[Coagulation management of trauma patients with unstabile circulation : establishment of a hemoglobin-oriented standard operating procedure]. / Gerinnungsmanagement beim kreislaufinstabilen Polytraumapatienten : Erarbeitung einer hämoglobinorientierten "standard operating procedure"

INTRODUCTION: Massive hemorrhage is the leading cause of death in the first few hours following multiple trauma, therefore, early and aggressive treatment of clotting disorders and surgical intervention to stop the bleeding are of utmost importance. However, commonly performed clotting tests have a considerable latency of at least 30-45 min, whereas hemoglobin (Hb) levels can be tested very quickly. If a multiple trauma patient has already received fluid resuscitation, a certain relationship may be observed between the hemoglobin value and the development of clotting disturbances. Hence, hemoglobin may be a useful and rapidly available parameter for guiding the initial treatment of clotting disturbances in multiple trauma patients. METHODS: A Hb-guided algorithm has been developed to initiate initial clotting therapy. The algorithm contains three stages of different aggressive clotting therapy with fibrinogen, prothrombin complex concentrate (PCC), factor VIIa, tranexamic acid and desmopressin, depending on the first Hb value measured. For admission Hb levels > 5.5 mmol/l (≈8.8 g/dl) coagulation therapy is managed on the basis of the laboratory tests and if in doubt 2 g fibrinogen is administered. For admission Hb levels between 5.5 mmol/l (≈8.8 g/dl) and 4 mmol/l (≈6.5 g/dl) 2-4 g fibrinogen and 2,500-3,000 IU PCC are administered and tranexamic acid and desmopressin administration should be considered. For admission Hb levels < 4 mmol/l (≈6.5 g/dl) 4-6 g fibrinogen, 3,000-5,000 IU PCC and 1 mg factor VIIa should be administered and tranexamic acid and desmopression should be considered. All drugs mentioned should be stored in a special "coagulation box" in the hospital pharmacy and this box is brought immediately to the patient on demand. In addition to the use of clotting factors, infusions should be performed with balanced crystalloids and transfusions with an RBC/FFP ratio of 2:1-1:1. To assess the efficiency of the algorithm the routinely measured clotting parameters at trauma bay admission were compared with intensive care unit (ICU) admission and the standardized mortality ratio (SMR) was calculated. RESULTS: During a 6-month investigation period 71 severe multiple trauma patients were admitted to the trauma center and 19 patients were treated using the coagulation box of which 13 required massive transfusions. The routinely used clotting parameters markedly improved between admission to the trauma bay and ICU admission: Quick 61% versus 97% (p < 0.001), partial prothromboplastin time (PTT) 50 s versus 42 s (not significant), fibrinogen 1.7 g/l versus 2.15 g/l (not significant). Of the 19 patients 11 (58%) survived. The revised injury severity classification (RISC) predicted a survival rate of 40%, which corresponds to an SMR of 0.69, thus implying a higher survival rate than predicted. CONCLUSIONS: The Hb-driven algorithm, in combination with the coagulation box and the early use of clotting factors, may be a simple and effective tool for improving coagulopathy in multiple trauma patients.

[Methohexital for treatment of intracranial hypertension]. / Methohexital zur Therapie des erhöhten intrakraniellen Drucks.

BACKGROUND: Barbiturate coma therapy is a useful method to control increased intracranial pressure (ICP) in patients with severe brain damage if standard measures have failed to lower ICP. Pentobarbital (not available in Germany) and thiopental (in Germany only approved for induction of anesthesia) have frequently been used in patients with intracranial hypertension and the effects and side-effects are well-described. However, little is known about the effect of methohexital (the only barbiturate in Germany approved for maintaining anesthesia) in lowering increased ICP. Therefore, the effect of methohexital on ICP was studied in patients where standard measures had failed to control intracranial hypertension. METHOD: A retrospective observational study was carried out with the inclusion criteria of patient age ≥18 years and methohexital therapy for 12 h or more with ICP monitoring in place. Methohexital was administered following a standardized algorithm to patients for whom standard measures, such as deep anesthesia, normoventilation, cerebral perfusion pressure (CPP) >65 mmHg, osmotherapy, neurosurgical evacuation of mass lesions, had failed to lower ICP. Methohexital was used if the ICP had risen above 20-25 mmHg for more the 20-30 min and otherwise manageable causes for the ICP increase had been ruled out. Methohexital was given continuously in addition to standard analgesia and sedation in doses of 2-4-6 mg/kg body weight (BW), depending on the ICP lowering effect. The records of the patient data management system from the years 2008/2009 were used to compare the ICP and CPP before and during methohexital administration. For statistical analyses Student's t-test was applied for measured values and the χ(2)-test was applied for percentage values whereby p<0.05 was defined as being statistically significant. RESULTS: During the study period 36 patients required methohexital therapy and 30 fulfilled the inclusion criteria. In 26 out of 30 patients the data were complete and these 26 patients were included in the data analyses. Of the patients 6 (23%) died due to elevated intracranial hypertension and 20 patients (77%) survived. In all patients methohexital lowered the ICP from 25.2 mmHg (standard deviation, SD ±4.3 mmHg) to 19.8 mmHg (SD ±12.5 mmHg) within the first 24 h, this result closely failed to reach a level of significance. In the 20 survivors methohexital lowered the ICP from 25.88 mmHg (SD ±4.8 mmHg) to 14.25 mmHg (SD ±6.9 mmHg) within the first 24 h, which is statistically highly significant. In non-survivors the ICP had risen from 24 mmHg (SD ±2.6 mmHg) to 32 mmHg (SD ±16.3 mmHg) within the first 24 h despite all efforts. Due to the CPP driven volume and vasopressor therapy no significant changes in the CPP during methohexital administration were observed. No significant changes in brain temperature (as possible cause for the decrease of the ICP) were observed. Non-survivors received significantly more methohexital due to increased ICP and required significantly more vasopressor therapy to maintain a sufficient CPP. CONCLUSIONS: Methohexital showed a clear trend for decreasing ICP in patients with intracranial hypertension refractory to standard therapeutic measures. In survivors the effect was highly significant. Patients not responding to methohexital therapy seemed to have an unfavorable outcome.

[Post-lobectomy bronchopleural fistula -- a challenge for postoperative intensive care]. / Bronchopleurale Fistel nach Lobektomie -- eine Herausforderung der postoperativen Intensivtherapie.

Bronchopleural fistula (BPF) and bronchial stump insufficiency (BSI) after lobectomies and pneumonectomies are dreaded complications with incidences of up to 12 % and a mortality rate of up to 51 %. Apart from the basic illness causes include complications like aspiration-pneumonia and ARDS, formation of empyema as well as histories of sepsis. Corticoid treatments, old age, diabetes mellitus, previous irradiation as well as post-operative mechanical ventilation (barotrauma) are often counted among contributing causes. Suturing the bronchus and reinforcement by tissue are still the methods of choice, but they are often counter-indicated in high-risk patients. Endoscopic treatments with partial lung occlusions, e. g. by insertion of spongiosa, coils, and/or fibrin glue have been described. However, they require the respective area to be probable. With only one third the rate of success is quite unsatisfactory. The retro-graded instillation of inflammatory-selerotizing substances, like doxycycline, via a chest tube leads to a pleurodesis caused by adhesion of the remaining lung parenchyma to the thoracic wall and a reduction in size of the residual pleural space. In an 82-year old female patient a BPF of the second upper lobe bronchus was detected after a middle lobe resection for abscess and post-radiation ulcer following a mastectomy for carcinoma. The leakage was detected on bronchoscopy by retro-graded instillation via the chest tube of methylene-blue solution into the thoracic cavity. After administering the water-soluble contrast agent amidotrizoic acid in a similar manner a CT confirmed the diagnosis. As the bronchial segment concerned could not be entered selectively, preservation of the right lung lobe's residual ventilation by endoscopic-occlusion procedures was ruled out. Employing a strictly conservative therapy (spontaneous ventilation, retro-graded doxycycline instillations) complete healing with a fully ventilated lower lobe could be achieved over a period of 78 days. BPF as well as residual intro-thoracic cavities after lobectomies pose a serious problem. Using methylene blue for a retro-graded demonstration of BPF during bronchoscopy presents a feasible and cost-efficient diagnostic method. A strictly applied conservative therapy including short-time low-pressure artificial respiration as well as obliteration by fibrous tissue of the thoracic cavity using doxycycline is a feasible procedure for inoperable high-risk patients.

Human cardiac beta1- or beta2-adrenergic receptor stimulation and the negative chronotropic effect of low-dose pirenzepine.

OBJECTIVES: The M1-muscarinic receptor antagonist pirenzepine in low doses (<1 mg intravenously) decreases heart rate. We investigated whether these effects of pirenzepine differ in volunteers with activated cardiac beta1-adrenergic receptors versus activated cardiac beta2-adrenergic receptors. METHODS: In 17 male volunteers (25 +/- 1 years) we studied effects of pirenzepine infusion (0.5 mg intravenous bolus followed by continuous infusion of 0.15 microg/kg/min) on heart rate and heart rate-corrected duration of electromechanical systole (QS2c, as a measure of inotropism) that had been stimulated by activation of cardiac beta1-adrenergic receptors (bicycle exercise in the supine position for 60 minutes at 25 W) or cardiac beta2-adrenergic receptors (continuous intravenous infusion of 100 ng/kg/min terbutaline). RESULTS: Bicycle exercise and terbutaline infusion significantly increased heart rate and shortened QS2c. When pirenzepine was infused 20 minutes after the beginning of the exercise or terbutaline infusion, heart rate decreased in both settings by approximately the same extent (approximately -10 to -14 beats/min), although exercise and terbutaline infusion continued; however, QS2c was not affected. Pirenzepine (0.05 to 1 mg intravenous bolus)-induced decrease in heart rate was abolished after 6 days of transdermal scopolamine treatment of volunteers. CONCLUSIONS: Low-dose pirenzepine decreased heart rate by muscarinic receptor stimulation, because this was blocked by scopolamine. Moreover, low-dose pirenzepine did not differentiate between cardiac beta1- or beta2-adrenergic receptor stimulation; however, low-dose pirenzepine did not affect cardiac contractility as measured by QS2c. Low-dose pirenzepine therefore exerted a unique pattern of action in the human heart: it decreased heart rate (basal and beta1- and/or beta2-adrenergic receptor-stimulated) without affecting contractility.

Disodium cromoglycate does not prevent terbutaline-induced desensitization of beta 2-adrenoceptor-mediated cardiovascular in vivo functions in human volunteers.

In humans, prolonged administration of the beta 2-adrenoceptor agonist terbutaline leads to a desensitization of beta 2-adrenoceptor-mediated cardiovascular responses, which can be blunted by concomitant administration of the antianaphylactic drug ketotifen. This study investigated the effect of disodium cromoglycate, another antiallergic drug, on terbutaline-induced desensitization of beta-adrenoceptor-mediated cardiovascular and noncardiovascular responses. In a double-blind, placebo-controlled, randomized design, nine healthy male volunteers received disodium cromoglycate (4 x 200 mg/day, p.o.) or placebo for 3 weeks with terbutaline (3 x 5 mg/day, p.o.) administered concomitantly during the last 2 weeks. beta 2-Adrenoceptor cardiovascular function was assessed by the increase in heart rate and reduction of diastolic blood pressure induced by an incremental intravenous infusion of the unselective beta-adrenoceptor agonist isoprenaline; beta 1-adrenoceptor cardiovascular function was assessed by exercise-induced tachycardia. Tremulousness was monitored as a beta 2-adrenoceptor-mediated noncardiovascular effect. After 2 weeks' administration of terbutaline, there was a marked and significant (p < 0.001) attenuation of isoprenaline-induced tachycardia (mean percentage attenuation, 53.3%) and of the isoprenaline-induced decrease in diastolic blood pressure (mean percentage attenuation, 55.6%). Exercise-induced tachycardia also was significantly (p < 0.001) blunted, but the magnitude of this attenuation was only very small (mean attenuation, 5.6%). Disodium cromoglycate affected neither the rightward shift of beta 2-adrenoceptor-mediated responses nor the small rightward shift in beta 1-adrenoceptor-mediated exercise tachycardia after 2 weeks' administration of terbutaline. Tremulousness observed during the first few days of terbutaline administration disappeared after 4 to 8 days, indicating development of desensitization of beta 2-adrenoceptor-mediated noncardiovascular responses. This was not prevented by disodium cromoglycate. These results confirm that long-term beta 2-adrenoceptor agonist therapy leads to a desensitization of beta 2-adrenoceptor-mediated cardiovascular and noncardiovascular effects in humans in vivo. However, unlike ketotifen, cromolyn sodium is not able to attenuate this desensitization.

Cardiac effects of beta-adrenoceptor antagonists with intrinsic sympathomimetic activity in humans: beta1- and/or beta2-adrenoceptor mediated?

The aim of this study was to find out whether cardiac responses to the beta-adrenoceptor antagonists with intrinsic sympathomimetic activity (ISA) xamoterol and celiprolol are mediated by cardiac beta1- or beta2-adrenoceptors or both. For this purpose we assessed, in six healthy male volunteers, the effects of xamoterol (100 and 200 mg, p.o.) and celiprolol (200, 600, and 1,200 mg, p.o.) on blood pressure, heart rate, and heart rate-corrected duration of the electromechanical systole (QS2c, as a measure of inotropism). Xamoterol, in both doses, increased systolic blood pressure and heart rate, transiently decreased diastolic blood pressure, and shortened QS2c; all these effects were attenuated after pretreatment of the volunteers with the beta1-adrenoceptor antagonist bisoprolol. Celiprolol, in all three doses, increased heart rate, decreased diastolic blood pressure, and shortened QS2c but only marginally increased systolic blood pressure. Bisoprolol did not attenuate these celiprolol effects but rather enhanced celiprolol effects on systolic blood pressure and heart rate. In a further set of experiments, we studied cardiovascular effects of celiprolol in six healthy volunteers whose beta2-adrenoceptors had been desensitized by a 2-week treatment with 3x5 mg/day terbutaline. Under these conditions, celiprolol failed to increase heart rate or to shorten QS2c. We conclude that, under resting conditions, in healthy volunteers, beta-adrenoceptor antagonists with ISA can exert increases in heart rate and contractility that are mediated by either cardiac beta1-adrenoceptor (xamoterol) or cardiac beta2-adrenoceptor (celiprolol) stimulation. Thus in the human heart, the ISA of beta-adrenoceptor antagonists can be a beta1- or beta2-adrenoceptor agonistic component.

Cardiac muscarinic receptors decrease with age. In vitro and in vivo studies.

The M1 muscarinic receptor antagonist pirenzepine in low doses decreases resting heart rate; this effect declines with age (Poller, U., G. Nedelka, J. Radke, K. Pönicke, and O.-E. Brodde. 1997. J. Am. Coll. Cardiol. 29:187-193). To study possible mechanisms underlying this effect, we assessed (a) in six young (26 yr old) and six older volunteers (61 yr old), pirenzepine effects (0.32 and 0.64 mg intravenous [i.v.] bolus) on isoprenaline-induced heart rate increases; (b) in five heart transplant recipients, pirenzepine effects (0.05-10 mg i.v. bolus) on resting heart rate in the recipient's native and transplanted sinus nodes; and (c) in right atria from 39 patients of different ages (5 d-76 yr) undergoing open heart surgery, M2 muscarinic receptor density (by [3H]N-methyl-scopolamine binding) and adenylyl cyclase activity. (a) Pirenzepine at both doses decreased heart rate in young volunteers significantly more than in older volunteers; (b) pirenzepine (< 1 mg) decreased resting heart rate in the recipient's native but not transplanted sinus node; and (c) M2 receptor density and carbachol-induced inhibition of forskolin-stimulated adenylyl cyclase activity decreased significantly with the age of the patients. We conclude that pirenzepine decreases heart rate via inhibition of presynaptic M1 autoreceptors, thereby releasing endogenous acetylcholine, and that the heart rate-decreasing effect of acetylcholine declines with age because right atrial M2 receptor density and function decrease.

Terbutaline-induced desensitization of human cardiac beta 2-adrenoceptor-mediated positive inotropic effects: attenuation by ketotifen.

BACKGROUND: In patients with chronic heart failure cardiac beta 1-adrenoceptors are desensitized whereas beta 2-adrenoceptors are only marginally affected. The mechanism underlying this differential regulation is not known. OBJECTIVES: To find out whether or not human cardiac beta 2-adrenoceptors might be 'resistant' to agonist-induced desensitization and whether or not the antiallergic drug ketotifen might attenuate possible desensitization. METHODS: We investigated, in a single blinded, randomised, placebo-controlled, cross-over study of ten healthy male volunteers (mean age, 25.3 +/- 0.7 years), the effects of two weeks treatment with the beta 2-adrenoceptor agonist terbutaline (3x5 mg/day p.o.) with and without simultaneous treatment with ketotifen (2x1 mg/day p.o. for three weeks) or placebo on beta-adrenoceptor-mediated cardiovascular effects. Cardiovascular effects were assessed as isoprenaline (3.5-35 ng/kg/min)- and terbutaline (25-150 ng/kg/min)-infusion-induced increases in heart rate and systolic blood pressure, decreases in diastolic blood pressure and shortening of the systolic time intervals (STIs), heart rate corrected duration of electromechanical systole (QS2c) and pre-ejection period (PEP; as a measure of inotropism). RESULTS: Ketotifen did not significantly affect basal haemodynamics in the volunteers. Isoprenaline- and terbutaline-infusion caused dose-dependent increases in systolic blood pressure and heart rate, decreases in diastolic blood pressure and shortening of QS2c and PEP, whereby isoprenaline effects were more pronounced. After two weeks of treatment with terbutaline p.o., isoprenaline- and terbutaline-infusion-induced increases in heart rate, shortening of QS2c and PEP were significantly reduced whereby terbutaline-infusion effects were markedly more attenuated than isoprenaline-infusion effects. Ketotifen significantly reduced terbutaline p.o. treatment-induced attenuation of all terbutaline-infusion effects (largely beta 2-adrenoceptor-mediated) and the isoprenaline-infusion-induced increase in heart rate (beta 1- and beta 2-adrenoceptor-mediated), but did not (or only marginally) affect reduction in isoprenaline-induced shortening of QS2c and PEP (largely beta 1-adrenoceptor-mediated). CONCLUSION: Human cardiac beta 2-adrenoceptors are not 'resistant' to agonist-induced desensitization: Ketotifen might prevent such beta 2-adrenoceptor-agonist-evoked desensitization.

Influence of atropine on the cardiovascular effects of noradrenaline and tyramine in elder volunteers.

The aim of this study, carried out in six elder healthy volunteers (mean age: 61 years), was to determine the influence of muscarinic receptor blockade with atropine (15 microg/kg i.v. loading dose followed by 0.15 microg/kg/min by i.v. infusion) on the effects of i.v. infusions of noradrenaline (5 incremental doses of 10-120 ng/kg/min) or tyramine, that releases endogenous noradrenaline (4 incremental doses of 5-20 microg/kg/min), on blood pressure, heart rate and systolic time intervals (STI's, as a measure of positive inotropism). These results were compared with those recently published for young healthy volunteers (mean age: 26 years; Schäfers et al. 1997). Noradrenaline caused increases in systolic and diastolic blood pressure, decreases in heart rate and a shortening of STI's that were not different from those in young volunteers. Atropine did not significantly affect these hemodynamic responses to noradrenaline, while in young volunteers it significantly enhanced noradrenaline-induced blood pressure increases and converted the heart rate decrease into an increase. In the present study in elder volunteers, tyramine caused a smaller increase in systolic blood pressure than in the previous study in young volunteers; in addition, it slightly increased diastolic blood pressure while it decreased diastolic blood pressure in young volunteers. Atropine did not significantly affect the hemodynamic effects of tyramine in the elder volunteers, while in the young volunteers it enhanced the increase in systolic blood pressure and converted the decreases in diastolic blood pressure and heart rate into increases. These results indicate a) that ageing is accompanied by a blunted baroreflex-mediated parasympathetic activation resulting in reduced cholinergic vasodilation and decreases in heart rate, and b) that ageing is associated with a decreased responsiveness of (cardiac) beta-adrenoceptors and (vascular) alpha1-adrenoceptors which is only unmasked when the counterregulatory action of parasympathetic activation is removed.