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Drotrecogin alfa (activated) ...
a sad final fizzle to a rollercoaster party
Following the failure of PROWESS-SHOCK to demonstrate efficacy, Eli Lilly and Company withdrew drotrecogin alfa (activated) from the worldwide market. Drotrecogin was initially approved after the original trial, PROWESS, was stopped early for overwhelming efficacy. These events prompt consideration of both the initial approval decision and the later decision to withdraw. It is regrettable that the initial decision was made largely on a single trial that was stopped early. However, the decision to approve was within the bounds of normal regulatory practice and was made by many approval bodies around the world.
Furthermore, the overall withdrawal rate of approved drugs remains very low. The decision to withdraw was a voluntary decision by Eli Lilly and Company and likely reflected key business considerations. Drotrecogin does have important biologic effects, and it is probable that we do not know how best to select patients who would benefit. Overall, there may still be a small advantage to drotrecogin alfa, even used non-selectively, but the costs of determining such an effect with adequate certainty are likely prohibitive, and the point is now moot. In the future, we should consider ways to make clinical trials easier and quicker so that more information can be available in a timely manner when considering regulatory approval. At the same time, more sophisticated selection of patients seems key if we are to most wisely test agents designed to manipulate the septic host response.
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Optimization of oxygen delivery during high-risk surgery: keep the concept but refining goals for inotrope infusion?
We read with great interest the recent study by Lobo and colleagues stating that fluid restriction during optimization of oxygen delivery (DO2) using dobutamine improves patient outcome after major surgery. Previous studies have shown that haemodynamic optimization using either an individualized goal-directed fluid substitution or inotrope to maximize DO2 reduces postoperative morbidity and hospital length of stay. Although the study brings important new insights, we believe however that some limits should be pointed.
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Clinical experience with power injectable peripherally inserted central catheters in intensive care patients
IntroductionIn intensive care units (ICU), peripherally inserted central catheters (PICC) may be an alternative option to standard central venous catheters, particularly in patients with coagulation disorders or at high risk for infection. Some limits of PICCs (such as low flow rates) may be overcome by the use of power-injectable catheters.MethodWe have retrospectively reviewed all the power injectable PICCs inserted in adult and pediatric patients in the ICU during a 12-month period, focusing on the rate of complications at insertion and during maintenance.
Results:
We have collected 89 power injectable PICCs (in adults and in children), both multiple and single lumen. All insertions were successful. There were no major complications at insertion and no episodes of catheter-related blood stream infection. Non-infective complications during management were not clinically significant. There was one episode of symptomatic thrombosis during the stay in ICU and one episode after transfer of the patient in a non-intensive ward.
Conclusions:
Power injectable PICCs have many advantages in the ICU: they can be used as multi-purpose central lines for any type of infusion including high flow infusion, for hemodynamic monitoring, and for high-pressure injection of contrast media during radiological procedures. Their insertion is successful in 100% of cases and is not associated with significant risks, even in patients with coagulation disorders. Their maintenance is associated with an extremely low rate of infective and non-infective complications.
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A prospective randomized open-label crossover trial of regional citrate anticoagulation vs. anticoagulation free
liver dialysis by the Molecular Adsorbents Recirculating System
IntroductionThe Molecular Adsorbent Recycling System (MARS) is used to treat patients with liver failure. Observational data suggest that citrate anticoagulation during MARS is feasible. Comparative studies on the optimal anticoagulation regimen during MARS are lacking. The aim of the current study was to evaluate two heparin-free anticoagulation regimens.
Methods:
We performed a prospective randomized open-label crossover study of regional citrate anticoagulation against no anticoagulation. Ten patients (age 55 +/- 11 years) with liver failure undergoing MARS treatment were included. The primary endpoint was completion of MARS sessions. Secondary endpoints included treatment efficacy and safety. Longevity of MARS treatment was plotted as a Kaplan-Meier estimate. Fisher's exact test was used for contingency table analysis.
Results:
Of a total of 27 6-hour sessions, four sessions had to be terminated prematurely, three due to occlusive clotting of the extracorporeal circuit and one due to uncontrollable bleeding from the vascular access site. All four events occurred in the group without anticoagulation. Between group comparison demonstrated citrate anticoagulation to significantly increase the likelihood of completed MARS treatment (Fisher's exact test, P 0.04). This translates into higher bilirubin reduction ratios when citrate was applied (reduction ratio 0.25 vs. 0.15, P 0.02). Systemic ionized calcium concentrations were significantly reduced during citrate anticoagulation (P<0.001) but remained within a safe range. We observed no major adverse events.
Conclusions:
Regional citrate anticoagulation in patients with liver failure is feasible. Citrate anticoagulation provides superior patency of the extracorporeal circuit. Avoidance of anticoagulation during MARS results in significant loss of treatment efficacy, due to treatment downtime. Additional studies are required to identify the optimal anticoagulation regimen for extracorporeal circulation in patients with liver failure.
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Age of blood and recipient factors determine the severity of transfusion-related acute lung injury (TRALI)
IntroductionCritical care patients frequently receive blood transfusions. Some reports show an association between aged or stored blood and increased morbidity and mortality, including the development of transfusion-related acute lung injury (TRALI). However, the existence of conflicting data endorses the need for research to either reject this association, or to confirm it and elucidate the underlying mechanisms.
Methods:
Twenty-eight sheep were randomised into two groups-- receiving saline or lipopolysaccharide (LPS). Sheep were further randomised to also receive transfusion of pooled and heat-inactivated supernatant from fresh (day 1) or stored (day 42) non-leucoreduced human packed red blood cells (PRBC) or infusion of saline. TRALI was defined by hypoxaemia during or within 2 hours of transfusion and histological evidence of pulmonary oedema. Regression modelling compared physiology between groups, and to a previous study using stored platelet concentrates (PLT). Samples of the transfused blood products also underwent cytokine array and biochemical analyses, and their neutrophil priming ability was measured in vitro.
Results:
TRALI did not develop in sheep that first received saline-infusion. In contrast, 80% of sheep that first received LPS-infusion developed TRALI following transfusion with "stored PRBC." The decreased mean arterial pressure and cardiac output as well as increased central venous pressure and body temperature were more severe for TRALI induced by "stored PRBC" than by "stored PLT." Storage-related accumulation of several factors was demonstrated in both "stored PRBC" and "stored PLT", and was associated with increased in vitro neutrophil priming. Concentrations of several factors were higher in the "stored PRBC" than in the "stored PLT," however there was no difference to neutrophil priming in vitro.
Conclusions:
In this in vivo ovine model, both recipient and blood product factors contributed to the development of TRALI. Sick (LPS infused) sheep rather than healthy (saline infused) sheep predominantly developed TRALI when transfused with supernatant from stored but not fresh PRBC. "Stored PRBC" induced a more severe injury than "stored PLT" and had a different storage lesion profile, suggesting that these outcomes may be associated with storage lesion factors unique to each blood product type. Therefore, the transfusion of fresh rather than stored PRBC may minimise the risk of TRALI.
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Pragmatic fluid optimization in high risk surgery patients: when pragmatism dilutes the benefits
There is increasing evidence that hemodynamic optimization by fluid loading, particularly when performed in the early phase of surgery, is beneficial in high-risk surgery patients: it leads to a reduction in postoperative complications and even to improved long-term outcome. However, it is also true that goal- directed strategies of fluid optimization focusing on cardiac output optimization have not been applied in the clinical routine of many institutions. Reasons are manifold: disbelief in the level of evidence and on the accuracy and practicability of the required monitoring systems, and economics. The FOCCUS trial examined perioperative fluid optimization with a very basic approach: a standardized volume load with 25 ml/kg crystalloids over 6 hours immediately prior to scheduled surgery in high-risk patients. The hypothesis was that this intervention would lead to a compensation of preoperative fluid deficit caused by overnight fasting, and would result in improved perioperative fluid homeostasis with less postoperative complications and earlier hospital discharge. However, the primary study endpoints did not improve significantly. This observation points towards the facts that: firstly, the differentiation between interstitial fluid deficit caused by fasting and intravascular volume loss due to acute blood loss must be recognized in treatment strategies; secondly, the type of fluid replacement may play an important role; and thirdly, protocolized treatment strategies should also always be tailored to suit the patients' individual needs in every individual clinical situation.
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Effect of acute hyperventilation on the venous-arterial PCO2 difference
I read with great interest the article by Morel et al. [1], suggesting that acute changes in the arterial partial pressure of carbon dioxide (PaCO2) can affect the venous-arterial difference in carbon dioxide tension ([increment]CO2). Ten ventilated and hemodynamically stable patients were included after elective cardiac surgery. Hypocapnia was induced by increasing of respiratory rate. The authors found that a decrease of PaCO2 was associated with a significant increase in [increment]CO2. This was explained by the fact that acute hypocapnia resulted in systemic vasoconstriction, thus decreasing the elimination of the total CO2 produced by the peripheral tissues, and therefore increased the gap. However, as all patients were monitored with a pulmonary artery catheter (PAC), the authors should have shown if there were any increase in systemic vascular resistance to support their hypothesize. Furthermore, there is a possible another explanation of the increase of [increment]CO2 induced by the decrease in PaCO2. Indeed, acute respiratory alkalosis has been shown to increase systemic oxygen consumption and CO2 production [2,3]. Thus, for a given venous blood flow the increase of tissue CO2 production should increase the PCO2 gap.On the other hand, it is unclear why the authors have used the central venous sample to calculate [increment]CO2 instead of the mixed venous sample (PAC), which is the gold standard. If a PAC is in place, even though the mixed and central PCO2 difference showed a good agreement [4], the clinical utility of an alternative method of measurement is diminished. Nevertheless, I agree that acute hyperventilation could be a potential limitation of clinical application of the [increment]CO2.
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Low doses of esmolol and phenylephrine act as diuretics during intravenous anesthesia
IntroductionThe renal clearance of infused crystalloid fluid is very low during anaesthesia and surgery, but experiments in conscious sheep indicate that the renal fluid clearance might approach a normal rate when the adrenergic balance is modified.
Methods:
60 females (mean age, 32 years) undergoing laparoscopic gynecological surgery were randomized to control group and received only the conventional anesthetic drugs and 20 ml/kg of lactated Ringer's over 30 mins. The others were also given an infusion of 50 ug/kg/min of esmolol (beta1-receptor blocker) or 0.01 ug/kg/min of phenylephrine (alpha1-adrenergic agonist) over 3 hours. The distribution and elimination of infused fluid was studied by volume kinetic analysis based on urinary excretion and blood hemoglobin level.
Results:
Both drugs significantly increased urinary excretion while heart rate and arterial pressure remained largely unaffected. The urine flow during non-surgery was 43, 147, and 176 ml in the control, esmolol, and phenylephrine groups, respectively (medians, P<0.03). When surgery had started the corresponding values were 34, 65 and 61 ml (P<0.04). At 3 hours, an average of 9%, 20%, and 25% of the infused volume had been excreted in the three groups (P<0.01). The kinetic analyses indicated that both treatments slowed down the distribution of fluid from the plasma to the interstitial fluid space, thereby preventing hypovolemia.
Conclusions:
Esmolol doubled and phenylephrine almost tripled urinary excretion during anesthesia-induced depression of renal fluid clearance.
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Use of carperitide infusion for acutely decompensated heart failure
In our retrospective observational study, carperitide had higher improvement rate of functional class, though some reports have been against the use of nesiritide in acute heart failure patients. Also, the use of carperitide was not associated with death or heart failure admission after adjustment. Carperitide compares favorably to nesiritide in several ways; it has a shorter half-life, does not mandate bolus infusion, and used mostly as a single agent. We surmise that these unique pharmacological profiles may be part of the reasons for the difference in outcomes and the use of carperitide should be judiciously evaluated in prospective trials.Key words: carperitide, nesiritide, acute heart failure
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Passive immunotherapy of sepsis with intravenous immune globulin: not all IVIg preparations are created equal
Normal intravenous immunoglobulin (IVIg) preparations are potentially promising drugs for the adjunctive treatment of sepsis as the pool of IgG antibodies neutralizes a wide array of pathogens plus their virulence factors and in addition possesses broad anti-inflammatory and immunomodulating activities. However, several high quality clinical studies have failed to show an effect of IVIg therapy on survival of sepsis patients. The reason behind this lack of success could be that the wrong immunoglobulin preparations have been used so far. We review evidence from experimental sepsis studies proving that licensed IVIg with additionally enhanced antigen-binding polyspecificity have significant beneficial effects in all sepsis models used.
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