Blood acid-base, haematological and haemostatic effects of hydroxyethyl starch (130/0.4) compared to succinylated gelatin colloid infusions in normovolaemic dogs.

Synthetic colloids are commonly administered to dogs to treat absolute or relative hypovolaemia. Voluven® (tetrastarch 130/0.4) and Gelofusine® (succinylated gelatin) are available to veterinarians in South Africa. In humans, use of these products has caused acid-base derangements, changes in haematology and impaired haemostasis. We aimed to investigate these effects in healthy normovolaemic dogs. Eight healthy adult beagle dogs underwent a cross-over study, receiving Voluven® or Gelofusine® (10 mL/kg/h for 120 min) once each with a 14-day washout between treatments. Dogs were premedicated with dexmedetomidine (10 µg/kg intramuscularly). Anaesthesia was induced with propofol and the dogs were maintained with isoflurane-in-oxygen. The anaesthetised dogs were connected to a multi-parameter monitor to monitor physiological parameters throughout. Catheters placed in a jugular vein and dorsal metatarsal artery allowed sampling of venous and arterial blood. Blood was collected immediately prior to commencement of colloid infusion, after 60 min infusion and at the end of infusion (120 min) to allow for arterial blood gas analysis, haematology and coagulation testing (activated partial thromboplastin time [aPTT], prothrombin time [PT] and thromboelastography [TEG]). There was no effect, between treatments or over time, on blood pH. The haemoglobin concentration, erythrocyte count and haematocrit decreased significantly over time (all p 0.01), with no differences between treatments, and remained within normal clinical ranges. There were no differences between treatments or over time for the TEG, aPTT and PT tests of haemostasis. At the dose studied, Voluven® and Gelofusine® had comparably negligible effects on blood acid-base balance and coagulation in normovolaemic dogs.

Quantification of volume loss and haemodynamic changes of Gelofusine-induced anaphylaxis during cardiopulmonary bypass.

A patient undergoing anaesthesia for coronary artery bypass surgery developed what was subsequently confirmed to be an anaphylactic reaction to succinylated gelatin (Gelofusine). By virtue of being on cardiopulmonary bypass, rapid detection, quantification and treatment of volume loss (by vasodilatation and extravasation) was possible. The patient required 51 ml/kg of resuscitative fluids in the 15 minutes after onset of anaphylaxis, or 73% of her calculated preoperative blood volume. Alpha-adrenoceptor agonists and vasopressin were required to manage ongoing vasoplegia. This case emphasises the importance of volume resuscitation and vasopressors in the treatment of anaphylaxis.

Is 6% hydroxyethyl starch 130/0.4 safe in coronary artery bypass graft surgery?

The aim of this study was to compare 6% hydroxyethyl starch 130/0.4 with 4% succinylated gelatin for priming the cardiopulmonary bypass circuit and as volume replacement in patients undergoing coronary artery bypass, in terms of postoperative bleeding, blood transfusion requirements, renal function, and outcome after surgery. Forty-five patients received 6% hydroxyethyl starch 130/0.4 (Voluven) and another 45 were given 4% succinylated gelatin (Gelofusine) as the priming solution for the cardiopulmonary bypass circuit as well as for volume replacement. Postoperative bleeding was quantified from the hourly chest drainage in the first 4 h and at 24 h postoperatively. The baseline characteristics of both groups were similar. In the hydroxyethyl starch group, the total amount of colloid used was 1.9 +/- 1.0 L, while the gelatin group had 2.0 +/- 0.7 L. There was no significant difference in hourly chest drainage between groups. Blood transfusion requirements, estimated glomerular filtration rate, extubation time, intensive care unit and hospital stay were similar in both groups. It was concluded that 6% hydroxyethyl starch 130/0.4 is a safe alternative colloid for priming the cardiopulmonary bypass circuit and volume replacement in patients undergoing coronary artery bypass surgery.

Does anaesthetic management affect early outcomes after lung transplant? An exploratory analysis.

BACKGROUND: Primary graft dysfunction (PGD) is a predominant cause of early morbidity and mortality after lung transplantation. Although substantial work has been done to understand risk factors for PGD in terms of donor, recipient, and surgical factors, little is understood regarding the potential role of anaesthetic management variables in its development. METHODS: We conducted a retrospective exploratory analysis of 107 consecutive lung transplants to determine if anaesthesia factors were associated with early graft function quantified by Pa(O(2))/Fi(O(2)). Multivariate regression techniques were used to explore the association between anaesthetic management variables and Pa(O(2))/Fi(O(2)) ratio 12 h after operation. The relationship between these variables and both time to tracheal extubation and intensive care unit (ICU) length of stay was further examined using the Cox proportional hazards. RESULTS: On multivariate analysis, increasing volume of intraoperative colloid, comprising predominantly Gelofusine (succinylated gelatin), was independently associated with a lower Pa(O(2))/Fi(O(2)) 12 h post-transplantation [beta coefficient -42 mm Hg, 95% confidence interval (CI) -7 to -77 mm Hg, P=0.02] and reduced rate of extubation [hazard ratio (HR) 0.65, 95% CI 0.49-0.84, P=0.001]. There was a trend for intraoperative colloid to be associated with a reduced rate of ICU discharge (HR 0.79, 95% CI 0.31-1.02, P=0.07). CONCLUSIONS: We observed an inverse relationship between volume of intraoperative colloid and early lung allograft function. The association persists, despite detailed sensitivity analyses and adjustment for potential confounding variables. Further studies are required to confirm these findings and explore potential mechanisms through which these associations may act.

Molecular imaging of reduced renal uptake of radiolabelled [DOTA0,Tyr3]octreotate by the combination of lysine and Gelofusine in rats.

AIM: In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, kidney uptake of radiolabelled compound is the major dose-limiting factor. We studied the effects of Gelofusine (20 mg) and lysine (100 mg) and the combination of both after injection of therapeutic doses of radiolabelled [DOTA0,Tyr3]octreotate (60 MBq 111In or 555 MBq 177Lu labelled to 15 microg peptide) in male Lewis rats. METHODS: Kidney uptake was measured by single photon emission computed tomography (SPECT) scans with a four-headed multi-pinhole camera (NanoSPECT) at 24 h, 5 and 7 days p. i. and was quantified by volume of interest analysis. For validation the activity concentration in the dissected kidneys was also determined ex vivo using a gamma counter and a dose calibrator. RESULTS: Gelofusine and lysine both reduced kidney uptake of [177Lu-DOTA0,Tyr3]octreotate significantly by about 40% at all time points. The combination of Gelofusine and lysine resulted in a 62% inhibition of kidney uptake (p < 0.01 vs. lysine alone). A weak but significant dose-response relationship for Gelofusine, but not for lysine, was found. In a study with [111In-DOTA0,Tyr3]octreotate, conclusions drawn from NanoSPECT data were confirmed by biodistribution data. CONCLUSIONS: We conclude that rat kidney uptake of radiolabelled somatostatin analogues can be monitored for a longer period in the same animal using animal SPECT. Gelofusine and lysine had equal potential to reduce kidney uptake of therapeutic doses of [177Lu-DOTA0,Tyr3]octreotate. The combination of these compounds caused a significantly larger reduction than lysine or Gelofusine alone and may therefore offer new possibilities in PRRT. The NanoSPECT data were validated by standard biodistribution experiments.

Severe anaphylaxis to Gelofusine during a transthoracic echo bubble study.

We describe a severe anaphylactic reaction to Gelofusin, used as part of a transthoracic echo study on a middle-aged woman who had suffered a prior cerebral event.

Portal hypertension and blood viscosity.

Previous studies, exploring the effect of blood viscosity on portal pressure in portal hypertensive humans and animal models, have shown conflicting results. In a series of studies, in portal vein constricted rats, we investigated effects of reduced blood viscosity on the hyperdynamic circulation, portal pressure, and vascular geometry. Blood was withdrawn at a rate of 0.3 mL/min for 15 minutes followed by 15 minutes of stabilization. The shed blood or Haemaccel was infused at the same rate and volume as used for withdrawal. Hemodynamic measurements were performed using radioactive microspheres. Blood viscosity was measured with an Ostwald viscometer. Vascular hindrance (reflecting vessel geometry) was calculated as resistance/viscosity ratio. In normal and portal hypertensive rats, acute volume replacement with Haemaccel, induced increase in systemic and splanchnic blood flows reflecting mainly changes in viscosity and not in blood vessel geometry. However, 24 hours later, in Haemaccel treated animals, an increased splanchnic arteriolar and porto-collateral vascular hindrance were observed. This indicated vasoconstriction in the porto-collateral vascular bed. The increase in portal venous inflow after acute volume restitution with Haemaccel was prevented by pretreatment with propranolol. Although, caution should be taken in extrapolating these results to humans, we would like to speculate that during a portal hypertensive-related bleeding episode: (1) volume replacement with low viscosity plasma expanders may aggravate the hyperdynamic circulation of portal hypertension. (2) Slow rate volume replacement enables hemodynamic adaptation to occur. (3) Volume replacement maybe more safe in a subject pretreated with propranolol.

Impairment of coagulation by commonly used resuscitation fluids in human volunteers.

BACKGROUND: This study compared the effects of two commonly used resuscitation fluids on whole blood coagulation. METHODS: 1000 ml of two resuscitation fluids each (saline and Gelofusine) were given to eight volunteers in a crossover design with a 2-week washout period. The effect on whole blood coagulation was assessed using the Sonoclot analyzer, a conventional coagulation screen and coagulation markers. RESULTS: No significant effect was found on whole blood coagulation by giving saline (time to peak clot increased by a mean of 106 s; (95% confidence interval (CI) -140 to 354), whereas Gelofusine delayed the time to peak by a mean of 845 s (95% CI 435 to 1255). By contrast, there was no change in the conventional coagulation screen with either fluid. CONCLUSION: It was concluded that some resuscitation fluids have an effect on clot formation that is not shown by the conventional coagulation screen, but is disclosed only if the whole coagulation process is studied.

Comparison of outcome in patients with cirrhosis and ascites following treatment with albumin or a synthetic colloid: a randomised controlled pilot trail.

BACKGROUND: The question of which colloid (albumin or synthetic colloids) used for plasma expansion following paracentesis or other complications requiring fluid loading in patients with cirrhosis remains controversial. AIMS: To compare outcome and hospital-related cost in patients with cirrhosis treated with 20% human albumin with those treated with a synthetic colloid (3.5% polygeline). METHODS: The primary end point was occurrence of a first liver-related complication. RESULTS: When the trial was prematurely discontinued because of safety concerns about bovine-derived products, 30 patients were assigned to receive albumin and 38 were assigned to receive a synthetic colloid. Sixty-three patients were included for ascites removal by paracentesis and five patients for ascites removal by paracentesis and renal impairment. The median time to first liver-related complication was not significantly longer in the albumin group (20 vs. 7 days). However, the total number of liver-related complications adjusted to a 100-day period was significantly lower in the albumin group. The median hospital cost for a 30-day period was significantly lower in the albumin group (1915 euros vs. 4612 euros). CONCLUSIONS: In patients with cirrhosis and ascites, human albumin appears to be more effective in preventing liver-related complications than synthetic colloid. This may be associated with decreased hospital costs.

Drug-induced anaphylaxis : case/non-case study based on an italian pharmacovigilance database.

OBJECTIVE: To identify the number of cases of anaphylaxis reported in association with different classes of drugs and compare it with other reports contained in the same database. METHODS: The data were obtained from a database containing all of the spontaneous reports of adverse drug reactions (ADRs) coming from the Italian regions of Emilia Romagna, Lombardy and the Veneto, which are the main contributors to the Italian spontaneous surveillance system. The ADRs reported between January 1990 and December 2003 with a causality assessment of certainly, probably or possibly drug related (according to the WHO criteria) were analysed using a case/non-case design. The cases were defined as the reactions already coded by the WHO preferred terms of 'anaphylactic shock' or 'anaphylactoid reaction' (this last term also included anaphylactic reaction) and those with a time of event onset that suggested an allergic reaction and involved at least two of the skin, respiratory, gastrointestinal, CNS or cardiovascular systems; the non-cases were all of the other ADR reports. The frequency of the association between anaphylaxis and the suspected drug in comparison with the frequency of anaphylaxis associated to all of the other drugs was calculated using the ADR reporting odds ratio (ROR) as a measure of disproportionality. RESULTS: Our database contained 744 cases (including 307 cases of anaphylactic shock with 10 deaths) and 27 512 non-cases. The percentage of anaphylaxis cases reported in inpatients was higher than that among outpatients (59.1% vs 40.9%). This distribution is significantly different from that of the other ADR reports that mainly refer to outpatients. After intravenous drug administrations, anaphylactic shock cases were more frequent than anaphylactoid reactions or other ADRs, but more than one-third of these reactions were caused by an oral drug. Blood substitutes and radiology contrast agents had the highest RORs. Among the systemic antibacterial agents, anaphylaxis was disproportionally reported more often for penicillins, quinolones, cephalosporins and glycopeptides, but diclofenac was the only NSAID with a significant ROR. As a category, vaccines had a significantly lower ROR, thus indicating that anaphylaxis is reported proportionally less than other ADRs. CONCLUSIONS: Anaphylaxis is a severe ADR that may also occur with commonly used drugs. It represents 2.7% of all of the ADRs reported in an Italian spontaneous reporting database.

Post-marketing surveillance of immediate allergic reactions: polygeline-based versus polygeline-free pediatric TBE vaccine.

Scattered cases of immediate allergic reactions occurred in the nineties after widespread use of the original (polygeline-based) pediatric tick-borne encephalitis (TBE) vaccine and were reported to Pharmacovigilance, Chiron Vaccines. Although, still indicating a very rare frequency of about two cases per 100,000 doses sold, the benefit/risk assessment resulted in its withdrawal from the market in early 1998. An intensive evaluation revealed that polygeline used as a vaccine stabilizer was the most probable cause of the reported allergic reactions. Consequently, an improved pediatric TBE vaccine, free of polygeline and other protein-derived vaccine stabilizers, was developed. A post-marketing surveillance analysis covering the first two vaccination seasons after the introduction of this new pediatric TBE vaccine in early 2002 reveals a very low reporting rate of immediate allergic reactions post immunization (within the range as noted for other widely used vaccines for childhood immunization), i.e., 0.08-0.24 cases per 100,000 doses sold depending on case definition and medical assessment. In conclusion, this analysis provides post-marketing surveillance evidence that the change in the vaccine formulation, with regards to the potential risk of immediate allergic reactions, has led to an intended improvement in the vaccine's safety profile.

Low concentrations of intravenous polygelines promote low-molecular weight proteinuria.

BACKGROUND: Previously we observed that atrial natriuretic peptide (ANP)-induced albuminuria was accompanied by an increase in urinary excretion of the low-molecular weight protein (LMW protein) beta2-microglobulin (beta2-m), suggesting that the albuminuria may at least partly be the result of blockade of tubular protein reabsorption. However, in our experiments ANP was dissolved in the polygeline Haemaccel (Hoechst, Behring-Werke, Marburg Germany) to prevent adhesion of ANP to the infusion system. Anecdotal reports have shown that high dosages of polygelines such as Haemaccel or Gelofusine (Braun NPBI Oss, the Netherlands) may influence tubular protein handling. In the present study we have evaluated the effect of a low and high doses of the polygeline Haemaccel on proteinuria. In addition, we have reassessed the effects of ANP. MATERIALS AND METHODS: We measured urinary beta2-microglobulin (beta2-m) and albumin excretion in healthy volunteers after infusion of a high-dose pure Haemaccel (0.04 mL kg(-1) min(-1) for 60 min), a low-dose Haemaccel (0.01 mL kg(-1) min(-1) for 60 min followed by infusion of 0.02 mL kg(-1) min(-1) for 60 min) and a low-dose Gelofusine (dose comparable to the low-dose Haemaccel). In addition we performed similar studies using ANP dissolved in saline and Haemaccel. RESULTS: Infusion of Haemaccel caused a dose-dependent increase in urinary excretion of beta2-m. There were no differences between Haemaccel and Gelofusine. After infusion of ANP dissolved in Haemaccel urinary beta2-m excretion increased from 0.05 +/- 0.03 microg min(-1) to 27 +/- 10 microg min(-1) and urinary albumin excretion increased from 4.5 +/- 1.1 microg min(-1) to 9.7 +/- 6.3 microg min(-1) (P<0.05). During ANP + saline infusion, urinary beta2-m excretion did not change, whereas the urinary albumin excretion increased from 5.3 +/- 1.5 microg min(-1) to 7.9 +/- 2.4 microg min(-1) (P<0.05). CONCLUSIONS: Our study demonstrates that even low doses of the polygelines Haemaccel and Gelofusine profoundly attenuate the tubular reabsorption of the low-molecular weight protein beta2-m. Atrial natriuretic peptide does not affect tubular protein reabsorption. Therefore, the rise in albuminuria during ANP infusion most likely reflects alterations in glomerular permeability.

Early and late histamine release induced by albumin, hetastarch and polygeline: some unexpected findings.

OBJECTIVE: The perioperative use of colloidal plasma substitutes is still under discussion. We therefore conducted a prospective randomised study with three commonly used plasma substitutes to examine their histamine releasing effects in 21 volunteers. MATERIAL OR SUBJETS: 21 male volunteers were enrolled in this prospective, randomised, controlled clinical study. Endpoints were the incidence of early and late histamine release and the time course of the release kinetics. Normovolemic hemodilution technique was used with hydroxyethyl starch (n = 6), human albumin (n = 6) and polygeline (n = 9). Measurement and observation period was 240 min after the start of the plasma substitute infusion. Heart rate, blood pressure, SaO(2), clinical symptoms/signs and plasma histamine were measured during the observation period. RESULTS: The incidence of histamine release over the whole observation period in all three groups was 100%. Histamine release occurred frequently in all three groups until 30 min (50%-78%) and up to 240 min (late release reaction: 67%-83%) after the start of infusion. Surprisingly even hydroxyethyl starch, which is regarded as a generally safe and effective plasma substitute, caused high incidences of late histamine release (67%). Histamine release is a well known side effect of polygeline and - to a lesser extent - also of albumin, but was a novel finding for hydroxyethyl starch. CONCLUSIONS: We demonstrated for the first time histamine releasing effects of hydroxyethyl starch over a long period of time after administration. This perioperatively and for intensive care possibly relevant finding should make clinicians aware of late side effects not yet connected with the clinical use of these colloidal plasma substitutes.