Erythropoietin-induced treatment costs in patients suffering from renal anemia - a comparison between biosimilar and originator drugs.

OBJECTIVES: Renal anemia is a serious concern for morbidity and lower quality-of-life of patients suffering from chronic kidney disease resulting in a high economic burden when administering erythropoiesis-stimulating agents (ESAs). The aim of this study was to estimate erythropoietin-induced treatment costs in patients suffering from renal anemia undergoing dialysis treated with originator or biosimilar drugs. METHODS: A retrospective analysis was undertaken of ESA-related pharmacotherapy between January 1, 2008 and December 31, 2010 based on treatment and pharmacy claims data of 16,895 dialysis patients contained in the database of the Association of Statutory Health Insurance Physicians, Bavaria. All patients received an ESA treatment (ATC code B03XA) and chronic maintenance hemodialysis due to chronic kidney disease stage 5. RESULTS: Total drug expenditures for ESA-originators and biosimilars amounted to € 78.447 million for the 3-year study period. In hemodialysis patients cumulative defined daily doses (DDDs) were 7,727,782.14. Mean costs per DDD were € 10.79 (originators) and € 8.56 (biosimilars). A biosimilar substitution quota of 50% provides a savings potential of € 6.14 million [range € 3.07-9.22 million (25-75% quota)]. CONCLUSION: A more common biosimilar prescription in renal anemia patients suffering from chronic kidney disease provides a noteworthy economic savings potential.

Acute hyperglycaemia following thermal injury: friend or foe?

INTRODUCTION: Hyperglycaemia and insulin resistance are common in severely burned patients, even if they have not previously had diabetes. Conventionally, hyperglycaemia is considered a part of the hypermetabolic stress response and blood glucose levels up to 215 mg/dl are tolerated before insulin therapy is initiated. Recent studies suggest that hyperglycaemia and insulin resistance are harmful and that correcting blood glucose to normal levels with insulin might improve the prognosis significantly. STUDY OBJECTIVE: The purpose of this clinical study was to evaluate blood glucose levels in severely burned patients with conventional management and to analyse the association between early hyperglycaemia and clinical outcome. DESIGN: Clinical, prospective, descriptive study. PATIENTS: Thirty seven severely burned adults (>25% total body surface area). INTERVENTIONS: Hyperglycaemia was treated according to conventional clinical practice. This included the infusion of insulin based on a blood glucose level >215 mg/dl and the maintenance of the glucose level between 180 and 200 mg/dl. MEASUREMENTS AND RESULTS: Measurements of whole-blood glucose were performed at 8, 16, 24, 36 and 48 h after the thermal injury. Additional measurements were performed if indicated. A total of 185 measurements were obtained and significant elevations of blood glucose levels (>140 mg/dl) were found in 108 (64%) of the measurements. Peak blood glucose values exceeded 140 mg/dl in all but three of the patients; however, only 17 patients received insulin treatment during the shock period. The inadequacy of the insulin treatment is shown by the mean glucose values, which exceeded 200 mg/dl in 27% of the patients. Despite a non-significant difference in the extent of burn (P=0.055), patients who died showed significantly higher maximum glucose values than patients who survived the thermal injury (P<0.05). Even though not statistically significant, blood glucose control was poorer in patients who later developed sepsis or acute renal failure (P>0.05). No correlation was found between burned surface area (TBSA) and mean plasma glucose levels during the first 48 h of resuscitation (r=0.12). CONCLUSION: Hyperglycaemia is very frequent during the resuscitation period of thermal injury and current guidelines for insulin therapy are inadequate to correct plasma glucose to normal levels. As an association between early hyperglycaemia and subsequent mortality seems to exist, more aggressive manoeuvres to reduce blood glucose may be warranted in this group of patients.

Acute renal failure in severely burned patients.

Acute renal failure (ARF) is a well known complication of severe burns and is an important factor leading to an increase in mortality. In order to analyze possible pathogenetic and prognostic factors associated with ARF in burned patients we reviewed in a retrospective study the files of 328 patients with burns > 10% body surface area (BSA), admitted to our burn unit between 01.01.94 and 01.05.98. We found 48 patients with acute renal failure corresponding with an incidence of 14.6%. Patients with ARF had a mean burned surface area of 48% (13-95) and an abbreviated burn severity index score (ABSI) of 9.8 (4-15). Thirty eight (79%) of these patients had an inhalation injury diagnosed. Renal insufficiency was divided in a late and an early form depending on its time of onset and we found 15 (31%) patients with ARF occurring within the first 5 days of the hospital stay and 33 (69%) patients with ARF developing >5 days following the thermal injury. The incidence of myoglobinuria and hypotension during the resuscitation phase was significantly higher in the group with early ARF, whereas patients with late ARF presented sepsis more frequently than patients with early occurring renal failure. Accordingly, potential nephrotoxic antibiotics were administered more often in patients with late ARF. Patients with ARF were treated by continuous arteriovenous hemofiltration (CAVH) for a mean period of 10.5 days (1-47) and CAVH was associated with a complication rate of 10%. Most of the complications were associated with the vascular access in the femoral artery. The mortality rate in patients with ARF was 85% and death was due to multiple organ failure in 83% of the cases. Only burned BSA and inhalation injury proved to be significantly correlated with the development of ARF, whereas age, third degree burn or electric injury were not significantly different between the two groups. Neither age, TBSA, day of onset of ARF nor duration of the renal replacement therapy proved to be significantly different comparing survivors with non-survivors, and thus predictive for the survival rate.

Haemodynamic and oxygen transport responses in survivors and non-survivors following thermal injury.

Resuscitation from shock based on invasive hemodynamic monitoring has been widely used in trauma and surgical patients, but has been only sparsely evaluated in thermally injured patients, probably due to fear of invasive monitoring in this group of patients. However, end-point resuscitation to fixed circulatory and oxygen transport values has been proposed to be associated with an improved survival rate following trauma and high-risk surgery. Furthermore, the early circulatory response to resuscitation has been shown to be predictive of survival in these patients. In this study the early hemodynamic and oxygen transport profile following thermal injury was analysed with the aim to detect possible differences in the response of survivors and non-survivors. The transpulmonary thermodilution technique was used for hemodynamic monitoring of 21 patients, who were admitted to our burn unit with severe burns. Six patients died and 15 patients survived to leave the intensive care unit. Survivors were found to have a significantly higher cardiac index and oxygen delivery rate during the early postburn period than non-survivors. Furthermore, initial serum lactate levels as well as the ability to clear elevated lactate were found to be significantly associated with survival. Blood pressure and heart rate were not significantly different between the two groups of patients. All patients received significantly higher volumes of crystalloids during the first 24 h than predicted from the Baxter formula, independent of outcome. We concluded that standard vital signs such as blood pressure and heart rate may be invalid as outcome related resuscitation goals, and too insensitive to ensure appropriate fluid replacement. The response to fluid therapy may be significantly associated with outcome; survivors responding with an augmentation of cardiac output and oxygen delivery not seen in non-survivors. Lactate levels seem to correlate with organ failure and death and appear a suitable end-point for resuscitation of severely burned patients.

Arterial thermodilution: an alternative to pulmonary artery catheter for cardiac output assessment in burn patients.

STUDY OBJECTIVE: To study the agreement between cardiac output measurements with the pulmonary artery catheter and with the transpulmonary thermodilution technique in patients with burns. DESIGN: Prospective, clinical study. PATIENTS: 23 patients with serious burns and an abbreviated burn severity index score (ABSI)>6. SETTING: intensive care unit for severely burned in a burn center in Germany. RESULTS: A total number of 218 cardiac output measurements obtained during the first 72 h postburn were analysed. In the pulmonary artery group, mean cardiac index was 3.93 l/min/m2 and ranged from 0.96 to 9.58. In the transpulmonary group the cardiac index measurements ranged from 0.96 to 9.61 with a mean of 4.0 l/min/m2. During the entire observation period cardiac index was consistently higher in the transpulmonary group than in the pulmonary artery group with a bias of 0.32 l/min/m2 and a standard deviation (S.D.) of 0.29 l/min/m2. Linear regression analysis revealed CI(arterial)=0.98xCI(pulm)+0.22l/min/m2 (r=0.9678, P<0.038). Bias and precision to each time point according to Bland and Altman demonstrated a good agreement between both techniques. CONCLUSION: The transpulmonary thermodilution offers an attractive, less invasive alternative to the pulmonary artery catheter in patients with burns. Arterial thermodilution for CO measurements is as precise as PA thermal dilution, and CO(pulm) can be replaced by CI(arterial) when basic methodological principles are respected.

A clinical randomized study on the effects of invasive monitoring on burn shock resuscitation.

BACKGROUND: Ever since Charles Baxter's recommendations the standard regime for burn shock resuscitation remains crystalloid infusion at a rate of 4 ml/kg/% burn in the first 24h following the thermal injury. A growing number of studies on invasive monitoring in burn shock, however, have raised a debate regarding the adequacy of this regime. The purpose of this prospective, randomised study was to compare goal-directed therapy guided by invasive monitoring with standard care (Baxter formula) in patients with burn shock. PATIENTS AND METHODS: Fifty consecutive patients with burns involving more than 20% body surface area were randomly assigned to one of two treatment groups. The control group was resuscitated according to the Baxter formula (4 ml/kg BW/% BSA burn), the thermodilution (TDD) group was treated according to a volumetric preload endpoint (intrathoracic blood volume) obtained by invasive haemodynamic monitoring. RESULTS: The baseline characteristics of the two treatment groups were similar. Fluid administration in the initial 24h after burn was significantly higher in the TDD treatment group than in the control group (P = 0.0001). The results of haemodynamic monitoring showed no significant difference in preload or cardiac output parameters. Signs of significant intravasal hypovolemia as indicated by subnormal values of intrathoracic and total blood volumes were present in both treatment groups. Mortality and morbidity were independent on randomisation. CONCLUSION: Burn shock resuscitation due to the Baxter formula leads to significant hypovolemia during the first 48 h following burn. Haemodynamic monitoring results in more aggressive therapeutic strategies and is associated with a significant increase in fluid administration. Increased crystalloid infusion does not improve preload or cardiac output parameters. This may be due to the fact that a pure crystalloid resuscitation is incapable of restoring cardiac preload during the period of burn shock.

The relationship between oxygen delivery and oxygen consumption during fluid resuscitation of burn-related shock.

Although burn-related shock resuscitation based on invasive hemodynamic monitoring has been reported at an increased rate, little is known about appropriate hemodynamic end points. Shock resuscitation based on oxygen transport criteria has been widely used for patients with trauma and patients who undergo surgery, and supranormal values of oxygen delivery (DO2) have been reported in association with an improved survival rate. This improved survival rate has been attributed to a shifting of the critical threshold of DO2 to higher values in these patients. In patients with thermal injuries, the effects of the manipulation of hemodynamics to optimize oxygen transport have not been proven. It is still unclear whether these patients exhibit delivery-dependent oxygen consumption (VO2) during the shock phase. The goal of this study was to evaluate the existence of oxygen supply dependency and to determine critical levels of DO2 in patients with burns. In a prospective study that included 16 patients with serious thermal injuries, we studied the effects of volume loading on DO2 and VO2. A transpulmonary double dilution technique was used for hemodynamic monitoring, and resuscitation end points included a normalization of preload and cardiac output parameters within 24 hours of the thermal injury. Fluid loading with crystalloids and colloids, according to our resuscitation protocol, was used to augment cardiac output and DO2. Of the 16 patients with a mean of 46% total body surface area burned (range, 22%-80%), 8 patients survived and 8 patients died. With the use of progressive fluid loading, cardiac index was restored within 24 hours of admission in all of the patients. Successful resuscitation was associated with increased levels of DO2 and VO2 and with declining serum lactate levels. VO2 appeared to be dependent on DO2 during the resuscitation period (r = 0.596), and the correlation was significantly stronger in the patients who survived (r = 0.744) than in the patients who died (r = 0.368; P < .05). A critical threshold of oxygen supply could not be identified. We concluded that increasing DO2 by fluid resuscitation increases VO2 during hypovolemic shock after a severe burn injury.

[Integration of preexisting diseases and risk factors in the Abbreviated Burn Severity Index (ABSI)]. / Integration von Vorerkrankungen und Risikofaktoren im Abbreviated Burn Severity Index (ABSI).

OBJECTIVE: There is no doubt that underlying medical problems such as concomitant diseases or risk factors play a role in increasing patient morbidity and mortality. These factors are already integrated in trauma scores but preexisting diseases have no impact on burn scores yet. This study was performed to examine the predictive value of the classical burn variables that are integrated in the Abbreviated Burn Severity Index (ABSI). The preexisting diseases and risk factors in burn patients within our burn center were evaluated, with the aim of incorporating these evaluations into a new burn score. This modified burn score was used to optimize the predictive value of burn mortality. METHODS: This study included 443 intensive care burn patients. Demographic, injury, age, total body surface area burned (TBSAB), full thickness burn (FTB), inhalation injury (IHT), sex, medical comorbidities, intensive care and outcome data were documented. Univariate analyses, stepwise logistic regression and the Receiver Operating Curve were used to generate values for the probability of death. RESULTS: Univariate analyses identified the following risk factors for their relationship with mortality: TBSAB, age, IHT, FTB, sex and medical comorbidities (cardiovascular, pulmonary, renal and endocrinological). Logistic Regression showed that total body surface area burned and age correlated most significantly with the probability of poor outcome. There were weaker correlations between IHT and FTB. No main effect was registered for gender and preexisting medical problems. The greatest area under the ROC curve was registered for our modified ABSI when comorbidities and risk factors were integrated. CONCLUSION: The results of this study show that the Abbreviated Burn Severity Index is an appropriate burn score for estimating the risk of mortality after burn trauma. However, in addition to the classical variables, preexisting diseases and risk factors have a significant influence on the outcome and therefore should be incorporated into a new burn score to predict mortality more accurately.

Intrathoracic blood volume as an end point in resuscitation of the severely burned: an observational study of 24 patients.

BACKGROUND: Treatment of burn shock according to empirical resuscitation formulas is still considered the gold standard, and the burn community does not advocate the use of invasive cardiorespiratory monitoring in general. As a consequence, data dealing with early postburn hemodynamics are sparse, and only few studies have paid attention to the topic of end-point burn shock resuscitation. However, recent studies have suggested that burn survival may be improved when invasive monitoring is used to guide fluid therapy during the shock phase. MATERIALS AND METHODS: In an observational study of 24 patients with severe burns, the transpulmonary double indicator dilution technique was used for semi-invasive hemodynamic monitoring. The clinical utility of the intrathoracic blood volume (ITBV) as an end-point variable for fluid resuscitation was evaluated, comparing correlation of filling pressure obtained by a pulmonary artery catheter and intrathoracic blood volume to cardiac index and oxygen delivery. In addition fluid volume predicted by the Parkland burn formula was compared with the actual fluid volume given when ITBV was used as end point for resuscitation. RESULTS: ITBV-guided resuscitation was associated with restoration of preload and peripheral delivery of oxygen within 24 hours in the majority of patients. Augmentation of ITBV was significantly correlated with changes in cardiac index and oxygen transport rate. No such correlation could be demonstrated for the conventional preload parameters such as central venous pressure and pulmonary capillary wedge pressure. Thus, ITBV seemed in burned, hypovolemic patients a better indicator of the preload component of the cardiac output than the conventional preload parameters obtained with the pulmonary artery catheter. Significantly larger volumes of crystalloids than predicted by the Parkland formula were administered when ITBV was used as end point for resuscitation. The extravascular lung water remained normal during this extraordinary high volume load. CONCLUSION: ITBV may be a reliable preload indicator to guide volume therapy in life-threatening burns, and end-point-fixed resuscitation to this parameter seems to be associated with significantly higher fluid administration than calculated compared with traditional burn formulas. The effects of burn resuscitation to fixed end points on survival and multiple organ failure should be evaluated in future randomly assigned trials.