from the ventilator. As NM-ARF may cause unplanned ICU readmission or even unexpected death, strict clinical surveillance and monitoring of respiratory muscle function is recommended after discharge to the general ward of patients with proven NM-ARF. Early intensive chest physiotherapy can resolve the condition.

Bedside burr hole for intracranial pressure monitoring performed by intensive care physicians. A 5-year experience.

OBJECTIVE: To assess the results of a 5-year experience with bedside burr hole for intracranial pressure (ICP) monitoring performed by intensive care physicians. DESIGN: Prospective, observational study in 120 patients. SETTING: A general-neurologic Intensive Care Unit in a University Hospital. PATIENTS: Patients admitted for acute neural lesion requiring ICP monitoring. METHOD: A 2.71 mm burr hole was made with positioning of a subarachnoid screw, through which a miniaturized fiberoptic, tip transducer device (Camino) was advanced and inserted 2 mm in the frontal cortex. MAIN RESULTS: Over a 5-year period 120 patients, mainly with severe head trauma, underwent ICP monitoring. None of the planned patients was excluded because of technical difficulties. No life-threatening complications were reported, and the overall morbidity rate related to the ICP monitor was 3.3%. Complications were infectious in nature, with 2.5% wound infections and 0.8% meningitis. Although seven patients bled when opening the dura, no intracranial hematomas were recorded due to the ICP monitor. The fiberoptic device was left in place for 5 +/- 1.6 (SD) days (range 1-12 days). Five patients (4.1%) required catheter substitution due to breakage of the system components (fiberoptics). CONCLUSIONS: Bedside insertion of a ICP monitor performed by intensive care physicians is a safe procedure, with a complication rate comparable to other series published by neurosurgeons. The overall morbidity rate is comparable to, or even lower than, that caused by central vein catheterization.

Free radical-induced lipoperoxidation and severe head injury. A clinical study.

Ten severely head injured patients (GCS less than or equal to 8), aged 17-62 years, were studied in order to investigate the role of lipoperoxidation in secondary brain damage. No patients had intracranial mass lesions, shock, hypoxemia, fever or sepsis. Blood samples were taken from the jugular bulb and from the right atrium, and thiobarbituric acid reacting substances (TBARS) were measured in plasma by spectrophotometry. Arterio-jugular venous oxygen differences (AVDO2) were obtained in seven patients, in order to estimate cerebral blood flow. Jugular TBARS (TBARSj) were always elevated (from To, to 2 h after injury) and correlated in a linear fashion with TBARS of right atrium (TBARSv): r = 0.74, p less than 0.001. TBARSj and AVDO2 are closely correlated, in accordance with an exponential function (R = 0.45, p less than 0.001) which describes how any cerebral perfusion derangement determines high levels of TBARSj, confirming lipoperoxidation as a key factor in the final common pathway of secondary posttraumatic brain damage.

Emergent decompressive craniectomy in patients with fixed dilated pupils due to cerebral venous and dural sinus thrombosis: report of three cases.

OBJECTIVE AND IMPORTANCE: Cerebral venous and dural sinus thrombosis is a rare cause of stroke. Although morbidity and mortality have greatly decreased in recent years as a result of early diagnosis and timely medical treatment, when coma occurs the prognosis remains poor. We evaluated whether emergent decompressive craniectomy has a role in the treatment of patients with brain herniation from dural sinus thrombosis and hemorrhagic infarct. CLINICAL PRESENTATION: Three patients developed large hemorrhagic infarct with coma and bilaterally fixed and dilated pupils resulting from aseptic dural sinus thrombosis. INTERVENTION: Two patients underwent emergent surgical decompression as soon as brain herniation developed, and these patients had complete functional recovery. One underwent delayed surgical decompression and remained severely disabled. CONCLUSION: Our results provide preliminary evidence that emergent decompressive craniectomy is effective in patients with brain herniation from dural sinus thrombosis, provided that the clinical onset is recent. We therefore recommend consideration of this aggressive surgical technique for such patients, who may survive with good outcomes.

Limits of intermittent jugular bulb oxygen saturation monitoring in the management of severe head trauma patients.

OBJECTIVE: To evaluate, in a prospective, observational study, whether bilateral monitoring of jugular bulb oxyhemoglobin saturation (SjO2), in addition to standard monitoring, results in modification of the management of severe head trauma. METHODS: The patients underwent bilateral jugular bulb cannulation and observation at 8-hour intervals, during which SjO2 was measured and the neurological condition and physiological variables were assessed. The study group was responsible for evaluating whether the physician's decision-making process was influenced by the detection of SjO2 abnormalities. The SjO2 discrepancy in simultaneous bilateral samples was also evaluated to determine whether it interfered with the interpretation of data and with clinical decision-making. The SjO2-related complications were monitored. RESULTS: Thirty patients underwent 319 observations. In 96% of patients, SjO2 was normal or high and had no influence on the diagnostic or therapeutic strategies. Treatment decisions were dictated by changes in clinical status and in intracranial and cerebral perfusion pressure. When these parameters were abnormal, treatment was administered, even if SjO2 was normal (101 observations). Conversely, when SjO2 was the only detected abnormality (34 observations), no treatment was administered. Abnormally low SjO2 values, caused by hypovolemia and hypocapnia, were detected in 3.4% of observations and actually modified the management. The discrepancies in simultaneous bilateral samples were substantial and gave rise to relevant interpretation problems. Fifteen percent of jugular catheters showed evidence of bacterial colonization. CONCLUSION: Intermittent SjO2 monitoring did not substantially influence the management of severe head trauma. Therefore, recommendation for its routine use in all patients seems inadvisable, and indications for this invasive method should no longer be defined on the basis of experts' opinions, but rather on randomized, prospective studies.

Acute quadriplegia with delayed onset and rapid recovery. Case report.

The authors describe a patient with severe head injury and sepsis who became acutely quadriplegic 3 days postinjury because of a critical illness polyneuropathy (CIP) and critical illness myopathy (CIM), which resolved rapidly after treatment of the underlying infection. In only 3 days the patient developed septic shock together with flaccid quadriplegia and absent deep tendon reflexes with no clinical or radiological evidence of central nervous system deterioration. Neurophysiological studies showed an acute axonal sensorimotor polyneuropathy, whereas the clinical course strongly suggested a concurrent myopathy. A severe Staphylococcus epidermidis infection accompanied by bacteremia was treated and the patient recovered fully within a few days. Although the case described here is unique because of its very early onset and rapid resolution, CIP and CIM are frequent complications of sepsis and multiple organ failure. The authors suggest that severely head injured patients with sepsis should be evaluated for CIP and CIM when presenting with unexplained muscle weakness or paralysis.

Impact of heat and moisture exchangers on ventilatory pattern and respiratory mechanics in spontaneously breathing patients.

The upper airways warm and saturate inspired air with water vapour. In intubated or tracheotomized patients, this function is replaced either by hot water humidifiers or by heat and moisture exchangers (HMEs). The aim of this study was to quantify the modifications of ventilatory mechanics and patients' work when two different HMEs were added to spontaneously breathing patients. We studied nine consecutive patients with no previous history of chronic obstructive lung disease. All patients had been weaned from mechanical ventilation. They were breathing through devices supplying positive end-expiratory pressure and/or O2 enrichment. Two different HMEs were used: Icor Mediflux 1 and Icor Mediflux 2. These HMEs have identical chemical composition and configuration, but the Mediflux 1 is larger than the Mediflux 2. The humidification of the inspired gases was obtained alternatively by an active humidifier and the two HMEs. Data regarding ventilatory pattern and respiratory mechanics were collected by pulmonary monitor CP100 (Bicore). Tidal volume, work of breathing and pressure-time product were greater with Mediflux 1 than with Mediflux 2 or active humidifier. There were no significant differences in respiratory rate, intrinsic positive end-expiratory pressure (PEEPi), rapid shallow breathing index, arterial CO2 and O2 partial pressure. The larger HME (Mediflux 1) increased patient's effort, with no evidence of patient discomfort. However, the smaller HME (Mediflux 2) did not add a detectable load and provided adequate humidification. In conclusion, the smaller HME appears to be preferable for the management of spontaneously breathing patients.