A multicenter trial to compare blood culture with polymerase chain reaction in severe human sepsis.

OBJECTIVE: To assess the presence of microbial DNA in the blood by polymerase chain reaction (PCR) and its association with disease severity and markers of inflammation in severe sepsis and to compare the performance of PCR with blood culture (BC). DESIGN: Prospective multicentric controlled observational study. SETTING: Three surgical intensive care units in university centers and large teaching hospitals. PATIENTS: One hundred forty-two patients with severe sepsis and 63 surgical controls. INTERVENTIONS: Presence of microbial DNA was assessed by multiplex PCR upon enrollment, and each time a BC was obtained. MEASUREMENTS AND MAIN RESULTS: Controls had both approximately 4% positive PCRs and BCs. In severe sepsis, 34.7% of PCRs were positive compared to 16.5% of BCs (P < 0.001). Consistently, 70.3% of BCs had a corresponding PCR result, while only 21.4% of PCR results were confirmed by BC. Compared to patients with negative PCRs at enrollment, those testing positive had higher organ dysfunction scores [SOFA, median (25th-75th percentile) 12 (7-15) vs. 9 (7-11); P = 0.023] and a trend toward higher mortality (PCR negative 25.3%; PCR positive 39.1%; P = 0.115). CONCLUSIONS: In septic patients, concordance between BC and PCR is moderate. However, PCR-based pathogen detection correlated with disease severity even if the BC remained negative, suggesting that presence of microbial DNA in the bloodstream is a significant event. The clinical utility to facilitate treatment decisions warrants investigation.

Effects of inhaled aerosolized iloprost and inhaled NO on pulmonary circulation and edema formation in ovine lung injury.

Although inhaled NO (iNO) has been shown to lower pulmonary pressures and edema accumulation in experimental acute lung injury, its clinical use has been questioned because of a lack of improvement in outcome, rebound phenomena, and potential toxicity. We investigated the effects of aerosolized iloprost, a stable prostacyclin analogue, compared with iNO on pulmonary pressures and lung edema in 20 female sheep with oleic acid lung injury. The most effective dose of iloprost was determined in healthy animals before the experiment. Anesthetized and ventilated sheep received a central venous oleic acid infusion and were continuously infused with Ringer lactate to achieve a positive fluid balance (5 mL.kg(-1).h(-1)). In the iNO group (n = 6), iNO (20 ppm) was administered continuously for 8 h. Animals in the iloprost group (n = 6) received aerosolized iloprost (40 microg 2 h(-1)). Animals in the control group (n = 6) had no further intervention. Oleic acid infusion was associated with impaired oxygenation, pulmonary hypertension, and lung edema in all groups. Although iNO significantly decreased pulmonary vascular resistance index, effective pulmonary capillary pressure, and extravascular lung water index, these parameters were unaffected by iloprost. Oxygenation index (Pao2/Fio2) increased significantly both during NO and iloprost inhalation but also tended to improve in the control group over time. In contrast to iNO, the investigated dose of iloprost was ineffective to attenuate acute lung injury-induced changes in pulmonary hemodynamics and lung edema in this experimental model.

Therapeutic administration of thoracic epidural anesthesia reduces cardiopulmonary deterioration in ovine pulmonary embolism.

OBJECTIVE: It was hypothesized that sympathetic blockade restricted to the thoracic levels and achieved by thoracic epidural anesthesia might be capable of reducing hemodynamic deterioration after pulmonary artery embolism and that this might represent a potential method of treatment in patients with pulmonary embolism. Cardiopulmonary function after pulmonary embolism was therefore studied in sheep, either without a sympathetic blockade (the control group) or with sympathetic blockade. DESIGN: Prospective, randomized laboratory investigation. SETTING: University research laboratory. SUBJECTS: Twelve adult, chronically instrumented Blackhead ewes. INTERVENTIONS: Pulmonary embolization was achieved by injecting autologous blood clots (0.75 mL/kg) intravenously into an external jugular vein. The treatment group (n = 6) received 6 mL of 0.175% bupivacaine and the control group (n = 6) received 6 mL of 0.9% NaCl 90 mins after the embolization procedure. The injections were made via an epidural catheter (at the level of T3). Results were considered to be statistically significant (with analysis of variance) at p < .05. MEASUREMENTS AND MAIN RESULTS: After epidural administration of bupivacaine in the thoracic epidural anesthesia group, the mean pulmonary artery pressure and heart rate were significantly reduced and the stroke volume index was significantly higher in comparison with the control group, in which the animals received epidural injections of saline. CONCLUSIONS: Thoracic epidural anesthesia administered after the occurrence of pulmonary artery embolism thus significantly reduces hemodynamic deterioration in awake, spontaneously breathing sheep and may represent an additional option in the treatment of pulmonary embolism.

Calcineurin inhibitor-free immunosuppression using everolimus (Certican) in maintenance heart transplant recipients: 6 months' follow-up.

BACKGROUND: Everolimus is a proliferation signal-inhibitor recently introduced in heart transplant recipients. To date, little is known about calcineurin inhibitor (CNI)-free immunosuppression using everolimus. This study reports the results of CNI-free immunosuppression using everolimus. METHODS: During a continuous 9-month period, 60 heart transplant recipients were enrolled. Reasons for switching to everolimus were side effects associated with prior CNI immunosuppression. All patients underwent standardized switching protocols and completed 6 months of follow-up. Blood was obtained for lipid status, renal function, routine controls, and levels of immunosuppressive agents. Echocardiography and a physical examination were performed on Days 0, 14, 28, and then every 3 months. RESULTS: After switching to everolimus, most patients recovered from the side effects associated with CNIs. Renal function improved significantly after 6 months (creatinine, 2.1 +/- 0.6 vs 1.5 +/- 0.9 mg/dl, p = 0.001; creatinine clearance, 42.2 +/- 21.6 vs 61.8 +/- 23.4 ml/[min x 1.73 m2], p = 0.018). Arterial hypertension improved after 3 months and remained decreased during the observation period. Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Adverse events occurred in 8 patients (13.3%), including interstitial pneumonia (n = 2), skin disorders (n = 2), reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3). CONCLUSION: Preliminary data suggest that CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance heart transplant recipients. Arterial hypertension and renal function improved significantly. CNI-induced side effects such as tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved in most patients.

[Invasive cardiovascular monitoring--four methods compared]. / Invasives Kreislaufmonitoring--Vier Methoden im Vergleich.

The impact of invasive hemodynamic monitoring on patient safety and outcome in perioperative medicine remains inadequately tested and unproven. The indications for the use of these tools should, therefore, be evaluated according to an individual risk-benefit analysis. The measurement of central venous oxygen saturation (ScvO2) is of little invasiveness as most high-risk patients are instrumented with central venous catheters, and ScvO2 has been shown to improve outcome in patients with septic shock. Transpulmonary thermodilution (e.g. PiCCO-system) delivers information not only on global cardiac function and intravascular volume status but also helps to define the pulmonary consequences of cardiovascular therapy. Transesophageal echocardiography (TEE) is a valuable tool in patients undergoing cardiac surgery and represents the beside-method of choice for rapid assessment of acute life-threatening cardiovascular instability. Apart from special indications, these tools tend to replace the pulmonary artery catheter (PAC) which has been shown to be of little value in various patient populations.

Cerebral response to norepinephrine compared with fluid resuscitation in ovine traumatic brain injury and systemic inflammation.

OBJECTIVE: Traumatic brain injury is frequently accompanied by a systemic inflammatory response. Systemic inflammation was associated with cerebral hyperperfusion uncoupled to global oxygen metabolism in ovine head trauma. The present study investigated the cerebral effects of cerebral perfusion pressure (CPP) management performed by either fluid resuscitation or vasopressor treatment of low CPP induced by systemic inflammation. DESIGN: Nonrandomized experimental study. SETTING: University hospital laboratory. SUBJECTS: A total of 12 adult sheep. INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: Sheep were anesthetized and ventilated throughout the experimental period (13 hrs). After baseline measurements (hour 0), blunt head trauma was induced by a nonpenetrating stunner. After postinjury measurements (hour 2), all animals received continuous endotoxin infusion. At hour 10, one group (n = 6) was infused with hydroxyethyl starch until CPP reached 60-70 mm Hg. A second group (n = 6) received norepinephrine for CPP elevation. In the norepinephrine group, blood was isovolemically exchanged by hydroxyethyl starch to achieve comparable hematocrit levels. Head trauma increased intracranial pressure and decreased brain tissue oxygen tension. Endotoxemia induced a hyperdynamic cardiovascular response with increased internal carotid blood flow in the presence of systemic hypotension and decreased CPP. Hydroxyethyl starch infusion further increased internal carotid blood flow from (mean +/- sd) 247 +/- 26 (hour 10) to 342 +/- 42 mL/min (hour 13) and intracranial pressure from 20 +/- 4 (hour 10) to a maximum of 25 +/- 3 mm Hg (hour 12) but did not significantly affect brain tissue oxygen tension, sinus venous oxygen saturation and oxygen extraction fraction. Norepinephrine increased internal carotid blood flow from 268 +/- 19 to 342 +/- 58 mL/min and intracranial pressure from 22 +/- 11 to 24 +/- 11 mm Hg (hour 10 vs. hour 13) but significantly increased sinus venous oxygen saturation from 49 +/- 4 (hour 10) to a maximum of 59 +/- 6 mm Hg (hour 12) and decreased oxygen extraction fraction. The increase in brain tissue oxygen tension during norepinephrine treatment was not significant. CONCLUSION: We conclude that despite identical carotid blood flows, only CPP management with norepinephrine reduced the cerebral oxygen deficit in this model.

Roles of MMP-2/-9 in cardiac dysfunction during early multiple organ failure in an ovine animal model.

Biventricular dilation and severe cardiac dysfunction are observed during septic shock. However, when endotoxemia and vasoconstrictor-masked hypovolemia work in concert in the pathogenesis of shock, the clinical scenario is more adverse compared to one of the insults acting alone. Matrix metalloproteinases (MMPs) are involved in chronic and acute heart failure by degrading the mechanical scaffold of the heart and several intracellular proteins. Therefore, the roles of MMP-2, MMP-9, MT1-MMP, focal adhesion kinase (FAK), and Paxillin in hearts of early multiple organ failure induced by norfenefrine-masked hypovolemia and endotoxemia were investigated in an ovine model. Experimental groups included (1) norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO) (n=6), (2) norfenefrine-masked hypovolemia without endotoxemia (NMH) (n=6), (3) recurrent endotoxemia during normovolemia (ENDO) (n=6), and (4) healthy untreated controls (CON) (n=3). Apoptosis was determined by TUNEL-staining. Gel zymography revealed significantly increased MMP-2 activity in NMH+ENDO compared to ENDO and controls. MMP-9 activity was significantly elevated in all experimental groups. MMP-2 was significantly increased at the protein level, while MMP-9 was unaltered. MT1-MMP was not significantly changed in any group. Increased MMP activities were associated with cardiac deterioration. MMP-2/-9 activity and phosphorylated Paxillin (p-Paxillin) expression correlated positively with cardiomyocyte apoptosis. This study underscores the pivotal roles of MMP in acute cardiac dysfunction during early multiple organ failure in combined vasoconstrictor-masked hypovolemic and endotoxemia shock.

The effect of high thoracic epidural anesthesia on systolic and diastolic left ventricular function in patients with coronary artery disease.

In patients with coronary artery disease, vasoconstriction is induced through activation of the sympathetic nervous system. Both alpha1- and alpha2-adrenergic epicardial and microvascular constriction are potent initiators of myocardial ischemia. Attenuation of ischemia has been observed when sympathetic nervous system activity is inhibited by high thoracic epidural anesthesia (HTEA). However, it is still a matter of controversy whether establishing HTEA may correspondingly translate into an improvement of left ventricular (LV) function. To clarify this issue, LV function was quantified serially before and after HTEA using a new combined systolic/diastolic variable of global LV function (myocardial performance index [MPI]) and additional variables that more specifically address systolic (e.g., fractional area change) or diastolic function (e.g., intraventricular flow propagation velocity [Vp]). High thoracic epidural catheters were inserted in 37 patients scheduled for coronary artery surgery, and HTEA was administered in the awake patients. Echocardiographic and hemodynamic measures were recorded before and after institution of HTEA. HTEA induced a significant improvement in diastolic LV function (e.g., Vp changed from 45.1 +/- 16.1 to 53.8 +/- 18.8 cm/s; P < 0.001), whereas indices of systolic function did not change. The change in the diastolic characteristics caused the MPI to improve from 0.51 +/- 0.13 to 0.35 +/- 0.13 (P < 0.001). We conclude that an improvement in cardiac function was due to improved diastolic characteristics.

Role of atrial natriuretic peptide in pulmonary permeability and vasoregulation in ovine sepsis.

OBJECTIVE: Atrial natriuretic peptide is regarded as an important regulator of pulmonary vasomotor tone and permeability. This study investigated the role of atrial natriuretic peptide in sepsis-associated pulmonary pathophysiology. DESIGN: Prospective experimental investigation. SETTING: Laboratory at a university hospital. SUBJECTS: Twelve awake, chronically instrumented sheep. INTERVENTIONS: The sheep were instrumented with lung lymph fistulas and received a continuous infusion with live Pseudomonas aeruginosa for 48 hrs. After 40 hrs, the atrial natriuretic peptide-receptor antagonist HS-142-1 was continuously infused in the HS-124-1 group (3 mg/kg/hr, n = 6) for 8 hrs, whereas the control group received the carrier (n = 6). MEASUREMENTS AND MAIN RESULTS: Lung lymph flow was markedly elevated in response to sepsis after 40 hrs in both groups. Atrial natriuretic peptide-receptor blockade further increased lymph flows by 41 +/- 17% (41 hrs) up to 64 +/- 20% (44 hrs, p < .05) in the presence of normal permeability to protein. Although mean pulmonary artery pressure increased (p < .05 vs. 40 hrs), capillary pressure remained unaffected. Despite identical fluid balances in both groups, cardiovascular filling variables significantly increased in the HS-142-1 group. This was associated with increasing cardiac index and mean arterial pressure (p < .05 vs. 40 hrs). In the control group, all variables remained constant between 41 and 48 hrs. CONCLUSION: Blockade of atrial natriuretic peptide receptors increases pulmonary transvascular fluid flux independent of changes in permeability to protein in chronic ovine sepsis. Atrial natriuretic peptide may therefore play a protective role for the alveolar-capillary barrier during sepsis.

Cerebral vascular and metabolic response to sustained systemic inflammation in ovine traumatic brain injury.

Traumatic brain injury (TBI) is frequently accompanied by a systemic inflammatory response secondary to multiple trauma, shock, or infections. This study investigated the impact of sustained systemic inflammation on cerebral hemodynamics and metabolism in ovine traumatic brain injury. Fifteen sheep were investigated for 14 hours. Head injury was induced with a nonpenetrating stunner in anesthetized, ventilated animals. One group (TBI/Endo, n = 6) subsequently received a continuous endotoxin infusion for 12 hours, whereas a second group (TBI, n = 6) received the carrier. Three instrumented animals served as sham controls. Head impact significantly increased intracranial pressure from 9 +/- 4 mm Hg to 21 +/- 15 mm Hg (TBI/Endo) and from 10 +/- 3 mm Hg to 24 +/- 19 mm Hg (TBI) (means +/- SD). Internal carotid blood flow increased and cerebral vascular resistance decreased (P < 0.05) during the hyperdynamic inflammatory response between 10 and 14 hours in the TBI/Endo group, whereas these parameters were at baseline level in the TBI group. Intracranial pressure remained unchanged during this period, but increased during hypercapnia. The CMRO2, PaCO2, and arterial hematocrit values were identical among the groups between 10 and 14 hours. It is concluded that chronic endotoxemia in ovine traumatic brain injury was associated with cerebral vasodilation uncoupled from global brain metabolism. Different mechanisms appear to induce cerebral vasodilation in response to inflammation and hypercapnia.

Heat shock protein 72 and apoptosis indicate cardiac decompensation during early multiple organ failure in sheep.

OBJECTIVE: Inducible heat shock protein 72 (HSP 72) preserves myocardial function and prevents apoptosis. We investigated the expression and localization of HSP 72 and apoptosis in our previously described new model of multiple organ failure. DESIGN: Eighteen adult-instrumented sheep and three healthy controls were randomly assigned to one of three groups: (a) norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO); (b) norfenefrine-masked hypovolemia without endotoxemia (NMH); (c) recurrent endotoxemia during normovolemia (ENDO); and (d) normovolemia without endotoxemia (CONTROLS). MEASUREMENTS AND RESULTS: Hearts were analyzed by light microscopy, Western blots, immunohistochemistry, and TUNEL staining. HSP 72 expression was approximately threefold increased in NMH+ENDO compared with the other groups ( p<0.05) and was localized mainly in left ventricular cardiomyocytes. HSP 72 was elevated in animals with norfenefrine-refractory shock compared to survivors ( p=0.015). TUNEL-positive cells in the left ventricle were significantly elevated in the NMH+ENDO group ( p=0.05) and correlated with HSP 72 expression (r=0.51, p=0.018). HSP 72 correlated positively with heart rate (r=0.76, p<0.0001), the prefinal hourly dose of norfenefrine (r=0.88, p<0.0001), and negatively with left ventricular stroke work index (r=-0.52, p=0.028). Double staining revealed TUNEL-positive cells with and without HSP 72 expression. Micronecroses were only detectable in NMH and NMH+ENDO without intergroup difference or correlations with hemodynamics. CONCLUSION: HSP 72 overexpression and apoptosis, but not necrosis, indicate cardiovascular decompensation and poor outcome during early multiple organ failure.

Inhaled nitric oxide reduces lung edema during fluid resuscitation in ovine acute lung injury.

OBJECTIVE: Fluid resuscitation in sepsis-related lung injury is limited by aggravation of pulmonary edema. Hypovolemia, however, may compromise tissue perfusion and contribute to organ dysfunction. We hypothesized that inhaled nitric oxide would reduce edema formation during fluid therapy. DESIGN AND SETTING: Prospective laboratory investigation in a university research laboratory. PARTICIPANTS: Eighteen chronically instrumented sheep. INTERVENTIONS: The animals were randomly assigned to one of three groups and received endotoxin (S. typhi, 10 ng kg(-1) min(-1)) for 30 h. After 24 h the sheep were anesthetized (ketamine/midazolam), mechanically ventilated with oxygen, and received 0.1 ml kg(-1) oleic acid: oxy group (n=6), an infusion of Ringer's lactate was restricted to 1 ml kg(-1) h(-1); fluid/oxy group (n=6), a bolus of 10 ml kg(-1) Ringer's lactate plus 10 ml kg(-1) h(-1) was given; fluid/NO group (n=6), the sheep were treated as in the fluid/oxy group, except that they inhaled nitric oxide (20 ppm). MEASUREMENTS AND RESULTS: The extravascular lung water index was measured using thermodye dilution. Oleic acid increased extravascular lung water, impaired oxygenation, and reduced cardiac index at 26 h in all groups. After 30 h the extravascular lung water in the fluid/NO group was not higher than in the oxy group and significantly than in the fluid/oxy group. While cardiac index returned to the level of sepsis baseline in fluid/NO and fluid/oxy, it was reduced in the oxy group after 30 h. There were no significant differences in cardiac index between groups. CONCLUSIONS: Inhaled nitric oxide may be an option for reducing edema formation secondary to fluid resuscitation in acute lung injury.

Cerebral blood flow is not altered in sheep with Pseudomonas aeruginosa sepsis treated with norepinephrine or nitric oxide synthase inhibition.

UNLABELLED: The origin of cerebral dysfunction in patients with sepsis is still unclear. However, altered cerebral perfusion may play an important role in its pathogenesis. Using an established, chronic model of hyperdynamic ovine sepsis, we examined cerebral perfusion in 20 sheep subjected to a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis, the hypotensive sheep (reduction in mean arterial blood pressure by 16%; P < 0.05) received the nitric oxide synthase inhibitor N(G)-mono-methyl-L-arginine (L-NMMA; 7 mg. kg(-1). h(-1); n = 7), norepinephrine (NE; n = 7), or normal saline (control; n = 6). NE infusion was individually targeted to achieve the same increase in mean arterial blood pressure as that observed in matched sheep of the L-NMMA group. Regional perfusion was measured by using colored microspheres. Although L-NMMA caused a significant increase in systemic vascular resistance index (1167 +/- 104 versus 793 +/- 59 dyne. cm(-5). m(2); P < 0.05), it caused a change neither in cerebrovascular resistance nor in cerebral blood flow. When related to systemic blood flow, a redistribution of blood flow to the brain became obvious. The NE-associated increase in systemic blood pressure (98 +/- 5 versus 83 +/- 5; P < 0.05) was accompanied by an increase in cardiac output (7.8 +/- 0.5 versus 6.7 +/- 0.6; P < 0.05) and, hence, systemic perfusion. However, blood flow to the brain remained unaffected. Although detrimental vasoconstrictive effects of NE and L-NMMA, including cerebral hypoperfusion, are discussed, neither drug had any effect on cerebral perfusion during experimental hyperdynamic sepsis. IMPLICATIONS: Cerebral dysfunction is often found in septic patients. In this regard, it is debated whether vasopressor drugs, such as norepinephrine and L(G)-mono-methyl-L-arginine, have harmful effects on the cerebral circulation. During experimental hyperdynamic sepsis, however, neither drug altered cerebral vascular resistance or cerebral blood flow.

Early multiple organ failure after recurrent endotoxemia in the presence of vasoconstrictor-masked hypovolemia.

OBJECTIVE: Critically ill patients who develop multiple organ failure during systemic inflammatory states are often predisposed to hypovolemia and vasoconstrictor therapy. Although numerous investigations have evaluated the sequelae of systemic inflammation, no data are available on the contribution of chronic vasoconstrictor-masked hypovolemia to organ dysfunction and morphology. DESIGN: Prospective, randomized laboratory investigation. SETTING: University research laboratory. SUBJECTS: Eighteen adult chronically instrumented sheep. INTERVENTIONS: The animals were randomly assigned to one of three groups. In the norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO) group, mean arterial pressures of 80 mm Hg were maintained by using the alpha1-adrenergic catecholamine norfenefrine for 52 hrs during hypovolemia. Hypovolemia was induced by hemorrhage (about 23 mL x kg(-1)) until mean arterial pressures reached 40 mm Hg. Endotoxin (0.5 microg x k(-1)) was then injected after 4, 16, 28, and 40 hrs. The NMH group received norfenefrine-masked hypovolemia but no endotoxin. In the ENDO group, recurrent endotoxemia was induced during normovolemia. MEASUREMENTS AND MAIN RESULTS: Despite profound differences in fluid management, cardiovascular filling pressures were not statistically different between groups. Endotoxemia induced norfenefrine-refractory shock (p < .05 vs. the other groups) and contributed to renal dysfunction only during vasoconstrictor-masked hypovolemia. Norfenefrine-masked hypovolemia caused disseminated cardiac cell necrosis independent of endotoxemia (p < .05 vs. ENDO). CONCLUSIONS: Hypovolemia can be masked when volume status is monitored by filling pressures. In this new model of endotoxemia-associated multiple organ failure, chronic vasoconstrictor-masked hypovolemia turned systemic inflammation into a life-threatening condition with renal and cardiovascular failure. Cardiomyocyte necroses were caused by vasoconstrictor-masked hypovolemia but were unrelated to cardiovascular failure.

Delayed onset of malignant hyperthermia in desflurane anesthesia.

IMPLICATIONS: Animal-experimental studies demonstrate desflurane's trigger effect for malignant hyperthermia (MH). In contrast to other anesthetics, the time interval from exposure to the occurrence of symptoms is much longer with desflurane. This case report focuses on MH induced by desflurane alone.