The prognostic value of global haemostatic tests in the intensive care unit setting.

BACKGROUND: Global haemostatic tests are often abnormal in critically ill patients, secondary to activation or consumption of coagulation factors or inhibitors. Methods for analysing plasma levels of these factors are, however, not widely available, and the predictive value of global tests is not known. We examined the clinical applicability to predict the outcome of the global haemostatic tests used at most hospitals. METHODS: Blood was collected from patients within 6 h of admission to an intensive care unit (ICU) and tested regarding platelet count, International Normalized Ratio (INR), and activated partial thromboplastin time (APTT). Ninety-two patients with platelet counts <100 x 10(9) l(-1), INR > 1.36 and/or APTT >45 s were included in a study group, and an additional 92 patients with a comparable age and sex distribution, but not fulfilling these laboratory criteria, constituted a control group. The following data were recorded for each patient: number of days in the ICU and hospital; alive or deceased when released from the ICU and hospital; survival at 30 days and 180 days. RESULTS: Survival upon discharge from the ICU and hospital was significantly reduced in the study group. This was especially pronounced in patients with medical disorders, whereas the survival rate was slightly higher in surgery patients. Expressing the survival predicting ability of the screening tests as odds ratios for all patients (study and control groups together) indicated that prolonged APTT in particular foretold a lower survival rate at studied time-points after admission to the ICU. CONCLUSIONS: The global haemostatic tests INR and APTT can predict survival in critically ill patients, and prolonged APTT in particular seems to be associated with a negative prognosis.

Dynamic behaviour of the common femoral artery: age and gender of minor importance.

The distensibility of elastic arteries has been extensively studied, while studies of muscular arteries are sparse. The influences of age and gender on the mechanical properties of the common femoral artery (CFA) were studied. The pulsatile diameter changes of the CFA were noninvasively measured using echo-tracking sonography in 173 healthy volunteers (95 females, 78 males, range 7-81 years). In combination with blood pressure measurements, stiffness (beta) and pressure strain elastic modulus (Ep) were calculated. Neither beta nor Ep was related to age or gender and a considerable interindividual variation was present. The CFA diameter increased with age. In conclusion, the distensibility of this muscular artery is not clearly affected by age or gender, although the diameter increases with age. This indicates remodelling of the arterial wall and an impact of vascular smooth muscles on long-term wall mechanics. Thus, there appear to be fundamental differences in the dynamic behaviour of the common femoral artery when compared to elastic arteries, such as the aorta and the common carotid artery.

Cardiovascular response to acute hypovolemia in relation to age. Implications for orthostasis and hemorrhage.

Venous compliance in the legs of aging man has been found to be reduced with decreased blood pooling (capacitance response) in dependent regions, and this might lead to misinterpretations of age-related changes in baroreceptor function during orthostasis. The hemodynamic response to hypovolemic circulatory stress was studied with the aid of lower-body negative pressure (LBNP) of 60 cmH(2)O in 33 healthy men [18 young (mean age 22 yr) and 15 old (mean age 65 yr)]. Volumetric technique was used in the study of capacitance responses in the calf and arm as well as transcapillary fluid absorption in the arm. LBNP led to smaller increase in heart rate (P < 0.001) and peripheral resistance (P < 0.01) and reduced transcapillary fluid absorption in the arm (P < 0.05) in old subjects. However, blood pooling in the calf was reduced in old subjects (1.66 +/- 0.10 vs. 2.17 +/- 0.13 ml/100 ml tissue; P < 0. 01). Accordingly, during similar blood pooling in the calf (LBNP 80 cmH(2)O in old subjects), no changes in cardiovascular reflex responses with age were found. The capacitance response in the arm (mobilization of peripheral blood to the central circulation) was still reduced, however (0.67 +/- 0.10 vs. 1.37 +/- 0.11 ml/100 ml tissue; P < 0.01). Thus the reduced cardiovascular reflex response found in the elderly during orthostatic stress seems to be caused by a reduced capacitance response in the legs with age and a concomitant smaller central hypovolemic stimulus rather than a reduced efficiency of the reflex response. With similar hypovolemic circulatory stress, no changes in cardiovascular reflex responses are seen with age. The capacitance response in the arm (mobilization of peripheral blood toward the central circulation) is reduced, however, by approximately 50% in the elderly. This might seriously impede the possibility of survival of an acute blood loss.

Influence of sympathetic stimulation on the mechanical properties of the aorta in humans.

The mechanical properties of the aorta play a major role in the regulation of blood pressure and cardiac performance. The effect of sympathetic stimulation on the mechanical properties of the human abdominal aorta was studied in 19 healthy volunteers, divided into young (25 +/- 2 years) and elderly individuals (69 +/- 2 years) of both sexes. A non-invasive ultrasonic echo-tracking system for measurement of systolic/diastolic variation of aortic diameter in combination with intra-aortic pressure measurements was used to determine wall mechanics. The pressure-diameter (P-D) relationship and the distensibility indices, stiffness (beta) and pressure strain elastic modulus (Ep) of the abdominal aorta were obtained. Measurements were made at rest and during sympathetic stimulation induced by lower body negative pressure (LBNP). As a sign of sympathetic activation, the peripheral resistance increased by 74-96% (P < 0.001) during LBNP. However, the mechanical properties of the abdominal aorta remained unaltered, as estimated either from the P-D relationship or from the indices Ep and beta, both in the young (rest: Ep = 0.53 +/- 0.18, beta = 4.5 +/- 1.5; LBNP: Ep = 0.51 +/- 0.15, beta = 4.5 +/- 1.2, NS) and in the elderly (rest: Ep = 2.17 +/- 0.70, beta = 17.6 +/- 5.8; LBNP: Ep = 2.11 +/- 0.60, beta = 16.9 +/- 3.9, NS). In conclusion, this investigation shows that LBNP-induced sympathetic activation does not change aortic wall mechanics. Thus, sympathetic modulation of the aortic smooth muscle contractile activity seems to be unimportant in the blood pressure regulation.

Sex difference in the mechanical properties of the abdominal aorta in human beings.

PURPOSE: A previous study has shown age- and sex-related differences in abdominal aortic compliance. In that study blood pressure determined by auscultation in the brachial artery was assumed to be equal to blood pressure in the abdominal aorta. To validate our findings we investigated the pressure-diameter (P-D) relationship of the abdominal aorta. METHODS: Diameter and pulsatile diameter change of the abdominal aorta were determined noninvasively by an ultrasound phase-locked echo-tracking system with simultaneous measurement of aortic pressure resulting in P-D curves in 27 healthy male and female volunteers 23 to 72 years of age. The degree of error in aortic compliance as calculated from blood pressure determined by auscultation of the brachial artery rather than from direct measurement of aortic pressure was evaluated. Compliance was defined as the inverse of pressure strain elastic modulus (Ep) or of stiffness (beta). RESULTS: There was no significant difference in the systolic pressure at the two sites, but the diastolic pressure was systematically overestimated by approximately 10 mm Hg when determined by the auscultatory method (p < 0.01) leading to a 15% to 20% underestimation of Ep and stiffness (beta). The individual P-D curves exhibited hysteresis, were nonlinear, and revealed that the aorta is more distensible at lower than at higher pressures. The steepness of the P-D curve decreased with increasing age and this occurred at an earlier age in men than in women. CONCLUSION: This investigation demonstrates a decrease in abdominal aortic wall distensibility with age, which occurs at an earlier age in men, and confirms earlier results by use of the indexes Ep and stiffness (beta). This implies that the abdominal aorta in men is more prone to degenerative changes, which may be one of the factors responsible for the sex difference in aortic vascular disease.

Evaluation of blood flow velocity waveform in an animal model.

Blood flow velocity waveforms in the abdominal aorta of three anesthetized pigs were recorded by a combined 3.5-MHz real-time and 2-MHz pulsed-Doppler ultrasound. The flow velocity waveforms were analyzed for pulsatility index, systolic to diastolic ratio, rising slope, descending slope, and the minimum diastolic velocity, and then were compared with volume blood flow measured by electromagnetic flowmeter (Q), mean arterial pressure (MAP), and total peripheral resistance (TPR). Total peripheral resistance was calculated according to the formula TPR = MAP/Q. A total of 111 recordings were performed over a range of heart rate: 90-250 beats/min, of Q: 65-1318 mL/min, of MAP: 72-165 mmHg and of total peripheral resistance 0.10-2.17 mmHg x min/mL. A significant positive correlation was found between pulsatility index and total peripheral resistance (correlation coefficient r ranging 0.64-0.87) and between systolic to diastolic ratio and total peripheral resistance (r: 0.59-0.83). The minimum diastolic velocity showed a negative correlation to TPR(r: -0.68 - -0.76). The pulsatility index was dependent on the heart rate, mean arterial pressure and rising slope; however, the relations were not consistent in all experiments. The results indicate that the pulsatility index is a good indicator of the flow velocity waveform changes depending on changes in the peripheral vascular resistance, and that the relationship between the total peripheral resistance and pulsatility index is linear. The systolic to diastolic ratio proved to be comparable even though it is somewhat less effective in performance than the pulsatility index.

Pharmacokinetics of terlipressin after single i.v. doses to healthy volunteers.

The pharmacokinetics of triglycyl-lysine-vasopressin (TGLVP) were studied in healthy male volunteers after single i.v. injections of 5, 10 and 20 micrograms/kg b. wt. The half-life of distribution and elimination was 8 and 50 min, respectively. The volume of distribution was 0.7 l/kg b.wt. and the plasma clearance 9 ml/kg b.wt./min. These values are different from those for arginine-vasopressin and lysine-vasopressin (LVP) but confirm to some extent earlier results on TGLVP. No dose-dependent changes of the pharmacokinetics of TGLVP were evident. The LVP formation after TGLVP is described in principle using a combination of pharmacokinetic and pharmacodynamic data. Therapeutically the results in this study suggest a 4-hour interval between injections.

Abnormal proteolysis (DIC)--successful treatment with antithrombin III concentrate and a concentrate containing F XIII and native von Willebrand factor.

Two patients with life-threatening disseminated intravascular coagulation (DIC) syndrome, one caused by Gram-negative bacteria and one by premature separation of the placenta, are described. Specific substitution was given by antithrombin III concentrate and AHF-Kabi, a low purity factor VIII concentrate containing native von Willebrand factor and factor XIII. The treatment quickly returned the extremely low levels of antithrombin III, factor VIII:C, fibrinogen and factor XIII, initially found, to normal, and also returned the multimeric pattern of von Willebrand factor to normal. This resulted in diminished bleeding, enabling surgical treatment of the underlying disease.

Effects of extradural anaesthesia on human fetal blood flow in utero. Comparison of three local anaesthetic solutions.

Twenty-seven women, scheduled for elective Caesarean section under extradural anaesthesia were allocated randomly to one of three groups: group Ea received 1.5% etidocaine with adrenaline, group Bp 0.5% bupivacaine plain, and group Ba 0.5% bupivacaine with adrenaline. There was no difference in the quality and distribution of sensory blockade between the three groups. Motor blockade was most profound in group Ea. Maternal heart rate and arterial pressure were only slightly affected in the three groups. Before induction of extradural anaesthesia, and 15 and 30 min after, fetal umbilical and aortic blood flows were examined using a combination of real-time ultrasonography and the pulsed Doppler technique. Blood flow in the umbilical vein was not affected in any of the groups, and blood flow in the fetal aorta remained unchanged in groups Ea and Bp, but was increased by 12% after 30 min in group Ba. We conclude that, with the three local anaesthetic solutions studied during extradural anaesthesia for elective Caesarean section, fetal circulatory variables remained stable and within normal limits, when in association with normal values of maternal arterial pressure.

The effect of triglycyl-lysine-vasopressin (terlipressin INN, Glypressin) on skin blood flow, measured with laser Doppler flowmetry, thermography and plethysmography. A dose-response study.

Triglycyl-lysine-vasopressin (TGLVP) has been shown to reduce blood loss in connection with early excision of experimentally induced burns in pigs. In order to determine an appropriate dosage of TGLVP in patients with burns, a dose-response study was undertaken. TGLVP was administered intravenously in various doses to healthy volunteers, and skin blood flow was measured with laser Doppler flowmetry, thermography and plethysmography. Blood pressure, heart rate and electrocardiac activity were monitored as well as serum and urine changes. The doses of 5, 10 and 20 micrograms TGLVP/kg b.wt. caused statistically significant reduction of skin blood flow; minimal values were 35, 26 and 25% of predrug values for the three doses, respectively. Thermography and plethysmography were less sensitive for detecting effects of TGLVP than laser Doppler flowmetry. Minor effects on blood pressure and heart rate were recorded after TGLVP, but no disturbances in electrocardiac activity. Urinalyses revealed an antidiuretic action of TGLVP. The study supports earlier findings and suggests a dose level of TGLVP for the use in excision of burns.

Circulatory and renal effects of triglycyl-lysine-vasopressin and excision in experimental burns.

The circulatory and renal effects of a deep dermal burn, covering one third of the total body surface area were studied in 12 thiopentone/N2O anesthetized piglets. Central circulation and renal function was monitored during 24 h and regional blood flows were determined before burn, 5 and 24 h after burn using radioactively labeled microspheres. One group was treated conservatively with fluid infusion only (control group) and the other with fluids, intermittent injections of a long-acting hormonogen, triglycyl-lysine-vasopressin (TGLVP), and excision 5 h after burn. There was earlier circulatory recovery in the TGLVP excision group with significantly higher arterial blood pressure and cardiac output than in the controls. TGLVP induced a major redistribution of blood flows, favoring the liver at the expense of the gastrointestinal tract, carcass and skin, while the blood flows were unchanged to the brain, heart and kidneys. There were also increased excretions of sodium and potassium and a temporarily increased diuresis. The earlier circulatory stabilization and blood flow redistribution might have clinical implications in burn care.

Cardiac function and central circulation in lysine-vasopressin treatment of experimental burns.

Anesthetized piglets were subjected to a standardized full thickness skin burn, covering one third of the body surface area, and given fluid treatment. One group was also submitted to early excision of the burned area 5 h after the burn and another group was excised and given lysine-vasopressin by continuous infusion. In both the excised groups there was earlier circulatory restitution compared with the conservatively treated animals. After 24 h, cardiac function was best in the pigs treated with vasopressin and excision. The mechanisms by which vasopressin treatment and excision might have favourable circulatory effects in burn treatment are discussed.

Fetal circulation during epidural analgesia for caesarean section.

Fetal blood flow was examined during epidural analgesia in six women with uncomplicated pregnancies undergoing elective caesarean section. A non-invasive, ultrasonic technique was used to measure blood flow in the fetal descending aorta and intra-abdominal part of the umbilical vein before induction of analgesia with etidocaine and bupivacaine and 15 and 30 minutes afterwards. No appreciable change in fetal blood flow was observed.

Triglycyl-lysine-vasopressin or lysine-vasopressin in early excision of burns. An experimental study comparing the effects on blood loss, hemodynamics and renal function.

Twelve piglets were submitted to a third degree burn covering one third of total body surface area under general anesthesia. Fluid treatment was given in amounts corresponding to 2.4 ml/kg/% burn/24 h, and hemodynamics and renal function were monitored for 24 h. Regional blood flows were determined with the aid of the radioactive microsphere technique before burn, 5 and 24 h after burn respectively. One group was treated with triglycyl-lysine-vasopressin (TGLVP) as bolus injections and the other with lysine-vasopressin (LVP) in infusion. Both groups were submitted to excision of the burned tissues after 5 h. Total blood loss was 39 +/- 9 g in the TGLVP group and 51 +/- 7 g in the LVP group (n.s.). TGLVP changed the distribution of cardiac output (CO) more than LVP did, leading to smaller blood flows to the splanchnic organs, skin and carcass while the perfusion of the brain, heart, liver and kidneys was similar after 5 h. The burn caused a 30% decrease of CO in both groups. After the first TGLVP injection there was a small further decrease in CO but after excision there were similar recoveries of CO in both groups. After 24 h the CO redistribution remained during LVP infusion, but those effects had almost vanished in the TGLVP group. Total diuresis and the glomerular filtration rate tended to be larger during LVP treatment but there was no significant difference in serum creatinine after 24 h. Thus both drugs decrease blood loss during early excision and they seem to have similar effects on circulation and renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of blood loss by triglycyl-lysine-vasopressin during early excision of burns in pigs.

In a burn model using anesthetized piglets, the circulatory and renal effects and the blood loss during and after excision were compared in two groups, one treated by triglycyl-lysine-vasopressin (TGLVP) given as intermittent bolus injections and the other serving as control. The third degree burn covered approximately 33% of the body surface area, and a solution containing 100 mmol NaCl/l in 2.5% glucose was infused at a rate of 2.4 ml/kg/% burn. Regional blood flows were determined before burn, 5 and 24 h after burn with the aid of radioactively labeled microspheres. Cardiac output (CO) decreased about 30% after burn and there was a slight further decrease of CO after the first TGLVP dose. After the excision there were similar restitutions of CO in the two groups. TGLVP induced an increase of blood flow to the hepatic artery, did not change flows to the brain, heart and kidneys and decreased flows to the preportal organs, carcass and skin 5 h after burn. After 24 h the perfusion of the skin and pancreas remained low but there were no differences in other organs. There was a significant decrease of blood loss associated with burn excision performed 5 h after burn in the TGLVP treated group, mean blood loss 39 g/25 kg versus 145 g/25 kg in the control group. There was a temporary increase in diuresis following TGLVP and also increased excretions of sodium and potassium. The results obtained in this study and possible clinical applications are discussed.

Effects of lysine-vasopressin treatment on renal function in burned pigs.

The effects of lysine vasopressin (LVP) on renal excretory function and renal blood flow were studied in anesthetized and burned pigs either treated conservatively or by early excision 5 hours after burn. Renal perfusion was measured with radioactive microspheres. Diuresis and the urinary excretion of sodium and potassium were determined. Glomerular filtration rate (GFR) was measured either as the endogenous creatinine clearance rate or the clearance rate of 51Cr-EDTA. LVP-treatment in pharmacologic doses after burn caused larger diuresis, and larger sodium and potassium excretion rates than in unburned controls and animals submitted to burn only, Renal blood flow decreased significantly early after burn whether LVP was given or not. After burn, GFR was moderately higher in the LVP-treated pigs than in the animals submitted to burn only. After 24 hours S-creatinine was lower in the pigs treated by LVP and excision of the burned tissues after 5 hours, compared with the conservatively treated animals. This implies that an active surgical approach to full thickness skin burns might support renal function. LVP-induced intrarenal effects causing increased GFR and secondary medullary interstitial electrolyte concentration and osmolar changes could be the mechanisms causing the renal functional changes found in this investigation.

Lysine-vasopressin in excisional treatment of burns in pigs. Decreased blood loss and earlier circulatory recovery.

The hemodynamics were monitored during 24 hours in piglets anesthetized with Pentothal-N2O/O2, submitted to 33% full-thickness skin burn and resuscitated with 2.4 ml/kg/% burn of 100 mmol NaCl in 2.5% glucose. Three groups were studied: (I) standardized burn, (II) standardized burn and excision after 5 hours, (III) standardized burn, excision and lysine-vasopressin (LVP) given as intravenous infusion in a vasopressor dose. All groups showed similar decrease of cardiac output (CO), which was about 30% 4 hours after burn. In the two groups with burn excision, however, CO recovery was earlier than in the conservatively treated group I. The improvement was significant between group III and group I. LVP led to higher CO fraction and greater blood flow to hepatic artery, reduced flow to proximal gastrointestinal tract and skin and unchanged flow to heart, kidneys and other organs 24 hours after burn. The mean blood loss during and after burn excision was greatly reduced in group III (50 g/25 kg) compared with group II (146 g/25 kg). The therapeutic implications of LVP in excisional burn treatment are discussed.

The effects of lysine-vasopressin on hemodynamics during early post burn period in pigs.

In order to investigate the central and peripheral circulatory effects of a vasoactive drug, lysin vasopressin (LVP), in the early postburn period, 18 piglets were submitted to an experimental study. Anaesthesia was performed by thiopentone sodium as i.v. infusion and mechanically controlled ventilation via endotracheal intubation. Burn injury was brought about by heated metal stamps applied to the back and sides of the animals causing a full thickness skin burn corresponding to 32-35% of the total body surface area. Cardiac output decreased significantly after burn and so did organ blood flow, measured with radioactively labelled microspheres, especially after 4 hours. LVP-infusion did not further decrease cardiac output after burn but decreased the blood flow to the skin, carcass and proximal gastrointestinal tract. The liver perfusion was increased, while the flow in the other organs was not different from that in burned pigs not given LVP. The therapeutical implications are discussed.