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Alexandria Journal of Anaesthesia and Intensive Care 44

Autoclaved Gelatin (Haemagel) Versus 6% Hydroxyethyl Starch 200/0.5 (Haes-steril) For Plasma Volume Expansion In Critically-ill Patients Magdy Ali Omera, MD* , Salah A. Ismail, MD* * Assistant Prof. of Anaesthesia, Faculty of Medicine, Suez Canal University.

ABSTRACT Synthetic colloids are used to optimize hemodynamics in the critically ill patients and a debate about the most suitable one is still present. The influence of short term infusion of autoclaved gelatin (Haemagel) and 6% hydroxyethyl starch 200/0.5 (Haes-steril) on hemodynamic, respiratory, , renal and oncotic parameters were examined in a prospective randomized study. Method: Thirty patients suffering from systemic hypoperfusion due to in ICU of Suez Canal University Hospital were assigned into 2 equal groups. In GEL group: 1000 ml of Haemagel was infused within an hour, while in HES group: 1000 ml of 6% Haes-steril 200/0.5 was given within an hour. The hemodynamic, respiratory, hematological, coagulation, renal and colloidal osmotic pressure parameters were recorded before and after infusion of both colloids. Results: There was a significant similar increase in hemodynamic variables (Mean arterial pressure, central venous pressure, cardiac index, stroke volume index and left ventricular stroke work index) in both groups. Also, a significant improvement in tissue perfusion as judged by decreased arterial lactate was found. There were no significant differences in any of the measured respiratory parameters (respiratory rate, arterial oxygen saturation, arterial gases and intrapulmonary shunt) in the studied groups. No significant intergroup difference in any haemodynamic or respiratory variable was demonstrated. A significant expansion in plasma volume as indicated by the significant reduction in haematocrit was detected. There were insignificant changes in coagulation profile (prothrombin time, activated partial thromboplastin time, bleeding time and fibrinogen) in either group except the count which was significantly reduced in both groups without any recorded bleeding complications. Creatinine, blood nitrogen, and potassium didn't change and were comparable in the two groups. Colloidal osmotic pressure and urine output increased significantly in either group. Anaphylactic reactions were not observed in any of the patients. However, no significant differences between both groups in haematological, coagulation, renal and oncotic parameters were found. Conclusion: Both autoclaved gelatin (Haemagel) and 6% hydroxyethyl starch 200/0.5 (Haes-steril) are safe and equally effective colloids for plasma volume expansion in critically ill patients without apparent adverse effects on respiration, coagulation and renal functions.

INTRODUCTION stabilization. There are several studies In critically-ill patients, acute circula- showing the advantages of colloid solution tory failure is often associated with over crystalloid volume replacement (3,4) intravascular volume depletion which and a debate about the choice of specific contributes to inadequate cardiac output, colloid is still present(5). Although the tissue hypoperfusion, and development of naturally occurring colloidal agent (albumin) multiple organ failure (1). Replacement of is effective for fluid resuscitation, it is also intravascular deficit remains the most very expensive with the potential risk of important therapeutic maneuver in mana- infection(6). has not been widely gement of those patients to ensure adeq- used because it might result in increased uate cardiac output(2). Whilst crystalloids bleeding, allergic reaction, possible renal are virtually free of major side effects, toxicity and problems with blood cross- they don't necessarily ensure adequate matching(7). volume replenishment or hemodynamic

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Hydroxyethyl starch (HES), a synthetic on a clinical ground in the presence of colloid with a high volume expanding sepsis and systemic hypo-perfusion. effect, is produced by hydroxylation of Sepsis was diagnosed, in addition to the starch amylopectin. HES (200/0.5) positive blood culture, by the presence has a molecular weight (200,000 D) of 3 of the following 5 criteria; which allows rapid elimination by tachycardia (HR >100 beat/min), tachy- (8). It also has a low molar substitution pnea (RR >25 breath/min), temperature ratio (0.5) making it more rapidly and (>380C or <360C), leucocytic count completely degraded by circulating (>15,000 or <3,500 /mm3), platelet count amylase with less tissue retention (8). (<150,000 /mm3)(19). Systemic hypo- Since HES has the fewest perfusion was diagnosed by the anaphylactoid reactions among the presence of mean arterial pressure less artificial colloids, it is the most comm.- than 60 mmHg, cardiac index less than only clinically used colloid (9). However, 2.2 L/min/m2 and arterial lactate more large doses of this solution may than 2.0 mmol/L (19). increase bleeding by inducing coagu- Exclusion criteria were patients less lopathy through an effect on factor VIII than 18 years, heart failure, renal activity (8, 10-12). impairment (creatinine > 2 mg/dl and Different colloid solutions containing BUN >100 mg/dl), cerebral hemorrhage, gelatin have been developed. Collagen patients having PT >18 sec, aPTT >45 is degraded via both a thermal effect sec, fibrinogen < 150 mg/dl or Hct <30% producing oxypolygelatin (OPG), and an and to any of the examined enzymatic effect producing either colloids. All patients were assessed by modified fluid gelatin (Gelofusine), or history, full clinical examination, arterial urea cross-linked gelatin (Haemaccel), blood gas analysis, 12 leads ECG and while double degradation and auto- laboratory investigations for the pre- claving producing (Haemagel). Haema- sence of inclusion and exclusion criteria. gel is a balanced salt gelatin-based The included patients were subjected to colloidal solution (100 mL contains 4 g the following: 1] Insertion of arterial line gelatin). It has a higher half-life, no in the dominant radial artery after pseudo agglutination, and no possible modified Allen's testing for sampling of contamination (13). Although researchers arterial blood gas and arterial lactate have studied gelatin for volume (AL) (using ABL 520 Radiometer), replacement, its safety and efficacy colloidal osmotic pressure (using a have not been fully investigated (14-18). Colloid Osmometer (20)). 2] Insertion of So, this study compared autoclaved central venous catheter for measure- gelatin (Haemagel) with 6% hydroxyl- ment of central venous pressure (CVP). ethyl starch 200/0.5 (Haes-steril) in term 3] Insertion of Foley's catheter for of efficacy and safety as a short term measurement of urine output (UOP). 4] in critically-ill patients. Placing a peripheral venous cannula for laboratory sampling. 5] Connecting the PATIENTS AND METHODS electrodes of thoracic electrical biome- After approval of the local ethics pedence apparatus (TEB), a non-invasive committee and an informed consent haemodynamic monitor (NCCOM-3, Bomed, from each patient or his/her family, thirty Medical manufacturing Ltd., Irvine, CA)(21) critically-ill patients in ICU of Suez Canal for non-invasive measure-ments of cardiac University Hospital suffering from systemic index (CI), stroke volume index (SVI), hypoperfusion due to sepsis were left ventricular stroke work index (LVSWI), enrolled in this study. Inclusion criteria and sys-temic vascular resistance index were patients who required fluid therapy (SVRI). 6] Continuous monitoring of ECG,

AJAIC-Vol. (8) No. 2 June 2005 Alexandria Journal of Anaesthesia and Intensive Care 46 heart rate (HR), core temperature physician not involved in the study and (Temp), respiratory rate (RR), arterial who was blind to the grouping. oxygen saturation (SaO2) and non- All results are expressed as means ± invasive mean arterial blood pressure SD. The change in different parameters (MAP) measurement through a continuous compared to the baseline values was display (S/5, Datex Ohmeda, Instru- analyzed using paired t-test. The mentation Corp, Finland). difference between the two groups was Baseline data were recorded before the assessed by one way analysis of variant start of infusion; (ANOVA). A p value <0.05 was A] Patient characteristics: Age, sex, considered statistically significant. weight, height, body surface area (BSA), temperature and clinical diagnosis. RESULTS B] Hemodynamic parameters: HR, Demographic data: MAP, CVP, CI, SVI, LVSWI and SVRI Age, sex, weight, height, BSA, were measured in supine position. temperature and clinical diagnosis were C] Respiratory data: RR, SaO2, arterial comparable in both groups (table 1). blood gases [pH, arterial oxygen tension (PaO2), arterial carbon dioxide tension Hemodynamic parameters: (PaCO2), bicarbonate (HCO3)] and There were no significant differences intrapulmonary shunt [obtained through in baseline hemodynamic values bet- ABL 520 Radiometer]. ween both groups. After infusion, there D] Hematological and coagulation was a significant increase in MAP, CVP, parameters: Haematocrit (Hct), platelet CI, SVI and LVSWI without intergroup count, prothrombin time (PT), activated differences. Significant decreases in partial thromboplastin time (aPTT), SVRI and AL level in addition to an bleeding time (BT) and fibrinogen (22). insignificant change in HR were found in E] Renal function and : Urine both groups with insignificant differe- output (UOP), serum creatinine, blood nces in between (table 2). urea nitrogen (BUN), serum sodium (Na+) and potassium (K+) (22). Respiratory data: F] Colloidal osmotic pressure (COP) There were no significant differences and arterial lactate (AL) were also in baseline respiratory parameters measured. between both groups. After infusion, Using a randomized sequence, the there were insignificant increases in patients were prospectively assigned to SaO2, pH, PaO2, PaCO2, and HCO3 one of the following groups: without intergroup differences. Insig- 1) Group (GEL): where 1000 ml of nificant changes in shunt fraction and Haemagel (each 100 ml contains: RR were detected in both groups with Autoclaved gelatin 4 g, 1 g, NaCl no significant differences in between 0.859 g, KCl 0.0389 g and CaCl 0.029 (table 3). g, Vacsera, Holding company for biological products and vaccines, Egypt) Hematological and coagulation variables: was infused during an hour. There were no significant differences 2) Group (HES): where 1000 ml of 6% in baseline hematological and coagul- Haes-steril (HES 200/0.5, MW 200,000, ation profile between both groups. After DS 0.5, Fresenius Kabi, Bad Hamburg, infusion, there was a significant decr- Germany) was infused during an hour. ease in in the studied After the end of infusion, all the previous groups. Also, PT, aPTT and BT were parameters were recorded again by a insignificantly prolonged with an insignificant decrease in fibrinogen in

AJAIC-Vol. (8) No. 2 June 2005 Alexandria Journal of Anaesthesia and Intensive Care 47 both groups. In addition, there was a still uncertain which solution is most significant decrease in platelet count in suitable for fluid resuscitation in these GEL and HES groups. However, no patients(9). The goal in fluid resuscitation significant differences between both is to maintain an effective intravascular groups in any hematological or coagu- blood volume, subsequently, enhancing lation parameter were detected (table cardiac output, oxygen delivery and 4). tissue perfusion(1,2,6). However, to achi- eve these goals, attempts are tried to Renal function and electrolytes minimize possible deterioration in Urine volume increased significantly pulmonary, renal and other system after infusion of both colloids without functions. significant differences between both The aim of this study was to groups. Creatinine, BUN and electro- compare the effect of short-term infusion lytes (Na+ and K+) were not changed of autoclaved gelatin and 6% hydroxyl- and were comparable in both groups ethyl starch on hemodynamic, res- (table 5). piratory, hematologic, coagulation, renal and oncotic pressure variables in a Colloidal osmotic pressure controlled prospective manner. In both groups, the baseline COP In the present study, MAP, CVP, CI, was within normal range (more than 18 SVI and LVSWI were significantly mmHg). After infusion, there was a increased in both groups. While SVRI significant increase in both groups and AL were significantly decreased, without intergroup differences (table 6). HR did not change significantly during No allergic reactions or bleeding the study. However, no significant complications were recorded in any differences between the studied groups studied patient in these parameters were found. The improvement in these hemodynamic DISCUSSION variables and arterial lactate levels are Hypovolemia is a common clinical always associated with favorable occurrence in severe sepsis and fluid prognosis in critically-ill patients (1, 2). resuscitation remains one of the most important interventions. However, it is

Table 1: Demographic data in both Haemagel (GEL) and Haes-steril (HES) groups. Parameter GEL group HES group Age (years) 55 ± 11 53 ± 13 Sex ( M/F) 7/8 8/7 Weight (kg) 73 ± 12 75 ± 10 BSA (m2) 1.88 ± 0.20 1.86 ± 0.23 Temperature (0C) 37.3 ± 0.4 38.0 ± 0.3 Number of patients 15 15 Diagnosis: Pneumonia 6 7 Peritonitis 6 6 Urinary infection 3 2 Data are represented as means ± SD unless otherwise noted. M = Male, F = Female, BSA = Body surface area.

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Table 2: Hemodynamic and arterial lactate changes in both Haemagel (GEL) and Haes-steril (HES) groups. Parameter Group Baseline data Post infusion data HR (beat/min) GEL 100 ± 7 99 ± 8 HES 102 ± 5 103 ± 7 MAP (mmHg) GEL 62.2 ± 2.7 74.3 ± 5.1* HES 60.5 ± 7.6 73.1 ± 4.3* CVP (cmH2O) GEL 5.6 ± 1.4 9.3 ± 1.5* HES 4.8 ± 1.9 8.5 ± 1.3* CI (L/min.m2) GEL 2.2 ± 0.3 3.5 ± 0.6* HES 2.3 ± 0.2 3.5 ± 0.4* SVI (ml/m2) GEL 29.0 ± 6.6 37.5 ± 3.8* HES 27.7 ± 3.1 35.5 ± 4.6* LVSWI (gm.m/m2) GEL 20.8 ± 3.6 35.6 ± 3.3* HES 21.6 ± 5.4 35.2 ± 4.2* SVRI (dyne.sec/cm5.m2) GEL 1861 ± 149 1558 ± 246* HES 1978 ± 222 1660 ± 234* AL (mmol/L) GEL 2.7 ± 1.6 1.4 ± 1.2* HES 2.9 ± 1.4 1.5 ± 1.5* Data are presented as means ± SD. *A significant difference within each group compared to baseline P < 0.05. HR = Heart rate, MAP = Mean arterial pressure, CVP = Central venous pressure, CI = Cardiac index, SVI = Stroke Volume index, LVSWI = Left ventricular stroke work index, SVRI = Systemic vascular resistance index, AL = Arterial lactate.

Table 3: Respiratory changes in both Haemagel (GEL) and Haes-steril (HES) groups. Parameter Group Baseline data Post infusion data RR (breath/min) GEL 20.0 ± 2 19.0 ± 3 HES 22.0 ± 4 21.0 ± 3 SaO2 (%) GEL 96.0 ± 1.7 97.1 ± 1.3 HES 97.5 ± 0.5 98.6 ± 0.7 pH GEL 7.33 ± 0.06 7.37 ± 7.34 ± 0.05 7.38 ± HES 0.03 0.02 PaO2 (mmHg) GEL 88.0 ± 16 90.0 ± 12 HES 86.0 ± 18 88.0 ± 14 PaCO2 (mmHg) GEL 33.0 ± 2.7 35.0 ± 2.3 HES 36.0 ± 1.5 38.0 ± 2.0 HCO3 (mmol/L) GEL 19.3 ± 2.3 20.0 ± 1.7 HES 17.9 ± 1.5 18.4 ± 1.4 Qs/Qt (%) GEL 16.5 ± 3 17.1± 5 HES 18.3 ± 4 19.0 ± 5 Data are presented as means ± SD and percentage. RR = Respiratory rate, SaO2 = Arterial oxygen saturation, PaO2 = Arterial oxygen tension, PaCO2 = Arterial carbon dioxide tension, HCO3 = Bicarbonate and Qs/Qt = Intra-pulmonary shunt fraction.

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Table 4: Hematologic and coagulation changes in both Haemagel (GEL) and Haes-steril (HES) groups. Parameter Group Baseline data Post infusion data Hct (%) GEL 38.8 ± 3.4 30.2 ± 3.2* HES 36.9 ± 2.8 29.5 ± 4.7* PT (sec) GEL 14.7 ± 0.5 15.0 ± 0.8 HES 13.9 ± 1.2 14.4 ± 0.6 aPTT (sec) GEL 35.7 ± 3.3 37.2 ± 3.1 HES 38.5 ± 2.9 39.8 ± 2.4 BT (min) GEL 6.2 ± 0.4 6.4 ± 0.2 HES 5.8 ± 0.6 6.0 ± 0.3 Fibrinogen (mg/dl) GEL 300 ± 88 295 ± 64 HES 320 ± 77 310 ± 45 (1000/mm3) GEL 200 ± 48 150 ± 86* HES 210 ± 55 150 ± 37* Data are presented as means ± SD. *A significant difference within each group compared to baseline P < 0.05. Hct = Hematocrit, PT = Prothrombin time, aPTT = Activated partial thromboplastin time, BT = Bleeding time.

Table 5: Electrolytes and renal changes in both Haemagel (GEL) and Haes- steril (HES) groups. Parameter Group Baseline data Post infusion data UOP (ml/h) GEL 50 ± 15 90 ± 20* HES 55 ± 10 95 ± 15* Creatinine (mg/dl) GEL 1.2 ± 0.4 1.3 ± 0.2 HES 1.3 ± 0.5 1.3 ± 0.3 BUN (mg/dl) GEL 20.5 ± 2.3 20.1 ± 1.5 HES 22.2 ± 1.4 21.8 ± 1.9 Na+ (mmol/L) GEL 138 ± 6 137 ± 5 HES 136 ± 9 136 ± 7 K+ (mmol/L) GEL 3.9 ± 0.4 4.0 ± 0.2 HES 4.1 ± 0.2 4.1 ± 0.6 Data are presented as means ± SD. *A significant difference within each group compared to baseline P < 0.05. UOP = Urine output, BUN = Blood urea nitrogen, Na+ = Sodium, K+ = Potassium.

Table 6: Changes in colloidal osmotic pressure (mmHg) in both Haemagel (GEL) and Haes-steril (HES) groups. Group Baseline data Post infusion data GEL 19.6 ± 1.1 22.1 ± 1.4* HES 18.5 ± 1.5 21.2 ± 1.2* Data are presented as means ± SD. *A significant difference within each group compared to baseline P <0.05.

These results are consistent with those 500 ml HES 200/0.6 versus 500 ml of other investigators who showed that Gelofusine on macro and micro- colloid solutions effectively improve circulation of the splanchnic region in hemodynamic in critically-ill patients. septic patients. They observed similar Asfar et al (14), examined the influence of improvement in hemodynamics with

AJAIC-Vol. (8) No. 2 June 2005 Alexandria Journal of Anaesthesia and Intensive Care 50 better normalization of the hypoxic colloids (6% HES 130/0.4, 6% HES gastric mucosal acidosis with Gelofusine 200/0.5 and Gelofusine) on the rather than HES. Beyer et al (15), coagulation system using Rotation compared 6% HES 200/0.5 with Thrombelastography (ROTEG). They Gelofusine for volume replacement in found that Gelofusine had the lowest patients undergoing orthopedic . effect on coagulation. Haisch et al(11) They studied the effect of either colloid examined the influence of HES 130/0.4 on hemodynamic, colloidal osmotic versus Gelofusine on coagulation and pressure and blood clotting. Equivalent hemodynamic data in patients under- hemodynamic effects were found going major abdominal surgery, where without alteration of coagulation profile. both colloids were effective with Molnar et al (23) investigated the short insignificant changes in coagulation term cardio-respiratory effects of 250 ml variables or blood loss. The effect of Gelofusine versus 250 ml HES 200/0.6 progressive in vitro hemodilution on in patients with septic and acute coagulation was measured by lung . They found significant SONOCLOT(17), where HES showed the increases in CI and O2 delivery in both largest impact on markers of groups with insignificant differences in coagulation compared with gelatin or extra vascular lung water (no interstitial lactated Ringer's solution. In an or ). experimental study(25), HES infusion in The respiratory and blood gas excess of 20 ml /kg was associated with parameters did not change significantly an increase in bleeding time, thrombin in both groups and were similar during time together with a decrease in platelet the study. Consistent results were count and serum fibrinogen. Also, Van demonstrated in previous studies (2, 6). Wyk et al(26) did not find any evidence Also, Ritto et al (16) showed no changes that haemaccel affects haemostasis; in arterial blood gases after Gelofusine neither does it increase bleeding relative or HES infusion, with no shunt affection. to Ringer's lactate in plasma expansion Expansion of plasma volume as during reduction mammoplasty. In indicated by the significant decrease in addition, Amany et al(27) showed only hematocrit was similar in both groups. minor effects on clotting variables and Both colloids have been shown to cause platelet aggregation compared to 6% a slight insignificant prolongation in PT, HES 200/0.5, even at doses more than aPTT and BT in addition to an 20 ml/Kg /day in patients undergoing insignificant decrease in fibrinogen. This major abdominal surgery. On the could be attributed to hemodilution contrary, limited data suggest that which in another previous study (24), was gelatin based solutions may affect proven to be dose related. There was a coagulation(28, 29). significant decrease in platelet count The significant increase in UOP was without significant change in bleeding probably due to increased blood volume time in any group of the current study. in both groups. Creatinine, BUN, Na+ The present work showed neither and K+ did not change significantly and significant differences between the two were comparable in both groups colloids with respect to coagulation indicating insignificant effects on kidney parameters, nor bleeding complications. functions. These results are consistent Several previous researches studied the with Vogt et al study(12). In contrast, influence of hydroxyethyl starch and Amany et al found that creatinine gelatin on coagulation and bleeding clearance was significantly decreased in parameters(10,11,17,24-29). Fries et al(10) HES group compared to Haemagel analyzed the influence of different group (27).

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Colloidal osmotic pressure (COP) 3. Nagy KK, Davis J, Duda J, et al. A could be a desirable goal in volume comparison of pentastarch and lactated replacement because it maintains Ringer's solution in the resuscitation of normal extravascular water content in patients with hemo-rrhagic shock. Circ many organs (1, 6). Profound reduction in Shock 1993; 40:289. 4. Olthof CG, de Vries JP, de Vries PM, et COP may reduce left ventricular al. The influence of Ringer's lactate and compliance, increase pulmonary extra- gelatin infusion on the internal fluid vascular water content and decrease (19) balance of healthy volunteers measured tissue oxygen delivery . In this study by a non-invasive conductivity GEL and HES were effective in technique. Eur J Anaesth 1993; 10:397. maintaining COP without significant 5. Boldt J, Müller M, Heesen M, et al. differences between both groups. This Influence of different volume thera-pies was also documented by several studies on platelet function in the critically ill. where plasma volume and colloid Intensive Care Med 1997; 23:709. osmotic pressure were maintained even 6. Boldt J, Heesen M, Müller M, et al. The in with capillary leak (30-32). effects of albumin versus hydro-xyethyl starch on cardio-respiratory and In fact, no allergic reactions to either circulatory variables in critically ill colloid were observed in any patient of patients. Anesth Analg 1996; 83:254. the present study. This is agrees with 7. Petroianu GA, Jie Liu, Maleck WH, et al. previous researches on either colloid The effect of in vitro hemo-dilution with where extremely low incidence of such gelatin, dextran, hydro-xyethyl starch, or reaction was reported (9, 33). Ringer's solution on In conclusion, autoclaved gelatin Thrombelastography. Anesth Analg (Haemagel) showed similar efficacy and 2000; 90:795. safety as 6% hydroxyethyl starch 8. Boldt J, Haisch B, Suttner S, et al. 200/0.5 (Haes-steril) for plasma volume Effects of a new modified, balanced expansion in critically ill patients. Both hydroxyethyl starch preparation (Hextend) on measures of coagula-tion. solutions improved the hemodynamic Br J Anaesth 2002; 89:722. responses and tissue perfusion without 9. Laxenaire M C, Mertes P, et al. apparent adverse effects on respiration, Anaphylaxis during anaesthesia: coagulation, and renal functions. A Results of two-years survey in France. further study may be required to Br J Anaesth 2001; 87: 549. evaluate the effects of prolonged 10. Fries D, Innerhofer P, Klinger A, et al. administration or larger doses of this The effects of the combined gelatin solution (Haemagel) in critically administration of colloids and lactated ill patients. Ringer's solution on the coagulation system: An in vitro study using ® REFERENCES thrombelastograph coagula-tion analysis (ROTEG®). Anesth Analg 2002; 1. Hankeln K, Radel C, Beez M, et al. 94:1280. Comparison of hydroxyethyl starch and 11. Haisch G, Boldt J, Krebs C, et al. The lactated Ringer's solution on influence of intravascular volume hemodynamics and oxygen transport of therapy with a new hydro-xyethyl starch critically ill patients in prospective preparation [6% HES 130/0.4] on crossover studies. Crit Care Med 1989; coagulation in patients undergoing 17: 133. major abdominal surg-ery. Anesth Analg 2. Rackow EC, Mecher C, Astiz ME, et al. 2001; 92:565. Effects of pentastarch and albumin 12. Vogt NH, Bothner U, Lerch G, et al. infusion on cardio-respiratory function Large-dose administration of 6% and coagulation in patients with severe hydroxyethyl starch 200/0.5 for total hip sepsis and systemic hypo-tension. Crit arthroplasty: Plasma homeo-stasis, Care Med 1989; 17:394. hemostasis, and renal func-tion

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32. Kohler H, Zchiedrich H, Clasen R, et al. 33. Kimme P, Jannsen B, Ledin T, et al. Blood volume, colloidal osmotic High incidence of pruritis after large pressure and renal function in doses of hydroxyethyl starch (HES) volunteers after infusion of middle- infusions. Acta Anaesthesiol Scand molecular 10% hydroxyethyl starch 2001; 45: 686. 200/0.5 and 10% dextran 40. Anaesthesist 1989; 38: 1.

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