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Background. Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. Methods. A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. Results. Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41–13.79; P < .001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21–13.39; P < .001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64–18.94; P < .001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04–0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4–3.8; P = .001). Mycograb was well tolerated. Conclusions. Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis.

The aim was to develop a practical method for estimation of the volume of pleural effusion using ultrasonography in mechanically ventilated patients. Prospective observational study. 20-bed general intensive care unit in the university hospital. 81 patients were included after initial suspicion of pleural fluid on chest supine X-ray and pre-puncture ultrasound confirming effusion. Patients with thoracic deformities, post-lung surgery, with diaphragm pathology, haemothorax, empyema and with incomplete aspiration of pleural fluid on post-puncture ultrasound were excluded. Patients were supine with mild trunk elevation at 15 degrees . Probe was moved upwards in posterior axillary line, and transverse section perpendicular to the body axis was obtained with pleural separation visible at lung base. The maximal distance between parietal and visceral pleura (Sep) in end-expiration was recorded. Thoracentesis was performed at previous probe position and volume of pleural fluid (V) recorded. 92 effusions were evaluated and drained; 11 (12%) were excluded for incomplete aspiration. Success rate of obtaining fluid under ultrasound guidance was 100%; the incidence of pneumothorax or bleeding was zero. Mean Sep was 35+/-13 mm. Mean V was 658+/-320 ml. Significant positive correlation between both Sep and V was found: r=0.72; r(2)=0.52; p<0.001. The amount of pleural fluid volume can be estimated with the simplified formula: V (ml)=20 x Sep (mm). Mean prediction error of V using Sep was 158.4+/-160.6 ml. Easy quantification of pleural fluid may help to decide about performing thoracentesis in high-risk patients, although thoracentesis under ultrasound guidance appears to be a safe procedure.

Brain perfusion is reduced early after subarachnoid hemorrhage (SAH) due to intracranial hypertension and early vasospasm. The contribution of these two mechanisms is unknown. By performing a prophylactic decompressive craniectomy (DC) in a rat model of SAH we aimed to study brain perfusion after the component of intracranial hypertension has been eliminated. We used 2x2 factorial design, where rats received either decompressive craniectomy or sham operation followed by injection of 250 µl of blood or normal saline into prechiasmatic cistern. The cortical perfusion has been continually measured by laser speckle-contrast analysis for 30 min. Injection of blood caused a sudden increase of intracranial pressure (ICP) and drop of cerebral perfusion, which returned to baseline within 6 min. DC effectively prevented the rise of ICP, but brain perfusion after SAH was significantly lower and took longer to normalize compared to non-DC animals due to increased cerebral vascular resistance, which lasted throughout 30 min experimental period. Our findings suggest that intracranial hypertension plays dominant role in the very early hypoperfusion after SAH whilst the role of early vasospasm is only minor. Prophylactic DC effectively maintained cerebral perfusion pressure, but worsened cerebral perfusion by increased vascular resistance.

Causes of early hypoperfusion after subarachnoid hemorrhage (SAH) include intracranial hypertension as well as vasoconstriction. The aim of the study was to assess the effect of intracerebroventricular (ICV) administration of sodium nitroprusside (SNP) on early hypoperfusion after SAH. Male Wistar rats (220-240 g) were used, SAH group received 250 μl of fresh autologous arterial blood into the prechiasmatic cistern; sham-operated animals received 250 μl of isotonic solution. Therapeutic intervention: ICV administration of 10 μg SNP; 5 μl 5 % glucose (SNP vehicle) and untreated control. Brain perfusion and invasive blood pressure were monitored for 30 min during and after induction of SAH. Despite SNP caused increase of perfusion in sham-operated animals, no response was observed in half of SAH animals. The other half developed hypotension accompanied by brain hypoperfusion. There was no difference between brain perfusion in SNP-treated, glucose-treated and untreated SAH animals during the monitored period. We did not observe expected beneficial effect of ICV administration of SNP after SAH. Moreover, half of the SNP-treated animals developed serious hypotension which led to brain hypoperfusion. This is the important finding showing that this is not the option for early management in patient after SAH.

Background. When combined with ceftazidime, the novel non–β-lactam β-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections. Efficacy and safety of ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239). Methods. The primary end point was clinical cure at test-of-cure visit 28–35 days after randomization, assessed by noninferiority of ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to-treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of −12.5%. Results. Ceftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, −3.5%; 95% confidence interval −8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (−2.4%; −6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (−0.8%; −4.61 to 2.89). The clinical cure rate with ceftazidime-avibactam plus metronidazole for ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups. Conclusions. Ceftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens. The safety profile of ceftazidime-avibactam plus metronidazole was consistent with that previously observed with ceftazidime alone. Clinical Trials Registration. NCT01499290 and NCT01500239.

Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, compared with meropenem in a multinational, phase 3, double-blind, non-inferiority trial (REPROVE). Adults with nosocomial pneumonia (including ventilator-associated pneumonia), enrolled at 136 centres in 23 countries, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) or 1000 mg meropenem (by 30-min intravenous infusion every 8 h) for 7–14 days; regimens were adjusted for renal function. Computer-generated randomisation codes were stratified by infection type and geographical region with a block size of four. Participants and investigators were masked to treatment assignment. The primary endpoint was clinical cure at the test-of-cure visit (21–25 days after randomisation). Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference was greater than −12·5% in the coprimary clinically modified intention-to-treat and clinically evaluable populations. This trial is registered with ClinicalTrials.gov (NCT01808092) and EudraCT (2012-004006-96). Between April 13, 2013, and Dec 11, 2015, 879 patients were randomly assigned. 808 patients were included in the safety population, 726 were included in the clinically modified intention-to-treat population, and 527 were included in the clinically evaluable population. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible. In the clinically modified intention-to-treat population, 245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group (difference −4·2% [95% CI −10·8 to 2·5]). In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group (difference −0·7% [95% CI −7·9 to 6·4]). Adverse events occurred in 302 (75%) of 405 patients in the ceftazidime-avibactam group versus 299 (74%) of 403 in the meropenem group (safety population), and were mostly mild or moderate in intensity and unrelated to study treatment. Serious adverse events occurred in 75 (19%) patients in the ceftazidime-avibactam group and 54 (13%) patients in the meropenem group. Four serious adverse events (all in the ceftazidime-avibactam group) were judged to be treatment related. Ceftazidime-avibactam was non-inferior to meropenem in the treatment of nosocomial pneumonia. These results support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens. AstraZeneca.

High frequency oscillatory ventilation (HFOV), contrary to conventional ventilation, enables a safe increase in tidal volume (VT) without endangering alveoli by volutrauma or barotrauma. The aim of the study is to introduce the concept of normocapnic high frequency oscillatory hyperventilation and to assess its effect upon oxygen gain under experimental conditions. Laboratory pigs (n=9) were investigated under total intravenous anesthesia in three phases. Phase 1: Initial volume controlled HFOV period. Phase 2: Hyperventilation – VT was increased by (46±12) % when compared to normocapnic VT during phase 1. All other ventilatory parameters were unchanged. A significant increase in PaO2 (by 3.75±0.52 kPa, p<0.001) and decrease in PaCO2 (by –2.05±0.31 kPa, p<0.001) were obtained. Phase 3: Normocapnia during hyperventilation was achieved by an iterative increase in the CO2 fraction in the inspiratory gas by a CO2 admixture. All ventilatory parameters were unchanged. A significant increase in PaO2 (by 3.79±0.73 kPa, p<0.001), similar to that which was observed in phase 2, was preserved in phase 3 whereas normocapnia was fully re-established. The concept of high frequency normocapnic hyperventilation offers a lung protective strategy that significantly improves oxygenation whilst preserving normocapnia.

The recently reported differences between pulmonary and extrapulmonary acute respiratory distress syndromes (ARDS(p), ARDS(exp)) are the main reasons of scientific discussion on potential differences in the effects of current ventilatory strategies. The aim of this study is to assess whether the presence of ARDS(p) or ARDS(exp) can differently affect the beneficial effects of high-frequency oscillatory ventilation (HFOV) upon physiological and clinical parameters. Thirty adults fulfilling the ARDS criteria were indicated for HFOV in case of failure of conventional ventilation strategy. According to the ARDS type, each patient was included either in the group of patients with ARDS(p) or ARDS(exp). Six hours after normocapnic HFOV introduction, there was no significant increase in PaO2/F(I)O2 in ARDS(p) group (from 129+/-47 to 133+/-50 Torr), but a significant improvement was found in ARDS(exp) (from 114+/-54 to 200+/-65 Torr, p<0.01). Despite the insignificant difference in the latest mean airway pressure (MAP) on conventional mechanical ventilation (CMV) between both groups, initial optimal continuous distension pressure (CDP) for the best PaO2/F(I)O2 during HFOV was 2.0+/-0.6 kPa in ARDS(p) and 2.8+/-0.6 kPa in ARDS(exp) (p<0.01). HFOV recruits and thus it is more effective in ARDS(exp). ARDS(exp) patients require higher CDP levels than ARDS(p) patients. The testing period for positive effect of HFOV is recommended not to be longer than 24 hours.

To determine the relationship between the degree of tricuspid regurgitation (TR) and accuracy of cardiac output measurement by thermodilution in mechanically ventilated patients. DESIGN AND SETTING. Prospective observational study in a 20-bed general intensive care unit in the university hospital. We examined 27 patients (not undergoing cardiac surgery): 8 with no or 1st degree TR, 9 with 2nd degree, and 10 with 3rd degree TR. All patients were measured twice using simultaneously transesophageal echocardiography and pulmonary artery catheter for cardiac output. Continuous Doppler measurements were taken in the left ventricular outflow tract at the level of the aortic valve. Cardiac output was calculated by multiplying the velocity-time integral by aortic valve area and heart rate. Simultaneous pulmonary artery catheter measurements were taken averaging the results of the three 10-cc boluses of iced saline. The difference between the methods was 0.5+/-1.1 l/min (mean +/-2 SD) in patients with no or 1st degree TR (r=0.96), 0.8+/-2.0 l/min in those with 2nd degree TR (r=0.92), and 1.9+/-2.3 l/min in those with 3rd degree TR (r=0.69). A high degree of TR is associated with underestimation of cardiac output measured by thermodilution.

The relationship between the volume of distribution, assessed according to the two-compartmental pharmacokinetic model, and extracellular water estimated by bioimpedance was studied in mechanically ventilated patients with sepsis and capillary leak. A prospective observational study was performed in a twenty-bed general intensive care unit in the university hospital. Patients received either vancomycin (n=16) or netilmicin (n=12) for more than 48 hours. Those with ascites, pleural effusion, on renal replacement therapy or with haemodynamic instability were excluded. Serum concentrations of drugs were taken for pharmacokinetic analysis before, 1 hour and 4 hours after the 30 minute infusion. Bioimpedance measurement was performed at the time of the third sampling. The protocol was repeated after 24 hours. Fluid balance during the 24 hour interval was recorded. Extracellular water was increased and represented 45.6 to 46.6% of total body water. Fluid balance correlated with the change of extracellular water (r=0.82, P<0.0001) and total body water (r=0.74, P<0.0001). Volumes of distribution of vancomycin (0.677±0.339 l/kg) and netilmicin (0.505±0.172 l/kg) were increased compared to normal values. A correlation was demonstrated between volume of distribution (Vd area ) of vancomycin and extra cellular water/total body ratio (r=0.70, P<0.0001). The central compartment distribution volume (V1) of netilmicin correlated with extracellular water/total body water ratio (r=0.60, P<0.003). Serum concentrations above the recommended therapeutic range were detected in 81.2% of patients on vancomycin and in 50% of patients on netilmicin. Increased volumes of distribution can be estimated by the bioimpedance measurements but are not associated with requirements for higher dosage of the glycopeptide or aminoglycoside antibiotics.