Critical Care

Published by Springer Nature

Online ISSN: 1875-7081


Print ISSN: 1364-8535


Table 1 Red blood cell storage lesion
Age of blood: Does it make a difference?
  • Literature Review
  • Full-text available

February 2004


386 Reads

During the past 20 years, the perceived value of blood transfusions has changed as it has become appreciated that transfusions are not without risk. Red blood cell transfusion has been associated with disease transmission and immunosuppression for some time. More recently, proinflammatory consequences of red blood cell transfusion have also been documented. Moreover, it has become increasingly evident that stored red blood cells undergo time-dependent metabolic, biochemical, and molecular changes. This 'storage lesion' may be responsible for many of the adverse effects of red blood cell transfusion. Clinically, the age of blood has been associated with multiple organ failure, postoperative pneumonia, and wound infection. The relationship between age of blood and clinical adverse effects needs further study.

Table 1 Baseline characteristics of the patients
Table 3 Primary and secondary outcomes
Table 4 Post hoc analysis 90-day mortality and need for renal replacement therapy
Hct, hematocrit; MAP, mean arterial pressure; ScvO
, central venous oxygen saturation; UO, urinary output.
Study flow diagram.
Early fluid resuscitation with hydroxyethyl starch 130/0.4 (6%) in severe burn injury: A randomized, controlled, double-blind clinical trial

December 2013


474 Reads



Mario Fasshauer




Thomas A Neff
There are limited data on the efficacy of early fluid resuscitation with third generation hydroxyethyl starch (HES 130) in burn injury. Adverse effects of HES on survival and organ function have been reported. In this randomized, controlled, double-blind trial 48 patients with severe burn injury were assigned to receive either Lactated Ringer's solution plus 6% HES 130/0.4 in a ratio of 2:1 or Lactated Ringer's solution with no colloid supplement for the first 72 hours. Primary outcome parameter was the group difference of administered total fluid from intensive care unit (ICU) admission up to day 3. Secondary outcomes included kidney and lung injury and failure, length of stay, and mortality. 3 days total of administered resuscitation fluid (medians) was 21,190 ml in the Lactated Ringer's group and 19,535 ml in the HES group (HES: -1,213 ml; P = 0.39). Creatinine levels day 1 to 3 (HES: +0.4 mumol/l; 95% CI -18.7 to 19.5; P = 0.97) and urinary output day 1 to 3 (HES: -58 ml; 95% CI -400 to 284; P = 0.90) were not different. 6 patients in each group developed acute respiratory distress syndrome (ARDS) (risk ratio 0.96; 95% CI 0.35 to 2.64; P = 0.95). Length of ICU stay (HES vs. Lactated Ringer's: 28 vs. 24 days; P = 0.80) and length of hospital stay (31 vs. 29 days; P = 0.57) were similar. 28-day mortality was 4 patients in each group (risk ratio 0.96; 95% CI 0.27 to 4.45; P = 0.95), in-hospital mortality was 8 in the HES group vs. 5 patients in the Lactated Ringer's group (hazard ratio 1.86; 95% CI 0.56 to 6.19; P = 0.31). There was no evidence that early fluid resuscitation with balanced HES 130/0.4 (6%) in addition to Lactated Ringer's solution would lead to a volume sparing effect in severe burn injury. Together with the findings that early renal function, incidence of ARDS, length of stay, and mortality were not negatively influenced by HES in this setting, balanced HES 130/0.4 (6%) plus Lactated Ringer's solution could not be considered superior to Lactated Ringer's solution alone.Trial registration: NCT01012648.

Table 4 Number of patients by the AKIN and RIFLE classifications
Figure 1 Study design.
Evolution of mean serum creatinine (SCr) levels over time.
Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study

May 2012


218 Reads

Inadequate initial treatment and delayed hemodynamic stabilization (HDS) may be associated with increased risk of death in severe sepsis patients. In order to compare the hemodynamic efficacy and safety of 6% HES 130/0.4 and NaCl 0.9% for HDS in patients with severe sepsis, we designed a prospective, multicenter, active-controlled, double-blind, randomized study in intensive care units. 174 out of 196 patients reached HDS (88 and 86 patients for HES and NaCl, respectively). Significantly less HES was used to reach HDS vs. NaCl (1,379 ±886 ml in the HES group and 1,709 ±1,164 ml in the NaCl group (mean difference = -331± 1,033, 95% CI -640 to -21, P = 0.0185). Time to reach HDS was 11.8 10.1 hours vs. 14.3 ±11.1 hours for HES and NaCl, respectively. Total quantity of study drug infused over four consecutive days, ICU and hospital LOS, and area under the curve of SOFA score were comparable. Acute renal failure occurred in 24 (24.5%) and 19 (20%) patients for HES and NaCl, respectively (P = 0.454). There was no difference between AKIN and RIFLE criteria among groups and no difference in mortality, coagulation, or pruritus up to 90 days after treatment initiation. Significantly less volume was required to achieve HDS for HES vs. NaCl in the initial phase of fluid resuscitation in severe sepsis patients without any difference for adverse events in both groups.

Survival time in severe hemorrhagic shock after perioperative hemodilution is longer with PEG-conjugated human serum albumin than with HES 130/0.4: A microvascular perspective

February 2008


67 Reads

Preoperative hemodilution is an established practice that is applied to reduce surgical blood loss. It has been proposed that polyethylene glycol (PEG) surface decorated proteins such as PEG-conjugated human serum albumin may be used as non-oxygen-carrying plasma expanders. The purpose of this study was to determine whether there is any difference in survival time after severe hemorrhagic shock following extreme hemodilution using a conventional hydroxyethyl starch (HES)-based plasma expander or PEG-albumin. Experiments were performed using the hamster skinfold window preparation. Human serum albumin that was surface decorated with PEG was compared with Voluven 6% (Fresenius Kabi, Austria; a starch solution that is of low molecular weight and has a low degree of substitution; HES). These plasma expanders were used for a 50% (blood volume) exchange transfusion to simulate preoperative hemodilution. Exchange transfusion was followed by a 60% (blood volume) hemorrhage to reproduce a severe surgical bleed over a 1 hour period. Observation of the animal was continued for another hour during the shock phase. The PEG-albumin group exhibited significantly greater survival rate than did the HES group, in which none of the animals survived the hemorrhage phase of the experiment. Among the treatment groups there were no changes in mean arterial pressure and heart rate from baseline after hemodilution. Both groups experienced gradual increases in arterial oxygen tension and disturbance in acid-base balance, but this response was more pronounced in the HES group during the shock period. Mean arterial pressure remained elevated after the initial hemorrhage period in the PEG-albumin group but not in the HES group. Maintenance of a greater mean arterial pressure during the initial stages of hemorrhage is proposed to be in part due to the improved volume expansion with PEG-albumin, as indicated by the significant decrease in systemic hematocrit compared with the HES group. PEG-albumin treatment yielded higher functional capillary density during the initial stages of hemorrhage as compared with HES treatment. The ability of PEG-albumin to prolong maintenance of microvascular function better than HES is a finding that would be significant in a clinical setting involving preoperative blood management and extreme blood loss.

Hydroxyethyl starch 130/0.4 or hypertonic saline solution to decrease inflammatory response in hemorrhagic shock?

October 2013


81 Reads

We read with great interest the study by Chen and colleagues highlighting interest in hydroxyethyl starch (HES) 130/0.4 in treatment after hemorrhagic shock to ameliorate oxidative stress and the inflammatory response in a rat model. Compared with HES 200/0.5 and succinylated gelatin, the authors showed that infusions of HES 130/0.4 significantly reduced malondialdehyde levels and myeloperoxidase activity and also inhibited about 50% of TNF-α production in the intestine [1]. However, we regret the lack of assessment of another resuscitative fluid: the hypertonic saline solution (HTS). In our level 1 trauma center, we chose to use HTS because we have some concerns about HES safety. Indeed, HES may induce coagulopathy and increase risk of renal-replacement therapy [2]. HTS has several advantages due to its osmotic effects. Firstly, it leads to restoration of circulating volume with a smaller volume of fluid. Secondly, it reduces intracranial pressure in case of associated traumatic brain injury [3]. In addition, HTS attenuates the increase in plasma concentration of IL-1β, IL-6, IFN-γ and TNF-α, suggesting that HTS may also limit the inflammatory response to hemorrhage and reperfusion [4]. One of its inconveniences may be the increased risk of acute kidney injury due to hyperchloremic metabolic acidosis decreasing renal blood flow; however, this effect was especially demonstrated when using large amounts of 0.9% saline solution [5]. We suggest that, in 2013, studies on fluid resuscitation should compare all the available resuscitative fluids, and not just HES, currently under concern for safety reasons. Abbreviations HES: hydroxyethyl starch; HTS: hypertonic saline solution; IFN: interferon; IL: interleukin; TNF: tumor necrosis factor. Competing interests The authors declare that they have no competing interests.

Assessment of hemodynamic efficacy and safety of 6% hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: how to guide fluid therapy?

November 2012


36 Reads

We argue that assessing the hemodynamic efficacy of hydroxyethyl starch (HES) versus NaCl in patients with severe sepsis requires an algorithm to direct the timing and amount of fluid resuscitation. Such an algorithm may include hemodynamic flow parameters. In a recent issue of Critical Care, Guidet and colleagues [1] reported that a smaller amount of 6% HES 130/0.4 versus 0.9% NaCl was required to achieve hemodynamic stability (HDS) during the initial phase of fluid resuscitation in patients with severe sepsis. The target parameters indicating HDS included central venous pressure (CVP) (8 to 12 mm Hg), a poor indicator of fluid responsiveness [2], and a large urine output (>2 mL/kg per hour), and therefore pose a risk of over-infusion. Other authors have reported that over-infusion, elevated CVP, and excessive fluid resuscitation with HES are associated with increased mortality in patients with sepsis [3,4]. In contrast, after initial HDS was achieved, no such target parameters were defined, and so the cumulative volumes of study drug infused over the course of four consecutive days in the intensive care unit (ICU) were similar for the HES (2,615 mL) and NaCl (2,788 mL) groups. No differences in mortality, hospital length of stay, or kidney function were found. This study may be showing only that, in the absence of an algorithm to guide fluid resuscitation, intensivists use an unvarying amount of fluids, but it is impossible to know whether these fluids were, in fact, indicated. In patients undergoing major abdominal surgery, hemodynamic algorithms that guide the timing and amount of fluid administration have helped determine the clinical efficacy of fluid therapy [5]. The negative results reported by Guidet and colleagues suggest that hemodynamic algorithms for patients with sepsis are urgently required to accurately compare the hemodynamic efficacy, safety, and outcome of HES versus NaCl fluid replacement.

Is hydroxyethyl starch 130/0.4 safe?

March 2012


49 Reads

ABSTRACT: It is heavily debated whether or not treatment with hydroxyethyl starch 130/0.4 contributes to the development of acute kidney failure in patients with severe sepsis. In the previous issue of Critical Care, Muller and colleagues report no association between initial resuscitation with hydroxyethyl starch 130/0.4 and renal impairment in a cohort of septic patients. Can we then consider hydroxyethyl starch 130/0.4 a safe intervention? The answer is no - observational data should be interpreted with caution and should mainly be used to identify risks, while safety must be assessed in randomised clinical trials. With these factors in mind, Muller's data associate the use of vasopressors with poor outcome, underlining the need for further randomised clinical trials to assess the potential harmful effects of common interventions in the critically ill.

Resuscitation with low volume hydroxyethylstarch 130 kDa/0.4 is not associated with acute kidney injury

March 2010


82 Reads

Acute kidney injury (AKI) in the ICU is associated with poorer prognosis. Hydroxyethylstarch (HES) solutions are fluid resuscitation colloids frequently used in the ICU with controversial nephrotoxic adverse effects. Our study objective was to evaluate HES impact on renal function and organ failures. This observational retrospective study included 363 patients hospitalized for more than 72 hours in our ICU. A hundred and sixty eight patients received HES during their stay and 195 did not. We recorded patients' baseline characteristics on admission and type and volume of fluid resuscitation during the first 3 weeks of ICU stay. We also noted the evolution of urine output, the risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function and end-stage kidney disease (RIFLE) classification and sepsis related organ failure assessment (SOFA) score over 3 weeks. Patients in the HES group were more severely ill on admission but AKI incidence was similar, as well as ICU mortality. The evolution of urine output (P = 0.74), RIFLE classification (P = 0.44) and SOFA score (P = 0.23) was not different. However, HES volumes administered were low (763+/-593 ml during the first 48 hours). Volume expansion with low volume HES 130 kDa/0.4 was not associated with AKI.

Figure 1
Figure 2
Effects of hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5 on in vitro clot formation in comparison with saline after haemodilution rates of 10% (white) or 40% (grey) with either HES solution or saline (Control). Clotting time (a), clot formation time (b) and maximum clot firmness (MCF) in EXTEM (c) as well as MCF in FIBTEM (d) were determined by ROTEM. Data are given as mean ± standard error of the mean obtained from six identical experiments. Significant differences between saline and HES 130/0.4 or HES 200/0.5: *P < 0.05, **P < 0.005, ***P < 0.001.
Effects of hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5 on platelet activation markers and formation of platelet-leukocyte conjugates. After haemodilution of 10% (white) or 40% (grey) with either HES solution or saline (Con), platelets were activated by adenosine diphosphate (ADP) (5 μM) or thrombin receptor-activating peptide (TRAP) (25 μM) for 5 minutes or remained inactivated (Basal). CD62P expression (a) and fibrinogen binding to platelets (b) as well as platelet-neutrophil (P-N) (c) and platelet-monocyte (P-M) (d) conjugates were determined by flow cytometry. The results are expressed as the relative numbers of platelets or leukocytes that were positive for CD62P or fibrinogen or the platelet-specific antigen CD42a. Data are given as mean ± standard error of the mean obtained from eight identical experiments. Significant differences between saline and HES 130/0.4 or HES 200/0.5: *P < 0.05, ** P < 0.005, *** P < 0.001. Significant differences between HES 130/0.4 and HES 200/0.5: §P < 0.05, §§P < 0.01.
HES 130/0.4 impairs haemostasis and stimulates pro-inflammatory blood platelet function

December 2009


210 Reads

Hydroxyethyl starch (HES) solutions are widely used for volume replacement therapy but are also known to compromise coagulation, impair renal function and increase long-term mortality. To test the hypotheses that HES 130/0.4 has fewer adverse effects than HES 200/0.5 and exerts anti-inflammatory properties, we compared the effects of HES 130/0.4, HES 200/0.5 and saline on in vitro haemostasis and pro-inflammatory platelet function. Whole blood samples from healthy volunteers were mixed with 6% HES 130/0.4, 10% HES 200/0.5, or normal saline to achieve a final haemodilution rate of 10% or 40%. Haemostatic capacity was characterised by thromboelastography (ROTEM) and measurement for FXIIIa activity. Platelet activation and pro-inflammatory platelet functions were characterised by flow cytometry measuring the platelet activation marker CD62P and binding of fibrinogen to platelets as well as the formation of heterotypic platelet-leukocyte conjugates. Compared with saline, HES 130/0.4 dose-dependently impaired formation and firmness of the fibrin clot but did not affect the fibrin crosslinking activity of FXIIIa. At 40% but not at 10% haemodilution rate, HES 200/0.5 also increased platelet fibrinogen binding and both HES solutions increased expression of CD62P, the main receptor for platelet-leukocyte adhesion. HES 130/0.4 but not HES 200/0.5 increased formation of platelet-neutrophil conjugates and, to a lesser degree, platelet-monocyte conjugates. Our data demonstrate that HES 130/0.4 has similar adverse effects as HES 200/0.5. In particular, both types of HES impair coagulation capacity and stimulate, rather than attenuate, pro-inflammatory platelet function.

Table 1 Arterial blood gas variables for all groups during the experiment
Design of the hemorrhagic shock protocol.
Tissue MDA concentrations following HS/R. Data are plotted as the means ± SD. *P <0.05 versus the sham group; &P <0.05 versus the HES 200 group; #P <0.01 versus the GEL group. GEL, gelatin; HES, hydroxyethyl starch; HS/R, hemorrhagic shock/fluid resuscitation; MDA, malondialdehyde.
MPO levels in the liver, lungs, intestine and brain following HS/R in four groups. Data are plotted as the means ± SD. *P <0.05 versus the sham group; &P <0.05 versus the HES 200 group; #P <0.01 versus the GEL group. GEL, gelatin; HES, hydroxyethyl starch; HS/R, hemorrhagic shock/fluid resuscitation; MPO, myeloperoxidase.
Effects of different resuscitation fluids on HS/R-induced intestinal levels of TNF-α and IL-6. Data are plotted as the means ± SD. *P <0.05 versus the sham group; &P <0.05 versus the HES 200 group; #P <0.01 versus the GEL group. GEL, gelatin; HES, hydroxyethyl starch; HS/R, hemorrhagic shock/fluid resuscitation.
Effects of synthetic colloids on oxidative stress and inflammatory response in hemorrhagic shock: Comparison of hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, and succinylated gelatin

July 2013


185 Reads

This study compared the effect of hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, and succinylated gelatin on oxidative stress and the inflammatory response in a rodent hemorrhagic shock model. Sodium pentobarbital-anesthetized adult male Wistar rats (200 g - 220 g) were subjected to a severe volume-controlled hemorrhage using arterial blood withdrawal (30 mL/kg - 33 mL/kg), and resuscitated with a colloid solution at the same volume as blood withdrawal (hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, or succinylated gelatin). Arterial blood gas parameters were monitored. Malondialdehyde (MDA) content, myeloperoxidase (MPO) activity in the liver, lungs, intestine, and brain were measured 2 hours after resuscitation. The levels of tumor necrosis factor (TNF)- alpha and interleukin (IL)-6 in the intestine were also measured. Infusions of hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, significantly reduced MDA levels and MPO activity in the liver, intestine, lungs, and brain, and it also inhibited the production of TNF-alpha in the intestine 2 hours after resuscitation. However, no significant difference between hydroxyethyl starch 200/0.5 and succinylated gelatin was observed. Hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 and succinylated gelatin, treatment after hemorrhagic shock ameliorated oxidative stress and the inflammatory response in this rat model. No significant differences were observed after hydroxyethyl starch 200/0.5 and succinylated gelatin administration at doses of approximately 33 mL/kg.

Efficiency of 7.2% hypertonic saline hydroxyethyl starch 200/0.5 versus mannitol 15% in the treatment of increased intracranial pressure in neurosurgical patients – a randomized clinical trial [ISRCTN62699180]

November 2005


210 Reads

This prospective randomized clinical study investigated the efficacy and safety of 7.2% hypertonic saline hydroxyethyl starch 200/0.5 (7.2% NaCl/HES 200/0.5) in comparison with 15% mannitol in the treatment of increased intracranial pressure (ICP). Forty neurosurgical patients at risk of increased ICP were randomized to receive either 7.2% NaCl/HES 200/0.5 or 15% mannitol at a defined infusion rate, which was stopped when ICP was < 15 mmHg. Of the 40 patients, 17 patients received 7.2% NaCl/HES 200/0.5 and 15 received mannitol 15%. In eight patients, ICP did not exceed 20 mmHg so treatment was not necessary. Both drugs decreased ICP below 15 mmHg (p < 0.0001); 7.2% NaCl/HES 200/0.5 within 6.0 (1.2-15.0) min (all results are presented as median (minimum-maximum range)) and mannitol within 8.7 (4.2-19.9) min (p < 0.0002). 7.2% NaCl/HES 200/0.5 caused a greater decrease in ICP than mannitol (57% vs 48%; p < 0.01). The cerebral perfusion pressure was increased from 60 (39-78) mmHg to 72 (54-85) mmHg by infusion with 7.2% NaCl/HES 200/0.5 (p < 0.0001) and from 61 (47-71) mmHg to 70 (50-79) mmHg with mannitol (p < 0.0001). The mean arterial pressure was increased by 3.7% during the infusion of 7.2% NaCl/HES 200/0.5 but was not altered by mannitol. There were no clinically relevant effects on electrolyte concentrations and osmolarity in the blood. The mean effective dose to achieve an ICP below 15 mmHg was 1.4 (0.3-3.1) ml/kg for 7.2% NaCl/HES 200/0.5 and 1.8 (0.45-6.5) ml/kg for mannitol (p < 0.05). 7.2% NaCl/HES 200/0.5 is more effective than mannitol 15% in the treatment of increased ICP. A dose of 1.4 ml/kg of 7.2% NaCl/HES 200/0.5 can be recommended as effective and safe. The advantage of 7.2% NaCl/HES 200/0.5 might be explained by local osmotic effects, because there were no clinically relevant differences in hemodynamic clinical chemistry parameters.

Figure 1: Kaplan-Meier survival curve and causes of death. Large effect towards a seven-fold higher mortality in the HES group (adjusted hazard ratio 7.12; P = 0.16). ARDS, acute respiratory distress syndrome; HES, hydroxyethyl starch.
Figure 2: Bloodmarkers at days one, two, three and seven. (a) Hematocrit, (b) white blood count, (c) C-reactive protein, (d) glutamat-pyruvat-transaminase (GPT) and (e) glutamat-oxalacetat-transaminase (GOT). Baxter group black bars, hydroxyethyl starch (HES) group grey bars. Plots show mean ± standard deviation, analysis of variance for repeated measurements. There were no differences between the groups.
Early fluid resuscitation with hyperoncotic hydroxyethyl starch 200/0.5 (10%) in severe burn injury

June 2010


106 Reads

Despite large experience in the management of severe burn injury, there are still controversies regarding the best type of fluid resuscitation, especially during the first 24 hours after the trauma. Therefore, our study addressed the question whether hyperoncotic hydroxyethyl starch (HES) 200/0.5 (10%) administered in combination with crystalloids within the first 24 hours after injury is as effective as 'crystalloids only' in severe burn injury patients. 30 consecutive patients were enrolled to this prospective interventional open label study and assigned either to a traditional 'crystalloids only' or to a 'HES 200/0.5 (10%)' volume resuscitation protocol. Total amount of fluid administration, complications such as pulmonary failure, abdominal compartment syndrome, sepsis, renal failure and overall mortality were assessed. Cox proportional hazard regression analysis was performed for binary outcomes and adjustment for potential confounders was done in the multivariate regression models. For continuous outcome parameters multiple linear regression analysis was used. Group differences between patients receiving crystalloids only or HES 200/0.5 (10%) were not statistically significant. However, a large effect towards increased overall mortality (adjusted hazard ratio 7.12; P = 0.16) in the HES 200/0.5 (10%) group as compared to the crystalloids only group (43.8% versus 14.3%) was present. Similarly, the incidence of renal failure was 25.0% in the HES 200/0.5 (10%) group versus 7.1% in the crystalloid only group (adjusted hazard ratio 6.16; P = 0.42). This small study indicates that the application of hyperoncotic HES 200/0.5 (10%) within the first 24 hours after severe burn injury may be associated with fatal outcome and should therefore be used with caution. NCT01120730.

Hydroxyethylstarch 200/0.5-the horse has bolted

February 2012


14 Reads

Hydroxyethylstarch (HES) 200/0.5 is associated with renal failure. Several studies have suggested that renal function is affected but the subsequent arguments leave the clinician in no man's land. A recent study in Critical Care by Simon and colleagues using a two hit animal model of shock demonstrates that the use of a higher molecular weight starch, HES 200/0.5, is associated with impaired renal function when compared with ringers acetate, gelatin or a lower molecular weight starch, HES 130/0.42. The authors conclude that both the lower molecular weight starch and the ringers acetate 'preserve renal function and attenuate tubular damage better than 10% hydroxyethylstarch 200/0.5 in saline'. Added to the previous evidence, the renal effects of HES200/0.5 are probably real. Many clinicians have already moved to the lower molecular weight starches on the basis of doubt rather than certainty, but this study tips the balance. The cause remains elusive and the lack of a mechanism should be seen as a problem.

Figure 1: The pulmonary delivery drug system. (a) Clinical in the 'on-vent configuration' and (b) with the hand-held device.
Figure 2: Day 3 serum amikacin concentrations before (0), and at hours 0.5, 1, 3, 6, 9, 12, 13 and 24 after starting the first aerosol. Results are expressed as medians (interquartile range). Black arrows indicate the timing of aerosols.
Figure 3: Day 3 amikacin concentration in the alveolar epithelial lining fluid (ELF) of the 28 assessable patients. The dotted line corresponds to 128 μg/mL, which is 10-fold the critical 90% minimum inhibitory concentration (MIC90) for Pseudomonas aeruginosa. T-bars represent the 10th and 90th percentiles; the horizontal line in the box is the median; the lower and upper limits of the box represent the 25th and 75th percentiles, respectively. Circles represent outliers.
Figure 4: Day 3 amikacin concentration in the tracheal aspirates of the 19 assessable patients. H1 to H6 corresponds to the first six hours following the first aerosol, H7 to H12 to the next six hours (before the second aerosol of the day), H13 to H18 to the six hours following the second nebulization, and H19 to H24 to the last six hours of the day, before next aerosol. T-bars represent the 10th and 90th percentiles; the horizontal line in the box is the median; the lower and upper limits of the box represent the 25th and 75th percentiles, respectively. Circles represent outliers.
Figure 5: Serum amikacin trough concentrations during the study from day 1 (D1) to D10 with the corresponding number of patients. T-bars represent the 10th and 90th percentiles; the horizontal line in the box is the median; the lower and upper limits of the box represent the 25th and 75th percentiles, respectively. Circles represent outliers.
Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia

December 2009


191 Reads

Aminoglycosides aerosolization might achieve better diffusion into the alveolar compartment than intravenous use. The objective of this multicenter study was to evaluate aerosol-delivered amikacin penetration into the alveolar epithelial lining fluid (ELF) using a new vibrating mesh nebulizer (Pulmonary Drug Delivery System (PDDS), Nektar Therapeutics), which delivers high doses to the lungs. Nebulized amikacin (400 mg bid) was delivered to the lungs of 28 mechanically ventilated patients with Gram-negative VAP for 7-14 days, adjunctive to intravenous therapy. On treatment day 3, 30 minutes after completing aerosol delivery, all the patients underwent bronchoalveolar lavage in the infection-involved area and the ELF amikacin concentration was determined. The same day, urine and serum amikacin concentrations were determined at different time points. Median (range) ELF amikacin and maximum serum amikacin concentrations were 976.1 (135.7-16127.6) and 0.9 (0.62-1.73) microg/mL, respectively. The median total amount of amikacin excreted in urine during the first and second 12-hour collection on day 3 were 19 (12.21-28) and 21.2 (14.1-29.98) microg, respectively. During the study period, daily through amikacin measurements were below the level of nephrotoxicity. Sixty-four unexpected adverse events were reported, among which 2 were deemed possibly due to nebulized amikacin: one episode of worsening renal failure, and one episode of bronchospasm. PDDS delivery of aerosolized amikacin achieved very high aminoglycoside concentrations in ELF from radiography-controlled infection-involved zones, while maintaining safe serum amikacin concentrations. The ELF concentrations always exceeded the amikacin minimum inhibitory concentrations for Gram-negative microorganisms usually responsible for these pneumonias. The clinical impact of amikacin delivery with this system remains to be determined. Identifier: NCT01021436.

Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics

July 2012


4,181 Reads

Introduction In order to assess the significance of drug levels measured in intensive care medicine, clinical and forensic toxicology, as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. Therefore, it makes sense to offer a carefully referenced compilation of therapeutic and toxic plasma concentration ranges, as well as half-lives, of a large number of drugs and other xenobiotics for quick and comprehensive information. Methods Data have been abstracted from original papers and text books, as well as from previous compilations, and have been completed with data collected in our own forensic and clinical toxicology laboratory. The data presented in the table and corresponding annotations have been developed over the past 20 years and longer. A previous compilation has been completely revised and updated. In addition, more than 170 substances, especially drugs that have been introduced to the market since 2003 as well as illegal drugs, which became known to cause intoxications, were added. All data were carefully referenced and more than 200 new references were included. Moreover, the annotations providing details were completely revised and more than 100 annotations were added. Results For nearly 1,000 drugs and other xenobiotics, therapeutic ("normal") and, if data were available, toxic and comatose-fatal blood-plasma concentrations and elimination half-lives were compiled in a table. Conclusions In case of intoxications, the concentration of the ingested substances and/or metabolites in blood plasma better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications, and to support forensic and clinical expert opinions.

Obese trauma patients are at increased risk of early hypovolemic shock: A retrospective cohort analysis of 1,084 severely injured patients

May 2012


237 Reads

Introduction Morbid obesity and its consequences are considered risk factors for adverse outcome in trauma, although the pathophysiologic mechanisms are incompletely understood. The aim of this study was to compare initial resuscitation, treatment, and short-term outcome of severely injured patients by body mass index (BMI). Methods A total of 1,084 severely injured patients with an injury severity score of 16 or greater were enrolled between 1996 and 2009 and grouped according to BMI. Their course of treatment and in-hospital outcome were analyzed by univariate and multivariate comparison. Results Of these patients, 603 (55.6%) were of normal weight with a BMI between 18.5 and 24.9, 361 (33.3%) had BMI values between 25 and 29.9, and 90 patients (8.3%) were obese (BMI ≥ 30). Thirty patients (2.8%) had BMI levels below 18.5. All groups were comparable with respect to injury severity, initial resuscitation, and time to ICU admission. There was a tendency towards higher mortality in obese patients (mortality 24.4%) and also overweight patients (mortality 18.8%) when compared with patients with a normal BMI (mortality 16.6%). Obese patients showed the highest mortality on day 0 (8.9% vs. 2.8% in the normal-weight group, P = 0.023), mostly due to persistent shock (6.7%). When corrected for BMI, obese patients are provided significantly lower volumes of intravenous fluids during the initial resuscitation period. Conclusion In contrast to the mostly American literature, only a low percentage of trauma patients at a European trauma center are obese. These patients are at risk of higher mortality from persistent hemorrhagic shock in the initial phase after trauma, which may potentially be related to relative hypovolemia during the resuscitation period. In the later course of treatment, no significant differences exist with respect to specific complications, hospital stay, or in-hospital mortality.

Table 1 The demographic and clinical data for the injured patients with or without intubation before hospitalization (600 patients per group)
Table 3 The intensive-care outcomes of the trauma patients with or without prehospital intubation
Prehospital intubation of the moderately injured patient: a cause of morbidity? A matched-pairs analysis of 1,200 patients from the DGU Trauma Registry

September 2011


56 Reads

Hypoxia and hypoxemia can lead to an unfavorable outcome after severe trauma, by both direct and delayed mechanisms. Prehospital intubation is meant to ensure pulmonary gas exchange. Limited evidence exists regarding indications for intubation after trauma. The aim of this study was to analyze prehospital intubation as an independent risk factor for the posttraumatic course of moderately injured patients. Therefore, only patients who, in retrospect, would not have required intubation were included in the matched-pairs analysis to evaluate the risks related to intubation. The data of 42,248 patients taken from the trauma registry of the German Association for Trauma Surgery (Deutsche Gesellschaft für Unfallchirurgie (DGU)) were analyzed. Patients who met the following criteria were included: primary admission to a hospital; Glasgow Coma Scale (GCS) of 13 to 15; age 16 years or older; maximum injury severity per body region (AIS) ≤ 3; no administration of packed red blood cell units in the emergency trauma room; admission between 2005 and 2008; and documented data regarding intubation. The intubated patients were then matched with not-intubated patients. The study population included 600 matched pairs that met the inclusion criteria. The results indicated that prehospital intubation was associated with a prolonged rescue time (not intubated, 64.8 minutes; intubated, 82.3 minutes; P ≤ 0.001) and a higher volume replacement (not intubated, 911.3 ml; intubated, 1,573.8 ml; P ≤ 0.001). In the intubated patients, coagulation parameters, such as the prothrombin time ratio (PT) and platelet count, declined, as did the hemoglobin value (PT not intubated: 92.3%; intubated, 85.7%; P ≤ 0.001; hemoglobin not intubated, 13.4 mg/dl; intubated, 12.2 mg/dl; P ≤ 0.001). Intubation at the scene resulted in an elevated sepsis rate (not intubated, 1.5%; intubated, 3.7%; P ≤ 0.02) and an elevated prevalence of multiorgan failure (MOF) and organ failure (OF) (OF not intubated, 9.1%; intubated, 23.4%; P ≤ 0.001). Prehospital intubation in trauma patients is associated with a number of risks and should be critically weighed, except in cases with clear indicators, such as posttraumatic apnea.

Table 1 Characteristics of singleinjury and multiple-injury patients.
Table 2 Diagnoses by body region of 3,177 injury diagnoses registered at People's Hospital of Deyang City after the 2008 Sichuan earthquake, China
Table 3 Most frequent combinations of injury diagnoses by body region in 856 two-injury patients.
Table 4 Most frequent combinations of injury diagnosess in 856 two-injury patients.
Flow diagram of the sample obtained at the People's Hospital of Deyang city (PHDC).
Multiple injuries after earthquakes: A retrospective analysis on 1,871 injured patients from the 2008 Wenchuan earthquake

May 2012


126 Reads

Introduction Multiple injuries have been highlighted as an important clinical dimension of the injury profile following earthquakes, but studies are scarce. We investigated the pattern and combination of injuries among patients with two injuries following the 2008 Wenchuan earthquake. We also described the general injury profile, causes of injury and socio-demographic characteristics of the injured patients. Methods A retrospective hospital-based analysis of 1,871 earthquake injured patients, totaling 3,177 injuries, admitted between 12 and 31 May 2008 to the People's Hospital of Deyang city (PHDC). An electronic, webserver-based database with International Classification of Diseases (ICD)-10-based classification of earthquake-related injury diagnoses (IDs), anatomical sites and additional background variables of the inpatients was used. We analyzed this dataset for injury profile and number of injuries per patient. We then included all patients (856) with two injuries for more in-depth analysis. Possible spatial anatomical associations were determined a priori. Cross-tabulation and more complex frequency matrices for combination analyses were used to investigate the injury profile. Results Out of the 1,871 injured patients, 810 (43.3%) presented with a single injury. The rest had multiple injuries; 856 (45.8%) had two, 169 (9.0%) patients had three, 32 (1.7%) presented with four injuries, while only 4 (0.2%) were diagnosed with five injuries. The injury diagnoses of patients presenting with two-injuries showed important anatomical intra-site or neighboring clustering, which explained 49.1% of the combinations. For fractures, the result was even more marked as spatial clustering explained 57.9% of the association pattern. The most frequent combination of IDs was a double-fracture, affecting 20.7% of the two-injury patients (n = 177). Another 108 patients (12.6%) presented with fractures associated with crush injury and organ-soft tissue injury. Of the 3,177 injuries, 1,476 (46.5%) were fractures. Most injuries were located in the head (22.9%) and lower extremities (30.8%). Conclusions Multiple injuries are put forward as an important component of the injury profile after this earthquake. A pattern of injury combinations and spatial aggregation of injuries was also found. Clinical diagnosis and treatment should be adapted to care of these patients. More studies are needed to generalize these findings.

Figure 1: Observed versus predicted probability of all-cause CVICU readmission and number needed to identify (NNI) one readmission across risk deciles. The number needed to identify (NNI) one readmission is lower in higher readmission risk deciles. CVIVU: cardiovascular intensive care unit.
Table 1 Clinical characteristics of cardiac surgical patients with and without a cardiovascular intensive care unit readmission
Figure 2: The APPROACH CVICU readmission risk model nomogram. (A) The CVICU readmission risk score and (B) mean predicted CVICU readmission by APPROACH CVICU readmission risk score. APPROACH: Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease; CVICU: cardiovascular intensive care unit.
Table 2 Operative variables in patients with and without a cardiovascular intensive care unit readmission
Table 3 Postoperative complications in patients with and without a cardiovascular intensive care unit readmission
Predicting cardiovascular intensive care unit readmission after cardiac surgery: Derivation and validation of the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) cardiovascular intensive care unit clinical prediction model from a registry cohort of 10,799 surgical cases

November 2014


247 Reads

Introduction: In medical and surgical intensive care units, clinical risk prediction models for readmission have been developed; however, studies reporting the risks for cardiovascular intensive care unit (CVICU) readmission have been methodologically limited by small numbers of outcomes, unreported measures of calibration or discrimination, or a lack of information spanning the entire perioperative period. The purpose of this study was to derive and validate a clinical prediction model for CVICU readmission in cardiac surgical patients. Methods: A total of 10,799 patients more than or equal to 18 years in the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) registry who underwent cardiac surgery (coronary artery bypass or valvular surgery) between 2004 and 2012 and were discharged alive from the first CVICU admission were included. The full cohort was used to derive the clinical prediction model and the model was internally validated with bootstrapping. Discrimination and calibration were assessed using the AUC c index and the Hosmer-Lemeshow tests, respectively. Results: A total of 479 (4.4%) patients required CVICU readmission. The mean CVICU length of stay (19.9 versus 3.3 days, P <0.001) and in-hospital mortality (14.4% versus 2.2%, P <0.001) were higher among patients readmitted to the CVICU. In the derivation cohort, a total of three preoperative (age ≥ 70, ejection fraction, chronic lung disease), two intraoperative (single valve repair or replacement plus non-CABG surgery, multivalve repair or replacement), and seven postoperative variables (cardiac arrest, pneumonia, pleural effusion, deep sternal wound infection, leg graft harvest site infection, gastrointestinal bleed, neurologic complications) were independently associated with CVICU readmission. The clinical prediction model had robust discrimination and calibration in the derivation cohort (AUC c index = 0.799; Hosmer-Lemeshow P = 0.192). The validation point estimates and confidence intervals were similar to derivation model. Conclusions: In a large population-based dataset incorporating a comprehensive set of perioperative variables, we have derived a clinical prediction model with excellent discrimination and calibration. This model identifies opportunities for targeted therapeutic interventions aimed at reducing CVICU readmissions in high-risk patients.

Table 1 Comparison of values for biomarkers between dead and alive 
Table 2 
Table 3 Comparison of values for biomarkers between remained coma and regained consciousness 
Table 4 Values of cutoff points and predictive accuracy for remained coma 
Table 5 
S-100B and neuron-specific enolase as predictors of neurological outcome in patients after cardiac arrest and return of spontaneous circulation: A systematic review
Neurological prognostic factors after cardiopulmonary resuscitation (CPR) in patients with cardiac arrest (CA) as early and accurately as possible are urgently needed to determine therapeutic strategies after successful CPR. In particular, serum levels of protein neuron-specific enolase (NSE) and S-100B are considered promising candidates for neurological predictors, and many investigations on the clinical usefulness of these markers have been published. However, the design adopted varied from study to study, making a systematic literature review extremely difficult. The present review focuses on the following three respects for the study design: definitions of outcome, value of specificity and time points of blood sampling. A Medline search of literature published before August 2008 was performed using the following search terms: "NSE vs CA or CPR", "S100 vs CA or CPR". Publications examining the clinical usefulness of NSE or S-100B as a prognostic predictor in two outcome groups were reviewed. All publications met with inclusion criteria were classified into three groups with respect to the definitions of outcome; "dead or alive", "regained consciousness or remained comatose", and "return to independent daily life or not". The significance of differences between two outcome groups, cutoff values and predictive accuracy on each time points of blood sampling were investigated. A total of 54 papers were retrieved by the initial text search, and 24 were finally selected. In the three classified groups, most of the studies showed the significance of differences and concluded these biomarkers were useful for neurological predictor. However, in view of blood sampling points, the significance was not always detected. Nevertheless, only five studies involved uniform application of a blood sampling schedule with sampling intervals specified based on a set starting point. Specificity was not always set to 100%, therefore it is difficult to indiscriminately assess the cut-off values and its predictive accuracy of these biomarkers in this meta analysis. In such circumstances, the findings of the present study should aid future investigators in examining the clinical usefulness of these markers and determination of cut-off values.

Table 2 Details of medical and surgical in-flight emergencies. Percentages are based on 10,189 incidents from two European airlines January 2002 to December 2007.
Surgical and medical emergencies on board European aircraft: A retrospective study of 10189 cases

February 2009


202 Reads

In-flight medical and surgical emergencies (IMEs) onboard commercial aircrafts occur quite commonly. However, little epidemiological research exists concerning these incidents. Thirty-two European airlines were asked to provide anonymous data on medical flight reports of IMEs for the years 2002 to 2007. The total number of incidents was correlated to revenue passenger kilometers (rpk). Additionally, on-board births and deaths, flight diversions, flight routes (continental/intercontinental) and involvement of a physician or medical professional in providing therapy were analysed. Only four airlines, of which two participated in this study, were able to provide the necessary data. A total of 10,189 cases of IMEs were analysed. Syncope was the most common medical condition reported (5307 cases, 53.5%) followed by gastrointestinal disorders (926 cases, 8.9%) and cardiac conditions (509 cases, 4.9%). The most common surgical conditions were thrombosis (47 cases, 0.5%) and appendicitis (27 cases, 0.25%). In 2.8% of all IMEs, an aircraft diversion was performed. In 86% of cases, a physician or medical professional was involved in providing therapy. A mean (standard deviation) of 14 (+/- 2.3, 10.8 to 16.6 interquartile range) IMEs per billion rpk was calculated. The study demonstrates that although aviation is regulated by a variety of national and international laws, standardised documentation of IMEs is inadequate and needs further development.

Table 3 Initial blood pressure and target ranges at enrollment
Patient entry into CLUE trial.
SBP changes over time in patients randomized to receive either nicardipine or labetalol. Mean percent change and 95% confidence interval (CI), evaluated by Student's T test, relative to presenting blood pressure, during the initial 30 minutes, with the median upper level of target range and median target range indicated by horizontal dotted lines, in patients randomized to receive either nicardipine or labetalol. SBP, systolic blood pressure.
Heart rate changes over time in patients randomized to receive either nicardipine or labetalol. CI, confidence interval; HR, heart rate.
multivariable logistic regression model † for "met target systolic blood pressure within first 30 minutes".
103: CLUE: A Comparative Effectiveness Trial of Nicardipine Versus Labetalol Use In the Emergency Department

June 2011


338 Reads

Our purpose was to compare the safety and efficacy of food and drug administration (FDA) recommended dosing of IV nicardipine versus IV labetalol for the management of acute hypertension. Multicenter randomized clinical trial. Eligible patients had 2 systolic blood pressure (SBP) measures ≥180 mmHg and no contraindications to nicardipine or labetalol. Before randomization, the physician specified a target SBP ± 20 mmHg (the target range: TR). The primary endpoint was the percent of subjects meeting TR during the initial 30 minutes of treatment. Of 226 randomized patients, 110 received nicardipine and 116 labetalol. End organ damage preceded treatment in 143 (63.3%); 71 nicardipine and 72 labetalol patients. Median initial SBP was 212.5 (IQR 197, 230) and 212 mmHg (IQR 200,225) for nicardipine and labetalol patients (P = 0.68), respectively. Within 30 minutes, nicardipine patients more often reached TR than labetalol (91.7 vs. 82.5%, P = 0.039). Of 6 BP measures (taken every 5 minutes) during the study period, nicardipine patients had higher rates of five and six instances within TR than labetalol (47.3% vs. 32.8%, P = 0.026). Rescue medication need did not differ between nicardipine and labetalol (15.5 vs. 22.4%, P = 0.183). Labetalol patients had slower heart rates at all time points (P < 0.01). Multivariable modeling showed nicardipine patients were more likely in TR than labetalol patients at 30 minutes (OR 2.73, P = 0.028; C stat for model = 0.72) Patients treated with nicardipine are more likely to reach the physician-specified SBP target range within 30 minutes than those treated with labetalol.

Figure 1: Bland and Altman's graph for end-hour intracranial pressure (ICP)
Figure 2: Bland and Altman's graph for mean hourly intracranial pressure (ICP)
Figure 3: Bar graphs depicting the capabilities of the digital and manual systems to capture increases in intracranial pressure (ICP)
Figure 4: Bar graphs depicting the (a) digital and (b) manual percentages of time of intracranial hypertension (HICP) (> 20 mm Hg) for each patient and (c) the difference of digital and manual percentages of time of HICP
Zanier ER, Ortolano F, Ghisoni L, Colombo A, Losappio S, Stocchetti N. Intracranial pressure monitoring in intensive care: clinical advantages of a computerized system over manual recording. Crit Care.11:R7

February 2007


198 Reads

The presence of intracranial hypertension (HICP) after traumatic brain injury (TBI) affects patient outcome. Intracranial pressure (ICP) data from electronic monitoring equipment are usually calculated and recorded hourly in the clinical chart by trained nurses. Little is known, however, about how precisely this method reflects the real patterns of ICP after severe TBI. In this study, we compared hourly manual recording with a validated and continuous computerized reference standard. Thirty randomly selected patients with severe TBI and HICP admitted to the neuroscience intensive care unit (Policlinico University Hospital, Milan, Italy) were retrospectively studied. A 24-hour interval with ICP monitoring was randomly selected for each patient. The manually recorded data available for analysis covered 672 hours corresponding to 36,492 digital data points. The two methods were evaluated using the correlation coefficient and the Bland and Altman method. We used the proportion test to analyze differences in the number of episodes of HICP (ICP > 20 mm Hg) detected with the two methods and the paired t test to analyze differences in the percentage of time of HICP. There was good agreement between the digitally collected ICP and the manual recordings of the end-hour values. Bland and Altman analysis confirmed a mean difference between the two methods of 0.05 mm Hg (standard deviation 3.66); 96% of data were within the limits of agreement (+7.37 and -7.28). The average percentages of time of ICP greater than 20 mm Hg were 39% calculated from the digital measurements and 34% from the manual observations. From the continuous digital recording, we identified 351 episodes of ICP greater than 20 mm Hg lasting at least five minutes and 287 similar episodes lasting at least ten minutes. Conversely, end-hour ICP of greater than 20 mm Hg was observed in only 204 cases using manual recording methods. Although manually recorded end-hour ICP accurately reflected the computerized end-hour and mean hour values, the important omission of a number of episodes of high ICP, some of long duration, results in a clinical picture that is not accurate or informative of the true pattern of unstable ICP in patients with TBI.

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