Mismatch of arterial and central venous blood gas analysis during haemorrhage.

BACKGROUND AND OBJECTIVE: Arterial base excess and lactate levels are key parameters in the assessment of critically ill patients. The use of venous blood gas analysis may be of clinical interest when no arterial blood is available initially. METHODS: Twenty-four pigs underwent progressive normovolaemic haemodilution and subsequent progressive haemorrhage until the death of the animal. Base excess and lactate levels were determined from arterial and central venous blood after each step. In addition, base excess was calculated by the Van Slyke equation modified by Zander (BE(z)). Continuous variables were summarized as mean +/- SD and represent all measurements (n = 195). RESULTS: Base excess according to National Committee for Clinical Laboratory Standards for arterial blood was 2.27 +/- 4.12 versus 2.48 +/- 4.33 mmol(-l) for central venous blood (P = 0.099) with a strong correlation (r(2) = 0.960, P < 0.001). Standard deviation of the differences between these parameters (SD-DIFBE) did not increase (P = 0.355) during haemorrhage as compared with haemodilution. Arterial lactate was 2.66 +/- 3.23 versus 2.71 +/- 2.80 mmol(-l) in central venous blood (P = 0.330) with a strong correlation (r(2) = 0.983, P < 0.001). SD-DIFLAC increased (P < 0.001) during haemorrhage. BE(z) for central venous blood was 2.22 +/- 4.62 mmol(-l) (P = 0.006 versus arterial base excess according to National Committee for Clinical Laboratory Standards) with strong correlation (r(2) = 0.942, P < 0.001). SD-DIFBE(z)/base excess increased (P < 0.024) during haemorrhage. CONCLUSION: Central venous blood gas analysis is a good predictor for base excess and lactate in arterial blood in steady-state conditions. However, the variation between arterial and central venous lactate increases during haemorrhage. The modification of the Van Slyke equation by Zander did not improve the agreement between central venous and arterial base excess.

Impact of the C2/C6 ratio of high-molecular-weight hydroxyethyl starch on pharmacokinetics and blood coagulation in pigs.

BACKGROUND: High-molecular-weight, low-substituted hydroxyethyl starch (HES) may not affect blood coagulation more than low-molecular-weight, low-substituted HES. The authors assessed in vivo the effect of a lowered C2/C6 ratio on pharmacokinetic characteristics and the impact on blood coagulation of high-molecular-weight, low-substituted HES. METHODS: A prospective, randomized, parallel study in 30 pigs compared HES 650/0.42/2.8 with HES 650/0.42/5.6. Before, during, and after infusion of 30 ml/kg body weight HES, blood samples were collected over 630 min to measure HES concentrations and plasmatic coagulation and to assess blood coagulation in whole blood by Thrombelastography (TEG; Haemoscope Corporation, Niles, IL). Pharmacokinetic parameters were estimated using a two-compartment model. RESULTS: The elimination constant was 0.009 +/- 0.001 min(-1) for HES 650/0.42/2.8 and 0.007 +/- 0.001 min(-1) for HES 650/0.42/5.6 (P < 0.001); the area under the plasma concentration-time curve was 1,374 +/- 340 min x g/l for HES 650/0.42/2.8 and 1,697 +/- 411 min x g/l for HES 650/0.42/5.6 (P = 0.026). The measured plasma HES concentrations were not different between HES 650/0.42/2.8 and HES 650/0.42/5.6. Both HES solutions equally affected blood coagulation: Thrombelastographic coagulation index decreased similarly at the end of infusion of HES 650/0.42/2.8 and at the end of infusion of HES 650/0.42/5.6 (P = 0.293). Also, activated partial thromboplastin and prothrombin times increased similarly for HES 650/0.42/2.8 and HES 650/0.42/5.6 (P = 0.831). CONCLUSION: Reducing the C2/C6 ratio in high-molecular, low-substituted HES solutions results in a slightly faster HES elimination. However, the blood coagulation compromising effect was unaffected.

Novel starches: single-dose pharmacokinetics and effects on blood coagulation.

BACKGROUND: Carboxymethyl starch (CMS) and carboxymethylated hydroxyethyl starch (CM-HES) might offer advantages over hydroxyethyl starch (HES) with regard to their volume expansion effect and their pharmacokinetic characteristics. The goal of the current study was to determine the pharmacokinetics of CMS and CM-HES and to investigate their influence on blood coagulation in comparison with the standard low-molecular, low-substituted HES (130/0.42) used in Europe. METHODS: The study was conducted as a randomized, blinded, parallel three-group study in 30 pigs. Twenty ml/kg of 6% HES (control), 6% CMS, or 6% CM-HES was infused as a single dose, and serial blood sampling was performed over 20 h to measure plasma concentration and molecular weight and to assess blood coagulation. Concentration-effect relations were assessed by pharmacokinetic-pharmacodynamic analysis. RESULTS: CMS and CM-HES showed significantly higher plasma concentrations and molecular weights over 20 h (P for both<0.001) with smaller volumes of distribution and longer elimination rates during the terminal phase (P for both<0.01) when compared with HES. CMS and CM-HES impaired whole blood coagulation more than HES as assessed by Thrombelastograph analysis (Haemoscope Corporation, Niles, IL). However, similar effects of all three starch preparations on blood coagulation were found when related to the plasma concentrations in mass units. CONCLUSIONS: Carboxymethylation of starch results in an increased intravascular persistence and a slower fragmentation compared with HES. The greater impairment of blood coagulation by CMS and CM-HES seems to be caused by the higher plasma concentrations.

Effect of high- and low-molecular-weight low-substituted hydroxyethyl starch on blood coagulation during acute normovolemic hemodilution in pigs.

BACKGROUND: Hydroxyethyl starches (HES) with lower impact on blood coagulation but longer intravascular persistence are of clinical interest. The current study aimed to investigate in vivo the isolated effect of molecular weight on blood coagulation during progressive acute normovolemic hemodilution. METHODS: Twenty-four pigs were normovolemically hemodiluted up to a total exchange of 50 ml . kg . body weight of HES 650/0.42 or HES 130/0.42. Serial blood sampling was performed to measure HES plasma concentration and to assess blood coagulation. Concentration-effect relations were analyzed by linear regression, followed by the Student t test on regression parameters. RESULTS: Blood coagulation was increasingly compromised toward hypocoagulability by acute normovolemic hemodilution with both treatments (P < 0.01). Significantly greater impact on activated partial thromboplastin time (P = 0.04) and significantly stronger decrease of maximal amplitude (P = 0.04), angle alpha (P = 0.02), and coagulation index (P = 0.02) was seen after acute normovolemic hemodilution with HES 650/0.42 as compared with HES 130/0.42. Except for factor VIII (P = 0.04), no significant differences between both treatments were observed when relating antihemostatic effects to HES plasma concentrations (P > 0.05). A significantly lesser decrease of hemoglobin concentration has been found with HES 650/0.42 as compared with HES 130/0.42 (P < 0.01) in relation to HES plasma concentrations. CONCLUSION: High-molecular-weight HES (650/0.42) shows a moderately greater antihemostatic effect than low-molecular-weight HES (130/0.42) during acute normovolemic hemodilution. However, similar effects on hemostasis were observed with both treatments when observed antihemostatic effects were related to measured HES plasma concentrations. In addition, HES 650/0.42 may have a lower efficacy in immediately restoring plasma volume.

Current status of artificial O2 carriers.

This article describes currently evaluated artificial O2 carriers, summarizes their efficacy, and discusses their side effects, based on and restricted to published data. For compounds in phase III testing, approximately 500 to 1000 patients have been dosed, and similar numbers of control patients have been investigated. For compounds in phase I or II testing, the number of patients dosed is significantly less. Unfortunately, there is a significant amount of nonpublished data, which renders the overall assessment difficult, and the direct comparison among different types of artificial O2 carriers is significantly limited by the virtual nonexistence of studies that directly compare different products.

Enzyme reactivator treatment in organophosphate exposure: clinical relevance of thiocholinesteratic activity of pralidoxime.

Organophosphate compounds are responsible for a large number of accidental and/or suicidal exposures and have been used also for warfare and terrorism. The mechanism of toxicity is by inhibition of cholinesterase. Oximes are the only enzyme reactivators clinically available but clinical experience with oximes is disappointing. There is a gap between laboratory data and clinical impression concerning the efficacy of oxime compounds. Oximes are responsible for thiocholinesteratic activity, a spurious signal caused by interaction between pralidoxime and the thiocholine substrate used for photometric enzyme activity determinations. In a prospective, controlled, non-randomized study performed in anaesthetized miniature pigs, we quantified the extent of pralidoxime-induced cholinesteratic pseudo-activity ex vivo (human blood) and in vivo (minipig) in order to be able to correct values obtained by photometric methods. Plasma cholinesteratic activity using two substrates (acetylthiocholine and butyrylthiocholine) was determined in vitro and in vivo in the presence of pralidoxime. Pralidoxime reacts with the substrate (acetyl- and butyrylthiocholine) used for enzyme activity determinations, producing a spurious signal implying cholinesterase activity (even in the absence of plasma and thus of any enzyme). Cholinesterase activities determined photometrically after pralidoxime therapy can be erroneously high. Although in theory this could mislead clinicians into assuming an efficacious therapy, this is unlikely to occur in vivo under normal pralidoxime dosing conditions. To avoid any ambiguity it is recommended that blood be drawn for enzyme activity determinations prior to reactivator use and no less than 1 h after its administration.

Intravenous pyruvic acid application in minipigs partially protects acetylcholine-esteratic but not butyrylcholine-esteratic activity in plasma from inhibition by paraoxon.

Intoxications with organophosphorus compounds such as paraoxon (POX) are frequent. Oximes are the only enzyme reactivators clinically available. In vitro and in vivo studies have shown that l-lactate reduces the inhibition of plasma acetylcholine-esteratic activity (AChEA) (in vitro and in vivo) and plasma butyrylcholine-esteratic activity (BChEA) (at least in vitro and possibly in vivo) by POX. However, a short infusion of 10 g of lactate was unable to elevate the plasma lactate level for >3 h. In this study we tested a substance related to l-lactate, i.e. pyruvic acid. The purpose of this animal experimental study (female minipigs with historical control group) was to determine in vivo whether intravenous (i.v.) pyruvic acid application under normoxic/normocapnic/normohydrogenaemic conditions is able to elevate blood lactate levels and whether it is able to protect AChEA and BChEA from POX inhibition. Animals were anaesthetized, intubated and mechanically ventilated. Each received 1 mg kg(-1) body wt. of POX in 50 ml of saline over 50 min and 10 g (ca. 0.5 g kg(-1) body wt.) of i.v. pyruvic acid in 50 ml of saline over 50 min. They were compared with a historical control group of six animals that received only 1 mg kg(-1) body wt. of POX in 50 ml of saline over 50 min. In central venous blood measurements of plasma AChEA and BChEA, the measurements were performed before (baseline), immediately after POX (50 min after start) and 110, 170, 230, 290, 530 and 1010 min after the start of infusion. A 10 g aliquot of i.v. pyruvic acid had a statistically significant protective effect in vivo on AChEA but not on BChE activity. Further study of the in vivo effects of pyruvic acid and l-lactate after paraoxon intoxication and a formal comparison with standard oxime therapy seems warranted. Also, a combination therapy with l-lactate and pyruvic acid in vivo should be investigated.