Central venous catheter tip positioning using ultrasound in pediatric patients-A prospective observational study.

BACKGROUND: In children, central venous catheter (CVC) placement is usually performed under ultrasound guidance for optimal visualization of vessels and reduction of puncture-related complications. Nevertheless, in many cases, additional radiographic examinations are performed to check the position of the catheter tip. AIM: The primary objective of this observational feasibility study was to determine the number of ultrasound-guided central venous catheter tips that can be identified in a subsequent position check using ultrasonography. Furthermore, we investigated the optimal ultrasound window, time expenditure, and success rate concerning puncture attempts and side effects. In addition, we compared the calculated and real insertion depths and analyzed the position of the catheter tip on postoperative radiographs with the tracheal bifurcation as a traditional landmark. METHODS: Ninety children with congenital heart defects who required a central venous line for cardiac surgery were included in this single-center study. After the insertion of the catheter, the optimal position of its tip was controlled using one of four predefined ultrasound windows. A chest radiograph was obtained postoperatively in accordance with hospital standards to check the catheter tip position determined by ultrasonography. RESULTS: The children had a median (IQR) age of 11.5 (4.0, 58.8) months and a mean (SD) BMI of 15.3 (2.91) kg/m2 Ultrasound visualization of the catheter tip was successful in 86/90 (95.6%) children (95% confidence interval [CI]: 91.3%, 99.8%). Postoperative radiographic examination showed that the catheter tip was in the desired position in 94.4% (95% CI: 89.7%, 99.2%) of the cases. None of the children needed the catheter tip position being corrected based on chest radiography. CONCLUSION: Additional radiation exposure after the placement of central venous catheters can be avoided with the correct interpretation of standardized ultrasound windows, especially in vulnerable children with cardiac disease.

Mechanistic Modeling of Reversed-Phase Chromatography of Insulins within the Temperature Range 10-40 °C.

In the many published theories on the retention in reversed-phase chromatography (RPC), the focus is generally on the effect of the concentration of the mobile phase modulator(s), although temperature is known to have a significant influence both on the retention and on the selectivity between the adsorbates. The aim of this study was to investigate and model the combined effects of the temperature and the modulator concentrations on RPC of three insulin variants. KCl and ethanol were used as mobile phase modulators, and the experiments were performed on two different adsorbents, with C18 and C4 ligands. The temperature dependence was investigated for the interval 10-40 °C and at two different concentrations of each modulator. The model is derived from the expression for the adsorption equilibrium, which assumes that ethanol is adsorbed to the ligands and displaced by the insulin molecules, similar to the displacement of counterions in the steric mass-action model for ion-exchange chromatography. A good model fit to the new linear-range retention data was achieved by only adding and calibrating three parameters for the temperature dependence of the equilibrium. We found that a lower temperature results in a longer retention time for all adsorbates, adsorbents, and modulator concentrations used in this study, indicating that the adsorption process is enthalpy-driven. A comparison of the different contributions to the temperature dependence revealed that the large contribution from the equilibrium constant is dampened by the significant contributions of the opposite sign from the changes in activity coefficients of insulins and ethanol. Neglect of these effects when comparing different adsorbents and modulators might yield incorrect conclusions because the equilibrium constant varies with both, whereas the activity coefficients should be independent of the adsorbent. As expected, the conditions that promote higher retention also give a higher selectivity between the adsorbates. Nonetheless, in relation to its effect on the retention, the influence of the KCl concentration on the selectivity was significantly stronger than that of the temperature or that of the ethanol concentration.

Pareto-optimal reversed-phase chromatography separation of three insulin variants with a solubility constraint.

With the shift of focus of the regulatory bodies, from fixed process conditions towards flexible ones based on process understanding, model-based optimization is becoming an important tool for process development within the biopharmaceutical industry. In this paper, a multi-objective optimization study of separation of three insulin variants by reversed-phase chromatography (RPC) is presented. The decision variables were the load factor, the concentrations of ethanol and KCl in the eluent, and the cut points for the product pooling. In addition to the purity constraints, a solubility constraint on the total insulin concentration was applied. The insulin solubility is a function of the ethanol concentration in the mobile phase, and the main aim was to investigate the effect of this constraint on the maximal productivity. Multi-objective optimization was performed with and without the solubility constraint, and visualized as Pareto fronts, showing the optimal combinations of the two objectives productivity and yield for each case. Comparison of the constrained and unconstrained Pareto fronts showed that the former diverges when the constraint becomes active, because the increase in productivity with decreasing yield is almost halted. Consequently, we suggest the operating point at which the total outlet concentration of insulin reaches the solubility limit as the most suitable one. According to the results from the constrained optimizations, the maximal productivity on the C4 adsorbent (0.41 kg/(m3 column h)) is less than half of that on the C18 adsorbent (0.87 kg/(m3 column h)). This is partly caused by the higher selectivity between the insulin variants on the C18 adsorbent, but the main reason is the difference in how the solubility constraint affects the processes. Since the optimal ethanol concentration for elution on the C18 adsorbent is higher than for the C4 one, the insulin solubility is also higher, allowing a higher pool concentration. An alternative method of finding the suggested operating point was also evaluated, and it was shown to give very satisfactory results for well-mapped Pareto fronts.

Mechanistic Modeling of Reversed-Phase Chromatography of Insulins with Potassium Chloride and Ethanol as Mobile-Phase Modulators.

The purpose of this study was to investigate the adsorption mechanism in reversed-phase chromatography (RPC) of proteins and to develop a model for the effect of dual mobile phase modulators-a salt and an organic solvent-on this process. Two different adsorption mechanisms were considered: (1) pure association of a protein molecule and one or more ligands and (2) displacement of the organic modulator, with which the adsorbent is saturated, by the protein upon association with one or more ligands. One model was then derived from each of the two considered mechanisms, combining thermodynamic theories on salting-in, RPC, and the solubility of proteins. The model was then applied to chromatographic data from an earlier report as well as supplementary data for solubility and vapor-liquid equilibria, and case-specific simplifications were made. We found that an adaptation of Kirkwood's electrostatic theories to hydrophobic interaction chromatography describes the observed effect of KCl well. Combining chromatographic and solubility data for one of the insulins, we concluded that the variation in the activity coefficient of the insulin with respect to the concentration of ethanol alone cannot describe its effect on retention. Consequently, one or more other phenomena must affect the adsorption process. Our second model fits the retention data well, supporting the hypothesis that ethanol is directly involved in the adsorption mechanism in this case. Using additional experiments at a high-protein load, we extended the linear-range equilibrium model into a dynamic model for preparative conditions. This model shows good agreement with the high-load data for one of the insulin variants, without any additional effects of the modulator concentrations on the adsorption capacity.

Combined effects of potassium chloride and ethanol as mobile phase modulators on hydrophobic interaction and reversed-phase chromatography of three insulin variants.

The two main chromatographic modes based on hydrophobicity, hydrophobic interaction chromatography (HIC) and reversed-phase chromatography (RPC), are widely used for both analytical and preparative chromatography of proteins in the pharmaceutical industry. Despite the extensive application of these separation methods, and the vast amount of studies performed on HIC and RPC over the decades, the underlying phenomena remain elusive. As part of a systematic study of the influence of mobile phase modulators in hydrophobicity-based chromatography, we have investigated the effects of both KCl and ethanol on the retention of three insulin variants on two HIC adsorbents and two RPC adsorbents. The focus was on the linear adsorption range, separating the modulator effects from the capacity effects, but some complementary experiments at higher load were included to further investigate observed phenomena. The results show that the modulators have the same effect on the two RPC adsorbents in the linear range, indicating that the modulator concentration only affects the activity of the solute in the mobile phase, and not that of the solute-ligand complex, or that of the ligand. Unfortunately, the HIC adsorbents did not show the same behavior. However, the insulin variants displayed a strong tendency toward self-association on both HIC adsorbents; on one in particular. Since this causes peak fronting, the retention is affected, and this could probably explain the lack of congruity. This conclusion was supported by the results from the non-linear range experiments which were indicative of double-layer adsorption on the HIC adsorbents, while the RPC adsorbents gave the anticipated increased tailing at higher load.

Hypertonic saline infusion during resuscitation from out-of-hospital cardiac arrest: a matched-pair study from the German Resuscitation Registry.

AIM: Survival rates after out-of-hospital-cardiac-arrest (OHCA) differ widely between EMS systems. Since hypertonic saline appears to improve long-term outcome after OHCA, some local EMS systems have included it in their treatment protocols for OHCA. Our first aim was to give a quality review of one of these protocols. Our second aim was to assess whether short-term survival improves when hypertonic saline is used in resuscitation after OHCA. METHODS: Matched pairs were identified for the independent "return of spontaneous circulation (ROSC) after cardiac arrest" (RACA) score variables and for use of ACD-CPR, adrenaline, and amiodarone from the German Resuscitation Registry (GRR) for January 2000 to March 2011. Patients received either 2mlkg(-1) hypertonic saline with hydroxyethyl starch (7.2% NaCl with 6% hydroxyethyl starch 200,000/0.5, HyperHAES® [HHS]) infused intravenously within 10min during CPR according to local treatment protocols or standard of care CPR (NON-HHS). The primary endpoint was admission to hospital rate (with spontaneous circulation); secondary endpoint was ROSC rate in relation to RACA score. RESULTS: 322 matched pairs were defined for 14 variables. Predicted ROSC-rate using RACA-score was similar in HHS (44.63%) and NON-HHS (43.63%; p=0.440). In contrast, 190 (59.0%) HHS patients achieved ROSC compared with only 136 NON-HHS patients (42.2%; χ(2): p<0.0001). Short term survival measured as rate of "admission to hospital with spontaneous circulation" was achieved in 169 HHS patients (52.5%) versus 108 NON-HHS patients (33.5%) (OR 2.19; 95%CI: 1.592-3.009; χ(2): p<0.0001). CONCLUSION: Locally implemented treatment protocols using hypertonic saline/HES after OHCA are safe and effective. Also, we verified that short-term survival rates were better in patients receiving HHS.

Randomised study of hypertonic saline infusion during resuscitation from out-of-hospital cardiac arrest.

AIM OF THE STUDY: Animal models of hypertonic saline infusion during cardiopulmonary resuscitation (CPR) improve survival, as well as myocardial and cerebral perfusion during CPR. We studied the effect of hypertonic saline infusion during CPR (Guidelines 2000) on survival to hospital admission and hospital discharge, and neurological outcome on hospital discharge. METHODS: The study was performed by the EMS of Bonn, Germany, with ethical committee approval. Study inclusion criteria were non-traumatic out-of-hospital cardiac arrest, aged 18-80 years, and given of adrenaline (epinephrine) during CPR. Patients were randomly infused 2 mlkg(-1) HHS (7.2% NaCl with 6% hydroxyethyl starch 200,000/0.5 [HES]) or HES over 10 min. RESULTS: 203 patients were randomised between May 2001 and June 2004. After HHS infusion, plasma sodium concentration increased significantly to 162±36 mmoll(-1) at 10 min after infusion and decreased to near normal (144±6 mmoll(-1)) at hospital admission. Survival to hospital admission and hospital discharge was similar in both groups (50/100 HHS vs. 49/103 HES for hospital admission, 23/100 HHS vs. 22/103 HES for hospital discharge). There was a small improvement in neurological outcome in survivors on discharge (cerebral performance category 1 or 2) in the HHS group compared to the HES group (13/100 HHS vs. 5/100 HES, p<0.05, odds-ratio 2.9, 95% confidence interval 1.004-8.5). CONCLUSION: Hypertonic saline infusion during CPR using Guidelines 2000 did not improve survival to hospital admission or hospital discharge. There was a small improvement with hypertonic saline in the secondary endpoint of neurological outcome on discharge in survivors. Further adequately powered studies using current guidelines are needed.

The impact of response time reliability on CPR incidence and resuscitation success: a benchmark study from the German Resuscitation Registry.

INTRODUCTION: Sudden cardiac arrest is one of the most frequent causes of death in the world. In highly qualified emergency medical service (EMS) systems, including well trained emergency physicians, spontaneous circulation may be restored in up to 53% of patients at least until admission to hospital. Compared with these highly qualified EMS systems, in other systems markedly lower success rates are observed. These data clearly show that there are considerable differences between EMS systems concerning treatment success following cardiac arrest and resuscitation, although in all systems international guidelines for resuscitation are used. This study investigates the impact of response time reliability (RTR) on cardio pulmonary resuscitation (CPR) incidence and resuscitation success using return of spontaneous circulation (ROSC) after cardiac arrest (RACA) score and data from seven German EMS systems participating in the German Resuscitation Registry. METHODS: Anonymized patient data after out of hospital cardiac arrest from 2006 to 2009 of seven EMS systems in Germany were analysed to socioeconomic factors (population, area, EMS unit hours), process quality (response time reliability, CPR incidence, special CPR measures, prehospital cooling), patient factors (age, gender, cause of cardiac arrest, bystander CPR). Endpoints were defined as ROSC, admission to hospital, 24 hour survival and hospital discharge rate. For statistical analyses, chi-square, odds-ratio and Bonferroni correction were used. RESULTS: 2,330 prehospital CPR from seven centres were included in this analysis. Incidence of sudden cardiac arrest differs from 36.0 to 65.1/100,000 inhabitants/year. We identified two EMS systems (RTR < 70%) reaching the patients within eight minutes in 62.0% and 65.6% while the other five EMS systems (RTR > 70%) achieved 70.4 up to 95.5%. EMS systems arriving relatively later at the patients side (RTR < 70%) less frequently initiate CPR and admit fewer patients alive to hospital (calculated per 100,000 inhabitants/year) (CPR incidence (1/100,000 inhabitants/year) RTR > 70% = 57.2 vs RTR < 70% = 36.1, OR = 1.586 (99% CI = 1.383 to 1.819); P < 0.01) (admitted to hospital with ROSC (1/100,000 inhabitants/year) RTR > 70% = 24.4 vs RTR < 70% = 15.6, OR = 1.57 (99% CI = 1.274 to 1.935); P < 0.01). Using ROSC rate and the multivariate RACA score to predict outcome, the two groups did not differ, but ROSC rates were higher than predicted in both groups (ROSC RTR > 70% = 46.6% vs RTR < 70% = 47.3%, OR = 0.971 (95% CI = 0.787 to 1.196); P = n.s.) (ROSC RACA RTR > 70% = 42.4% vs RTR < 70% = 39.5%, OR = 1.127 (95% CI = 0.911 to 1.395); P = n.s.). CONCLUSION: This study demonstrates that on the level of EMS systems, faster ones will more often initiate CPR and will increase number of patients admitted to hospital alive. Furthermore it is shown that with very different approaches, all adhering to and intensely training in the ERC guidelines 2005, superior and, according to international comparison, excellent success rates following resuscitation may be achieved.

Out-of-hospital cardiopulmonary resuscitation with the AutoPulse system: a prospective observational study with a new load-distributing band chest compression device.

OBJECTIVE: To evaluate the effectiveness, the safety, and the practicability of the new automated load-distributing band resuscitation device AutoPulse in out-of-hospital cardiac arrest in the midsized urban emergency service of Bonn city. STUDY DESIGN: Prospective, observational study. METHODS: Measurements of effectiveness were the proportion of patients with a return of spontaneous circulation (ROSC) and end-tidal carbon-dioxide (etCO(2)) values during cardiopulmonary resuscitation (CPR). The indications of safety was the proportion of injuries caused by the device, and practicability was assessed by the measurement of the time taken to setup the AutoPulse. RESULTS: Forty-six patients were resuscitated with the device from September 2004 to May 2005. In 25 patients (54.3%) ROSC was achieved, 18 patients (39.1%) were admitted to intensive care unit (ICU), and 10 patients (21.8%) were discharged from ICU. End-tidal capnography showed significantly higher etCO(2) values in patients with ROSC than in patients without ROSC. The mean time to setup the AutoPulse was 4.7+/-5.9 min, but activation of the device after arrival at the scene in 2 min or less was possible in 67.4%. No injuries were detected after use of the AutoPulse-CPR. CONCLUSION: The AutoPulse system is an effective and safe mechanical CPR device useful in out-of-hospital cardiac arrest CPR. Automated CPR devices may play an increasingly important role in CPR in the future because they assure continuous chest compressions of a constant quality.

Hypertonic saline during CPR: Feasibility and safety of a new protocol of fluid management during resuscitation.

BACKGROUND AND PURPOSE: In experimental studies infusion of hypertonic saline during cardiopulmonary resuscitation (CPR) increased resuscitation success rate and improved myocardial and cerebral reperfusion during CPR. We tested the feasibility and the safety of this new therapeutic measure in a randomised, preclinical pilot study. METHODS: The study was performed in the EMS system of Bonn after approval of the local ethical committee. Study inclusion criteria were out-of-hospital cardiac arrest (CA) of non-traumatic origin, age > or =18 years, application of adrenaline (epinephrine) during CPR, duration of CA < or = 15 min, and estimated body weight < or = 125 kg. Patients randomly received 2 ml/kg/10 min HHS (7.2% NaCl with 6% hydroxy ethyl starch 200,000/0.5 [HES]) or HES alone. Haemoglobin, blood gases, plasma sodium and potassium concentrations were measured before and 10 min after infusion, and after admission to hospital. Feasibility and safety of the new fluid management was evaluated by looking for side effects and determination of resuscitation success and admission rates. RESULTS: Sixty-six patients were included. After infusion of HHS, plasma sodium concentration increased to 168+/-29 mmol/l at 10 min after application but already decreased to near normal (147+/-5.5 mmol/l) at admission to hospital. Patients receiving HHS showed a trend to higher resuscitation success and hospital admission rates (ROSC: HHS 66.7%, HES 51.5%, p = 0.21; admission: HHS 57.6%, HES 39.4%, p = 0.14). The benefit of HHS was more pronounced if duration of untreated CA was >6 min or if initial rhythm was asystole or pulseless electrical activity (PEA). Negative side-effects were not observed after HHS. CONCLUSIONS: HHS after CA is feasible and safe and might improve short term survival after CPR. However, whether giving HHS could be a useful measure to increase resuscitation success after out-of-hospital CA requires a larger preclinical trial.

Effects of hypertonic versus isotonic infusion therapy on regional cerebral blood flow after experimental cardiac arrest cardiopulmonary resuscitation in pigs.

OBJECTIVE: To evaluate the effects of hypertonic, isooncotic, and isotonic infusion therapy on cerebral blood flow (CBF) during and after cardiopulmonary resuscitation (CPR) from experimental cardiac arrest (CA). METHODS: In 32 domestic swine (13-23 kg) open chest CPR was initiated after 8 min of ventricular fibrillation. With the onset of CPR animals randomly received 2 ml/kg per 10 min of either hypertonic saline (HS: 7.2% NaCl), hypertonic-isooncotic HES-saline (HHS: 7.2% NaCl in 6% HES 200,000/0.5), isooncotic HES (6% HES 200,000/0.5), or isotonic (normal) saline (NS: 0.9% NaCl). Haemodynamic variables were monitored continuously, and coloured microspheres were used to measure CBF quantitatively before CA, during CPR, and 20, 90 and 240 min after restoration of spontaneous circulation (ROSC). RESULTS: In HES/NaCl treated animals, CBF significantly decreased during CPR compared to the prearrest level (P < 0.01, respectively; MANOVA). In contrast, CBF was sustained during CPR in HS/HHS treated animals and significantly higher compared to animals receiving NS (P < 0.05, respectively). During recirculation severe postischaemic hypoperfusion as indicated by a decrease of CBF below the prearrest level, was present only in animals receiving HES and NS. CONCLUSIONS: Hypertonic solutions (HS/HHS) applied during internal cardiac massage enhanced CBF during CPR and after ROSC.

Hypertonic saline improves myocardial blood flow during CPR, but is not enhanced further by the addition of hydroxy ethyl starch.

OBJECTIVE: To evaluate the effects of hypertonic saline (HS) and/or hydroxy ethyl starch (HES) on myocardial perfusion pressure (MPP) and blood flow (MBF), and cardiac index (CI) during and after cardiopulmonary resuscitation (CPR). METHODS: In 32 domestic swine (13-23.5 kg) open chest CPR was initiated after 8 min of ventricular fibrillation. With the onset of CPR animals randomly received 2 ml/kg per 10 min of either HS (7.2% NaCl) or hypertonic HES saline (HHS) (6% HES 200000/0.5 in 7.2% NaCl) or HES (6% HES 200000/0.5 in 0.9% NaCl) or normal saline (NS) (0.9% NaCl). Haemodynamic variables were monitored continuously, and coloured microspheres were used to measure MBF and CI before cardiac arrest, during CPR, and 20, 90 and 240 min after restoration of spontaneous circulation. RESULTS: During CPR HS and HHS significantly increased MBF in comparison to HES and NS (P<0.05, respectively, MANOVA). MPP and CI were not different between the groups. HS and HHS significantly increased resuscitation success and the 240 min survival rate. 14/15 animals receiving HS or HHS and 8/17 after HES-or NS -infusion survived the observation period (P<0.05, chi(2)-test). No negative side effects of HS with or without the addition of HES were observed. CONCLUSIONS: Hypertonic solutions (HS and HHS) applied during internal cardiac massage enhanced MBF and significantly increased resuscitation success and survival rate. Addition of HES to HS did not further improve the positive haemodynamic effects of HS alone.