Veno-venous extracorporeal membrane oxygenation (vv-ECMO) for severe respiratory failure in adult cancer patients: a retrospective multicenter analysis.

PURPOSE: The question of whether cancer patients with severe respiratory failure benefit from veno-venous extracorporeal membrane oxygenation (vv-ECMO) remains unanswered. We, therefore, analyzed clinical characteristics and outcomes of a large cohort of cancer patients treated with vv-ECMO with the aim to identify prognostic factors. METHODS: 297 cancer patients from 19 German and Austrian hospitals who underwent vv-ECMO between 2009 and 2019 were retrospectively analyzed. A multivariable cox proportional hazards analysis for overall survival was performed. In addition, a propensity score-matched analysis and a latent class analysis were conducted. RESULTS: Patients had a median age of 56 (IQR 44-65) years and 214 (72%) were males. 159 (54%) had a solid tumor and 138 (47%) a hematologic malignancy. The 60-day overall survival rate was 26.8% (95% CI 22.1-32.4%). Low platelet count (HR 0.997, 95% CI 0.996-0.999; p = 0.0001 per 1000 platelets/µl), elevated lactate levels (HR 1.048, 95% CI 1.012-1.084; p = 0.0077), and disease status (progressive disease [HR 1.871, 95% CI 1.081-3.238; p = 0.0253], newly diagnosed [HR 1.571, 95% CI 1.044-2.364; p = 0.0304]) were independent adverse prognostic factors for overall survival. A propensity score-matched analysis with patients who did not receive ECMO treatment showed no significant survival advantage for treatment with ECMO. CONCLUSION: The overall survival of cancer patients who require vv-ECMO is poor. This study shows that the value of vv-ECMO in cancer patients with respiratory failure is still unclear and further research is needed. The risk factors identified in the present analysis may help to better select patients who may benefit from vv-ECMO.

Feasibility, safety, and resource utilisation of active mobilisation of patients on extracorporeal life support: a prospective observational study.

BACKGROUND: There is scarce evidence on the feasibility, safety and resource utilisation of active mobilisation in critically ill patients on extracorporeal life support (ECLS). METHODS: This prospective observational single-centre study included all consecutive critically ill patients on ECLS admitted to an academic centre in Germany over a time period of one year. The level of mobilisation was categorised according to the ICU Mobility Scale (IMS). Primary outcome was complications during mobilisation. RESULTS: During the study period, active mobilisation with an activity level on the IMS of ≥ 3 was performed at least on one occasion in 43 out of 115 patients (37.4%). A total of 332 mobilisations with IMS ≥ 3 were performed during 1242 ECLS days (26.7%). ECLS configurations applied were va-ECMO (n = 63), vv-ECMO (n = 26), vv-ECCO2R (n = 12), av-ECCO2R (n = 10), and RVAD (n = 4). Femoral cannulation had been in place in 108 patients (93.9%). The median duration of all mobilisation activities with IMS ≥ 3 was 130 min (IQR 44-215). All mobilisations were undertaken by a multi-professional ECLS team with a median number of 3 team members involved (IQR 3-4). Bleeding from cannulation site requiring transfusion and/or surgery occurred in 6.9% of actively mobilised patients and in 15.3% of non-mobilised patients. During one mobilisation episode, accidental femoral cannula displacement occurred with immediate and effective recannulation. Sedation was the major reason for non-mobilisation. CONCLUSIONS: Active mobilisation (IMS ≥ 3) of ECLS patients undertaken by an experienced multi-professional team was feasible, and complications were infrequent and managed successfully. Larger prospective multicentre studies are needed to further evaluate early goal directed sedation and mobilisation bundles in patients on ECLS.

[Prevention of delirium in the intensive care unit]. / Prävention des Delirs auf der Intensivstation.

A delirium in patients in the intensive care unit (ICU) is a manifestation of a severe acute dysfunction of the brain. It has a high prevalence and is associated with a relevant increase in morbidity and mortality. A cholinergic deficit and dopaminergic overactivity are considered to be a cause of delirium. Polypharmacy, which is often present before admission to the ICU, especially in the elderly, plays a key role as a trigger. The knowledge and identification of risk factors for delirium is a precondition for the early and effective prevention of delirium. The aim is the pre-operative or pre-interventional optimization of modifiable risk factors. Early and effective prevention of delirium can improve clinical outcome, reduce mortality, and positively impact long-term functional outcome. Non-pharmacological measures are always the basis for the prevention of delirium: maintenance of the day-night rhythm, sleep promotion at night and stimulation during the day, involvement of relatives, the avoidance of dehydration and malnutrition, and others more. They are pharmacologically accompanied by an effective analgesia and a target and symptom-oriented sedation with well controllable, as little as possible delirogenic substances. Interdisciplinary and interprofessional cooperation is essential so that preventive concepts significantly reduce the risk of delirium, even in high-risk patients.

Pharmacokinetics of meropenem in septic patients on sustained low-efficiency dialysis: a population pharmacokinetic study.

BACKGROUND: The aim of the study was to describe the population pharmacokinetics (PK) of meropenem in critically ill patients receiving sustained low-efficiency dialysis (SLED). METHODS: Prospective population PK study on 19 septic patients treated with meropenem and receiving SLED for acute kidney injury. Serial blood samples for determination of meropenem concentrations were taken before, during and after SLED in up to three sessions per patient. Nonparametric population PK analysis with Monte Carlo simulations were used. Pharmacodynamic (PD) targets of 40% and 100% time above the minimal inhibitory concentration (f T > MIC) were used for probability of target attainment (PTA) and fractional target attainment (FTA) against Pseudomonas aeruginosa. RESULTS: A two-compartment linear population PK model was most appropriate with residual diuresis supported as significant covariate affecting meropenem clearance. In patients without residual diuresis the PTA for both targets (40% and 100% f T > MIC) and susceptible P. aeruginosa (MIC ≤ 2 mg/L) was > 95% for a dose of 0.5 g 8-hourly. In patients with a residual diuresis of 300 mL/d 1 g 12-hourly and 2 g 8-hourly would be required to achieve a PTA of > 95% and 93% for targets of 40% f T > MIC and 100% f T > MIC, respectively. A dose of 2 g 8-hourly would be able to achieve a FTA of 97% for 100% f T > MIC in patients with residual diuresis. CONCLUSIONS: We found a relevant PK variability for meropenem in patients on SLED, which was significantly influenced by the degree of residual diuresis. As a result dosing recommendations for meropenem in patients on SLED to achieve adequate PD targets greatly vary. Therapeutic drug monitoring may help to further optimise individual dosing. TRIAL REGISTRATION: Clincialtrials.gov, NCT02287493 .

Clinical characteristics and outcome of very elderly patients ≥90 years in intensive care: a retrospective observational study.

BACKGROUND: Since the overall prognosis of very elderly patients is generally limited, admissions to intensive care in these patients are often restricted. Therefore, only very few information is available on the prognosis of nonagenarians after intensive care treatment. The aim of this study was to analyze the clinical characteristics and outcomes of very elderly patients (≥90 years) admitted to an intensive care unit (ICU). METHODS: Monocentric, retrospective observational study of all patients aged ≥90 years admitted to the Department of Intensive Care Medicine with a total capacity of 132 ICU beds at the University Medical Center Hamburg in Germany between January 2008 and June 2013. A multivariate Cox regression analysis was used to identify risk factors for 28-day outcome. RESULTS: A total of 372 patients ≥90 years of age were admitted to one of the departments ICUs. The majority of patients (66.7 %) were admitted as an emergency admission, of which half underwent unscheduled surgery. 39.8 % of patients required support by mechanical ventilation and vasoactive drugs, and 1.9 % of patients received renal replacement. ICU and hospital mortality rates were 18.3 and 30.9 %, respectively. Overall survival at 1 year after hospital discharge was 34.9 %. Multivariate Cox regression analysis revealed creatinine, bilirubin, age, and necessity of catecholamines as independent risk factors and scheduled surgery as protective factor for 28-day outcome. CONCLUSION: Nearly 70 % of patients aged ≥90 years were discharged alive from hospital following treatment at the ICU, and more than half of them were still alive 1 year after their discharge. The results suggest that 1-year survival prognosis of very old ICU patients is not as poor as often perceived and that age per se should not be an exclusion criterion for ICU admission. TRIAL REGISTRATION: WF-0561/13.

High-flow nasal cannula oxygen versus non-invasive ventilation in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy--a prospective randomised trial.

INTRODUCTION: Critically ill patients with respiratory failure undergoing bronchoscopy have an increased risk of hypoxaemia-related complications. Previous studies have shown that in awake, hypoxaemic patients non-invasive ventilation (NIV) is helpful in preventing gas exchange deterioration during bronchoscopy. An alternative and increasingly used means of oxygen delivery is its application via high-flow nasal cannula (HFNC). This study was conducted to compare HFNC with NIV in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy. METHODS: Prospective randomised trial randomising 40 critically ill patients with hypoxaemic respiratory failure to receive either NIV or HFNC during bronchoscopy in the intensive care unit. RESULTS: After the initiation of NIV and HFNC, oxygen levels were significantly higher in the NIV group compared to the HFNC group. Two patients were unable to proceed to bronchoscopy after the institution of HFNC due to progressive hypoxaemia. During bronchoscopy, one patient on HFNC deteriorated due to intravenous sedation requiring non-invasive ventilatory support. Bronchoscopy was well tolerated in all other patients. There were no significant differences between the two groups regarding heart rate, mean arterial pressure and respiratory rate. Three patients in the NIV group and one patient in the HFNC group were intubated within 24 hours after the end of bronchoscopy (P = 0.29). CONCLUSIONS: The application of NIV was superior to HFNC with regard to oxygenation before, during and after bronchoscopy in patients with moderate to severe hypoxaemia. In patients with stable oxygenation under HFNC, subsequent bronchoscopy was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01870765. Registered 30 May 2013.

Rescue bedside laparotomy in the intensive care unit in patients too unstable for transport to the operating room.

INTRODUCTION: The prognoses of critically ill patients with a requirement for emergency laparotomy and severe respiratory and/or hemodynamic instability precluding transport to the operating room (OR) are often fatal without surgery. Attempting emergency surgery at the bedside might equally result in an adverse outcome. However, risk factors and predictors that could support clinical decision making have not been identified so far. This study describes the clinical characteristics, indicative pathophysiology and outcomes in patients undergoing resuscitative laparotomy in the intensive care unit (ICU). METHODS: This was a retrospective observational study of all critically ill adult patients undergoing resuscitative laparotomy in the ICUs of a German university hospital from January 2005 to July 2013. Clinical characteristics, risk factors, and treatments were compared between survivors and non-survivors. The primary endpoint was 28-day survival. RESULTS: A total of 41 patients with a median age of 64 (21 to 83) were included. The most frequent reasons for ICU admission were sepsis, pneumonia, and pancreatic surgery. All patients were mechanically ventilated, receiving vasopressors, and were in multiple organ failure. Twenty-nine patients (70.7%) were on renal replacement therapy and two patients (4.9%) on extracorporeal membrane oxygenation. The main reasons for surgery were suspected intra-abdominal bleeding (39.0%), suspected intestinal ischemia (24.4%) or abdominal compartment syndrome (24.4%). Twenty-eight-day, ICU and hospital mortalities were 75.6%, 80.5%, and 82.9%, respectively. In six out of ten patients (60%) who survived surgery for more than 28 days, bedside laparotomy was rated as a life-saving procedure by an interdisciplinary group of the investigators. CONCLUSIONS: These findings suggest that in selected critically ill patients with a vital indication for emergency laparotomy and severe cardiopulmonary instability precluding transport to the OR, a bedside resuscitative laparotomy in the ICU can be considered as a rescue procedure, even though very high mortality is to be expected.

Safety of percutaneous dilatational tracheostomy in patients on extracorporeal lung support.

PURPOSE: To evaluate the safety of percutaneous dilatational tracheostomy (PDT) in critically ill patients on an extracorporeal lung assist device requiring therapeutic anticoagulation. METHODS: This was a retrospective, observational study on all patients undergoing tracheostomy while on pumpless extracorporeal lung assist or extracorporeal membrane oxygenation in intensive care units of two university hospitals in Germany between 2007 and 2013. RESULTS: During the study period PDT was performed on 118 patients. The median platelet count, international normalized ratio, and activated partial thromboplastin time before tracheostomy were 126 × 10(9)/L (range 16-617 × 10(9)/L), 1.1 (0.9-2.0) and 49 s (28-117 s), respectively. Seventeen patients (14.4%) received a maximum of three bags of pooled platelets, and eight patients (6.8%) received a maximum of four units of fresh frozen plasma before the procedure. In all patients the administration of intravenous heparin was briefly paused periprocedurally. No periprocedural clotting complication within the extracorporeal circuit was observed. Two patients (1.7%) suffered from procedure-related major bleeding, with one patient requiring conversion to a surgical tracheostomy. Two pneumothoraces (1.7%) were related to the PDT. One patient (0.8%) had analgosedation-related hypotension with brief and successful cardiopulmonary resuscitation. Minor bleeding from the tracheostomy site occurred in 37 cases (31.4%). No fatality was attributable to tracheostomy. CONCLUSIONS: The complication rates of PDT in the patients on extracorporeal lung support were low and comparable to those of other critically ill patients. Based on these results, we conclude that PDT performed by experienced operators with careful optimization of the coagulation state is a relatively safe procedure and not contraindicated for this patient group.

Virtual autopsy as an alternative to traditional medical autopsy in the intensive care unit: a prospective cohort study.

BACKGROUND: Autopsy is an important educational and quality-control tool in the intensive care unit (ICU), but rates of traditional medical autopsies have declined worldwide. "Virtual" autopsy involving only advanced radiographic techniques might provide an alternative approach to postmortem examinations. OBJECTIVE: To assess the value of postmortem multidetector computed tomography as an alternative to medical autopsy. DESIGN: Prospective cohort study. (ClinicalTrials.gov registration number: NCT01040520) SETTING: 9 ICUs in a single academic medical center. Consent for both medical and virtual autopsies was sought from the families of all consecutive patients who died in the ICU between 1 January and 30 June 2010. Clinical records were reviewed to determine whether unsuspected autopsy findings would have altered care if known (major diagnosis) or would not have altered care (minor diagnosis). RESULTS: Of 285 patients, 47 underwent both virtual and medical autopsy. Of 196 clinical diagnoses made before death, 173 (88%) were identified by virtual autopsy and 183 (93%) by medical autopsy. Fourteen new major and 88 new minor diagnoses were detected by any autopsy method. The main diagnoses missed by virtual autopsy were cardiovascular events (9 of 72) and cancer (12 of 30). In contrast, medical autopsy missed 13 traumatic fractures and 2 pneumothoraces. Among 115 additional patients in whom only virtual autopsy was performed, 11 new major diagnoses were made. LIMITATION: Virtual autopsy was performed in only 57% of patients (n = 162); among this group, consent for traditional medical autopsy was obtained for only one third. CONCLUSION: Virtual autopsy may be useful for identifying diagnoses that traditionally have been identified by medical autopsy. This may also hold true, at least in part, for the educational aspect of medical autopsy (confirming antemortem clinical diagnoses). Further studies are required to confirm these preliminary results. PRIMARY FUNDING SOURCE: University Medical Center Hamburg-Eppendorf, Germany.

Rescue therapy with a pumpless extracorporeal lung assist device in a patient with acute interstitial lung disease and severe refractory hypercapnia.

Idiopathic interstitial pneumonia frequently causes severe pulmonary restriction that in turn makes mechanical ventilation difficult. We report the case of a 44-year-old woman who developed a refractory severe hypercapnic respiratory failure (P(aCO(2)) 281 mm Hg, pH 6.77) despite mechanical ventilation with high inspiratory pressure and PEEP. A pumpless extracorporeal lung assist device, Novalung, was used as rescue therapy for carbon dioxide removal, enabling lung-protective ventilation and normalization of life-threatening acidosis. Open lung biopsy revealed an idiopathic interstitial pneumonia with histological features of a nonspecific interstitial pneumonia. Corticosteroid therapy led to progressive improvement of pulmonary function, soon permitting cessation of mechanical ventilation and extracorporeal therapy. The patient was discharged from the intensive care unit after 20 days. This case demonstrates the successful use of pumpless extracorporeal lung assist as an alternative device to pump-driven extracorporeal membrane oxygenation in severe hypercapnic respiratory failure secondary to nonspecific interstitial pneumonia.

Diagnostic value of positron emission tomography combined with computed tomography for evaluating patients with septic shock of unknown origin.

PURPOSE: (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with computed tomography (CT) is a promising new tool for the identification of infectious foci. The aim of our work was to evaluate the diagnostic value of FDG-PET/CT in critically ill patients with septic shock of unknown origin. METHODS: We performed a single-center, 6-year retrospective evaluation of the value of FDG-PET/CT in critically ill patients with severe sepsis or septic shock of unknown origin. RESULTS: Eighteen patients underwent FDG-PET/CT. Microbiological tests (blood culture, urine, and respiratory secretions), chest x-rays, CT scans, and transesophageal echocardiography were performed on all patients before FDG-PET/CT scanning. Pathologic FDG accumulation could be demonstrated in 14 of 18 FDG-PET/CT scans. On a per-patient basis, 11 were "true positive," 3 were "false positive," 4 were true negative, and there were no false negatives. In 6 cases, the results of the PET/CT scan had direct therapeutic consequences (surgery, 2; pacemaker removal, 2; initiation of antibiotic therapy, 1; and prolonged antibiotic therapy, 1); 12 (66%) of the 18 patients survived to hospital discharge. CONCLUSIONS: The FDG-PET/CT is a valuable tool for the localization of infectious foci in critically ill patients with severe sepsis/septic shock in whom conventional diagnostic methods fail to detect these foci. Prospective studies with more patients are warranted to further evaluate the diagnostic accuracy and feasibility of this diagnostic tool in critically ill patients with severe sepsis.

Fiber optic bronchoscopy in patients with acute hypoxemic respiratory failure requiring noninvasive ventilation--a feasibility study.

INTRODUCTION: Noninvasive ventilation (NIV) is a standard procedure in selected patients with acute respiratory failure. Previous studies have used noninvasive ventilation to ensure adequate gas exchange during fiberoptic bronchoscopy in spontaneously breathing hypoxemic patients, thus avoiding endotracheal intubation. However, it is unknown whether bronchoscopy can be performed safely in patients with acute hypoxemic respiratory failure already in need of NIV prior to the decision for bronchoscopy. METHODS: We prospectively investigated 40 consecutive, critically ill, adult patients with acute hypoxemic respiratory failure (14 women, 26 men, age 61 ± 15 years, partial pressure for oxygen/fraction of inspired oxygen (PaO2/FiO2) < 300 under noninvasive ventilation, Simplified Acute Physiology scores (SAPS II) 47 ± 9.9 points). All patients required noninvasive ventilation prior to the decision to perform bronchoscopy (median 10.5 h; range 2.2 to 114). Blood gases, heart rate, blood pressure and ventilation were monitored before, during and up to 120 minutes after bronchoscopy. RESULTS: Bronchoscopy could be completed in all patients without subsequent complications. Oxygen saturation fell to < 90% in two patients (5%), and the lowest value during the procedure was 84%. The mean PaO2/FiO2 ratio improved from 176 ± 54 at baseline to 240 ± 130 (P < 0.001) at the end of bronchoscopy and 210 ± 79 after 120 minutes. The transient mean partial pressure of carbon dioxide in the arterial blood (PaCO2) increase was 9.4 ± 8.1 mm Hg. Four patients (10%) required endotracheal intubation during the first eight hours after the procedure. Bronchoalveolar lavage yielded diagnostic information in 26 of 38 (68%) patients. CONCLUSIONS: In critically ill patients with acute hypoxemic respiratory failure requiring noninvasive ventilation, bronchoscopy can be performed with an acceptable risk. Since these patients per se have a high likelihood of subsequent endotracheal intubation due to failure of NIV, bronchoscopy should only be performed by experienced clinicians.

Establishment of a benign meningioma cell line by hTERT-mediated immortalization.

Meningioma represents the most common intracranial tumor, but well-characterized cell lines derived from benign meningiomas are not available. A major reason for the lack of benign tumor cell lines is senescence of nonmalignant cells in vitro, while malignant cells are often immortal. We have developed a meningioma cell line by retrovirally transducing primary cells derived from a human WHO grade I meningothelial meningioma with the human telomerase reverse transcriptase (hTERT) gene, which enables bypassing cellular senescence. Five clones have been cultured for more than 21 months so far, while corresponding nontransfected cells ceased proliferation within 3 months. Quantitative RT-PCR and a telomeric repeat amplification protocol (TRAP) assay revealed high hTERT mRNA levels and high telomerase activity in all transduced populations, while nontransduced cells were negative. The average telomere size of transduced cells was considerably longer than that of parental cells and the biopsy specimen. One clone, designated Ben-Men-1, was characterized in more detail, and exhibited typical cytological, immunocytochemical, ultrastructural and genetical features of meningioma, including whorl formation, expression of epithelial membrane antigen, desmosomes and interdigitating cell processes, as well as -22q. Following subdural transplantation into nude mice, tumor tissue with typical histological features of meningothelial meningioma was found. We conclude that Ben-Men-1 represents an immortalized yet differentiated cell line useful for biological and therapeutical studies on meningioma.

Glioblastoma cells release factors that disrupt blood-brain barrier features.

The blood-brain barrier (BBB), mediated by endothelial tight junctions, is defective in malignant gliomas such as glioblastoma, resulting in cerebral edema and contrast enhancement upon neuroradiological examination. The mechanisms underlying BBB breakdown are essentially unknown. Since non-neoplastic astrocytes are required to induce BBB features of cerebral endothelial cells, it is conceivable that malignant astrocytes have lost this ability due to dedifferentiation. Alternatively, glioma cells might actively degrade previously intact BBB tight junctions. To examine the latter hypothesis, we have employed a transepithelial electrical resistance breakdown assay using monolayers of the C7 subclone of Madin-Darby canine kidney (MDCK-C7) cells forming tight junctions similar to those of BBB endothelial cells. We found that glioblastoma primary cells co-cultured with the MDCK-C7 monolayer (without direct contact of the two cell types) resulted in marked breakdown of electrical resistance, whereas primary cultures derived from low-grade gliomas (fibrillary astrocytoma, oligoastrocytoma) showed delayed or no effects. These results suggest that malignant gliomas have acquired the ability to actively degrade tight junctions by secreting soluble factors, eventually leading to BBB disruption within invaded brain tissue.