Peter Siostrzonek

Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock.

ObjectiveCurrent guidelines for adjusting antimicrobial therapy regimens commonly are based on drug concentrations measured in plasma. In septic patients, however, the interstitial space of soft tissues in addition to the central compartment represents the target site of infection. We thus hypothesized that one explanation for therapeutic failure during antibiotic treatment might be the inability to achieve effective antimicrobial concentrations in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered &bgr;-lactam antibiotic, often fails to be effective despite documented susceptibility of the causative pathogen in vitro. DesignProspective comparative study of two groups. SettingThe intensive care unit and research ward of an university hospital. SubjectsSix patients with septic shock and a control group of six gender- and age-matched healthy volunteers. InterventionsTo measure piperacillin penetration into the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue, we employed microdialysis after a single intravenous administration of 4.0 g of piperacillin to patients and healthy volunteers. Piperacillin concentrations were assayed by using reversed-phase high-pressure liquid chromatography. Measurements and Main Results In septic shock patients, interstitial piperacillin concentrations in skeletal muscle and subcutaneous adipose tissue were five- to ten-fold lower than corresponding free plasma concentrations (p < .03). Mean piperacillin concentrations in subcutaneous adipose tissue never exceeded 11 &mgr;g/mL, which is below the minimal inhibitory concentration for a range of relevant pathogens in patients with septic shock. ConclusionThe results of the present study demonstrate that in septic shock patients, piperacillin concentrations in the interstitial space may be subinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might be attributable to inadequate target site penetration of antibiotics.

Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis.

OBJECTIVE Melatonin is involved in the regulation of the sleep-wake cycle and exhibits multiple interactions with the neuroendocrine and the immune system. Melatonin secretion in healthy individuals follows a stable circadian rhythm. Critical illness, continuous administration of drugs, and loss of external zeitgeber might impair the circadian rhythm of melatonin secretion in the intensive care unit (ICU), thereby compromising the physiologic stress-induced immune response. DESIGN Prospective, controlled clinical study. SETTING Medical intensive care unit in a university hospital. PATIENTS Seventeen septic, sedated ICU patients (group A); 7 nonseptic ICU patients (group B); and 21 control patients (group C) were studied. MEASUREMENTS AND MAIN RESULTS 6-Sulfatoxymelatonin (aMT6s) was determined from urine samples taken at 4-hr intervals over a total period of 24 hrs. aMT6s was measured by enzyme-linked immunosorbent assay. Circadian mesors, phase amplitudes, and timing of the acrophase were assessed by cosinor analysis. Differences between groups were calculated by contingency data analysis and by analysis of variance. Circadian mesors of urinary aMT6s were 3904 +/- 1597, 2622 +/- 927, and 3183 +/- 1514 ng/4 hrs in groups A, B, and C, respectively (p = NS). aMT6s exhibited significant circadian periodicity in only 1/17 (6%) patients of group A but in 6/7 (86%) patients of group B and in 18/23 (78%) patients of group C (group A vs. groups B and C: p = .0001) Phase amplitudes were markedly lower in group A (1071 +/- 1005 ng/4 hrs) compared with group B (2284 +/- 581 ng/4 hrs, p = .009) and C (2838 +/- 2255 ng/4 hrs, p = .006). The acrophase was significantly delayed in patients of group A (10:35 am +/- 255 mins) compared with group B (05:43 am +/- 114 mins, p = .01) and group C (4:20 am +/- 107 mins, p < .0001). In sepsis survivors, aMT6s excretion profiles tended to normalize, but still lacked a significant circadian rhythm at ICU discharge. CONCLUSION The present study revealed striking abnormalities in urinary aMT6s excretion in septic ICU patients. In contrast, circadian rhythm was preserved in nonseptic ICU patients, indicating that impaired circadian melatonin secretion in septic patients is mainly related to the presence of severe sepsis and/or concomitant medication. Further investigations are required to examine the underlying pathophysiologic mechanism and the clinical implications of this finding.

Intracoronary Thrombectomy With the X-Sizer Catheter System Improves Epicardial Flow and Accelerates ST-Segment Resolution in Patients With Acute Coronary Syndrome A Prospective, Randomized, Controlled Study

Background—In patients with acute coronary syndrome (ACS), percutaneous coronary intervention (PCI) may cause thrombus dislodgment followed by reduced flow and impaired microcirculatory function. We prospectively compared conventional PCI to a strategy of additional pretreatment using the X-sizer thrombectomy system. Methods and Results—Sixty-six patients (51 [77%] men; 54.9±9.9 years) with ACS (49 with ST-elevation infarction [STEMI]) and suspected intracoronary thrombus were randomized 1:1 to pretreatment with X-sizer and conventional PCI alone. Various aspects of epicardial flow and microvascular function were studied. Baseline data were similar in both groups. Postprocedural TIMI 3 flow was obtained in 90% of X-sizer–treated patients and in 84% of controls (NS); however, corrected TIMI frame count was lower in X-sizer– treated patients (18.3±10.2 versus 24.7±14.1;P <0.05). No significant group differences were observed in final coronary flow reserve, myocardial blush grade, and myocardial dye intensity. In STEMI, the sum of ST elevation was significantly lower in X-sizer–treated patients immediately after (2.78±3.05 versus 6.15±6.32 mm;P <0.03) and 6 hours after (2.17±2.31 versus 4.14±3.7 mm;P <0.05) intervention. ST-segment resolution >50% was observed in 83% of X-sizer–treated patients and in 52% of controls (P <0.03). Multivariate analysis identified X-sizer treatment as the single independent predictor of ST-segment resolution >50% (OR 4.35; 95% CI, 1.13 to 16.9;P <0.04). Major adverse cardiac events after 30 days occurred in 2 patients in each group. Conclusions—In ACS with suspected thrombus, pretreatment with the X-sizer catheter system improves epicardial flow and accelerates ST-segment resolution compared with conventional PCI alone.

Improvement in left ventricular systolic function after successful radiofrequency his bundle ablation for drug refractory, chronic atrial fibrillation and recurrent atrial flutter

Incessant supraventricular tachyarrhythmia may lead to a reversible impairment of left ventricular (LV) function. This issue was investigated in 10 patients (aged 64 +/- 13 years) who underwent radiofrequency His bundle ablation for control of drug refractory, chronic atrial fibrillation (n = 9) and recurrent atrial flutter (n = 1). LV function was assessed by 2-dimensional guided M-mode echocardiography within 24 hours (baseline) and 49 +/- 18 days (follow-up) after successful ablation, both during VVI pacing at 70 beats/min. Fractional shortening increased from 28 +/- 9% at baseline to 35 +/- 8% at follow-up (p = 0.006). This increase in fractional shortening was due to a significant reduction of end-systolic diameter from 41 +/- 10 to 36 +/- 10 mm (p = 0.02), whereas there was no appreciable change in end-diastolic diameter (56 +/- 7 to 55 +/- 10 mm; p = 0.5). These changes were substantially greater in patients with baseline impairment of LV function (fractional shortening less than 27%). Fractional shortening increased by 12% (p = 0.14) in patients with normal LV function (n = 5) and by 44% (p = 0.02) in those with impaired LV function at baseline (n = 5). The greater increase in fractional shortening in patients with preexisting LV impairment was due to a more pronounced decline in end-systolic dimensions (-11.9%; p = 0.08) compared with that of patients with normal LV function at baseline (-9.21%; p = 0.2). End-diastolic diameter showed no significant change in either group (-3.53% [p = 0.8] and -0.58% [p = 0.4]).(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias

Objective To compare the rate-lowering effect of diltiazem and two amiodarone regimens in critically ill patients with recent-onset atrial tachyarrhythmias. Design Prospective, randomized, controlled study. Setting Medical cardiologic intensive care unit in a university hospital. Patients Sixty critically ill patients (Acute Physiology and Chronic Health Evaluation [APACHE] III score 70 ± 30, age 67 ± 10 yrs). Interventions Patients with atrial fibrillation (n = 57), atrial flutter (n = 2), or atrial tachycardia (n = 1, and a heart rate consistently >120 beats/min over 30 mins were randomly assigned to one of three intravenous treatment regimens. Group 1 received diltiazem in a 25-mg bolus followed by a continuous infusion of 20 mg/hr for 24 hrs, group 2 received amiodarone in a 300-mg bolus, and group 3 received amiodarone in a 300-mg bolus followed by 45 mg/hr for 24 hrs. Measurements and Main Results The primary study end point was a >30% rate reduction within 4 hrs. The secondary study end point was a heart rate <120 beats/min (a patient was considered to have uncontrolled tachycardia if heart rate was >120 beats/min 4 hrs after study drug). The primary study end point was achieved in 14/20 (70%), 11/20 (55%), and 15/20 (75%) of patients in groups 1, 2, and 3, respectively (&khgr;2 = 1.95, p = .38). Uncontrolled tachycardia was more frequently observed in group 2 (0/20, 9/29 [55%], and 1/20 [5%] of patients in groups 1, 2, and 3, respectively; &khgr;2 = 17, p = .00016). In patients achieving tachycardia control, diltiazem showed a significantly better rate reduction (p = .0001 group 1 vs. group 3, p = .0001 over time;p = .0001 group 1 vs. group 2, p = .001 over time) when compared with the amiodarone groups. Premature drug discontinuation due to hypotension was required significantly more often in group 1 (6/20 [30%], 0/20, and 1/20 [5%] for groups 1, 2, and 3, respectively; &khgr;2 = 10, p = .01). Conclusion Sufficient rate control can be achieved in critically ill patients with atrial tachyarrhythmias using either diltiazem or amiodarone. Although diltiazem allowed for significantly better 24-hr heart rate control, this effect was offset by a significantly higher incidence of hypotension requiring discontinuation of the drug. Amiodarone may be an alternative in patients with severe hemodynamic compromise.

Prognosis of patients who develop acute renal failure during the first 24 hours of cardiogenic shock after myocardial infarction.

PURPOSE Acute renal failure has important prognostic implications in critically ill patients, but the effects of acute renal failure on in-hospital mortality in the subset of patients with cardiogenic shock are not known. SUBJECTS AND METHODS All consecutive patients who presented with acute coronary syndrome at our cardiovascular intensive care unit from 1993 to 2000 and who were in cardiogenic shock were enrolled. Acute renal failure was defined as a urine volume < 20 mL/h associated with an increase in serum creatinine level > or = 0.5 mg/dL or > 50% above the baseline value. RESULTS There were 118 patients (83 men [70%]; mean [+/- SD] age, 66 +/- 10 years), 39 (33%) of whom developed acute renal failure within 24 hours after the onset of shock. In-hospital mortality was 87% (34/39) in patients with acute renal failure and 53% (42/79) in patients without acute renal failure (odds ratio [OR] = 6.0; 95% confidence interval [CI]: 2.1 to 17; P < 0.001). Other significant univariate predictors of mortality included the peak serum lactate level, epinephrine dose, and the maximum serum creatinine level. Multivariate logistic regression analysis identified acute renal failure as the only independent predictor of mortality. CONCLUSION Acute renal failure was common in patients with cardiogenic shock and strongly associated with in-hospital mortality.

Comparison of transesophageal and transthoracic contrast echocardiography for detection of a patent foramen ovale

Abstract Presence of a patent foramen ovale may indicate paradoxic embolism in patients with otherwise unexplained embolie disease.1–3 Transthoracic contrast echocardiography has been used as a simple technique for detecting patent foramen ovale.4–6 However, particularly in patients with poor transthoracic image quality, presence of a patent foramen ovale might be missed. Transesophageal contrast echocardiography provides superior visualization of the atrial septum and therefore is believed to improve diagnostic accuracy. The present study investigates the influence of image quality on the detection of a patent foramen ovale by both transthoracic and transesophageal contrast echocardiography.

Significance of left-sided heart disease for the detection of patent foramen ovale by transesophageal contrast echocardiography

Detection of patent foramen ovale by contrast echocardiography is based on transient inversion (right atrial pressure higher than left atrial pressure) of the interatrial pressure gradient. Therefore, the presence of left-sided heart disease with potential elevation of left atrial pressure might obscure the diagnosis of patent foramen ovale. Accordingly, 150 patients (88 men, 62 women; mean age 51.7 +/- 15.2 years) were evaluated for a patent foramen ovale by transesophageal contrast echocardiography. Additionally, atrial septal motion during normal respiration and during the Valsalva maneuver was analyzed. Patency of the foramen ovale was observed in 20 (27%) of 74 patients without left-sided heart disease and with previous arterial embolism, in none (0%) of 25 patients with left-sided heart disease and embolism, in 7 (39%) of 18 patients without left-sided heart disease and without embolism and in 3 (9%) of 33 patients with left-sided heart disease and without embolism. The detection rate of patent foramen ovale was lower in patients with than without left-sided heart disease (5% vs. 29%, p = 0.0007) but was similar in patients with and without embolism (20% vs. 19.5%, p = NS). Abnormal atrial septal motion was more frequently observed in patients with left-sided heart disease (p = 0.0003) and was inversely correlated to detection of patent foramen ovale (p = 0.0003). Multivariate analysis revealed an independent association between the absence of left-sided heart disease and the detection of patent foramen ovale (p = 0.0003). These data suggest that in patients with left-sided heart disease, patency of the foramen ovale may be missed even by transesophageal contrast echocardiography.

Soluble selectins and the systemic inflammatory response syndrome after successful cardiopulmonary resuscitation.

Objective Elevated cytokine levels have been reported after ischemia/reperfusion injury and might cause a systemic inflammatory response syndrome (SIRS) after successful cardiopulmonary resuscitation (CPR). It is unknown whether patients with SIRS after CPR exhibit higher levels of soluble adhesion molecules than patients without SIRS and whether SIRS or elevation of adhesion molecules is associated with outcome after CPR. We analyzed the relationships among various CPR-related variables, plasma levels of E- and P-selectin, the occurrence of SIRS after CPR, and the development of sepsis and outcome. Design Prospective, controlled study. Setting Intensive care unit at a university hospital. Patients A total of 25 patients on the second day after successful CPR and 7 non-critically ill control patients. Interventions Blood sampling for determination of plasma levels of soluble (s) E- and P-selectin. Measurements and Main Results SIRS was a frequent finding after CPR (66% of all patients) unrelated to time until return of spontaneous circulation (SIRS, 17 ± 13 mins; no SIRS, 19 ± 16 mins;p = .761), epinephrine dose (SIRS, 4 ± 5 mg; no SIRS, 5 ± 6 mg;p = .906), or serum lactate level after CPR (SIRS, 8.6 ± 2.6 mmol/L; no SIRS, 8.7 ± 4.0 mmol/L;p = .174). sP-selectin levels were higher in patients with SIRS (291.7 ± 227.4 ng/mL) compared with patients without SIRS (113.4 ± 88.4 ng/mL;p = .018) or with non-critically ill patients (116.9 ± 33.4 ng/mL;p = .031). Compared with non-critically ill control patients (42.8 ± 19.4 ng/mL), sE-selectin levels were higher in patients with (96.2 ± 47.3 ng/mL;p = .023) and without SIRS (99.5 ± 65.7 ng/mL;p = .030). sP-selectin was higher in patients developing sepsis within 1 wk after CPR (n = 9) than in patients without sepsis (350.2 ± 233.4 ng/mL vs. 158.5 ± 157.8 ng/mL;p = .022) and sE-selectin levels were higher in nonsurvivors (n = 5) than in survivors (144.2 ± 62.4 ng/mL vs. 85.7 ± 45.3 ng/mL;p = .025) whereas SIRS was unrelated to the development of sepsis (p = .4) and unrelated to survival (p = .4). Conclusions SIRS is an unspecific finding after CPR with only minor impact on outcome. Determination of sP- and sE-selectin early after CPR might help to identify patients at a high risk for sepsis or for an adverse outcome, respectively.

Hemodynamic and hemorheologic determinants of left atrial spontaneous echo contrast and thrombus formation in patients with idiopathic dilated cardiomyopathy

The purpose of the present study was to evaluate the specific role of hemorheologic and hemodynamic parameters for spontaneous echo contrast and thrombus formation in vivo. We therefore investigated the association between the presence of left atrial spontaneous echo contrast and thrombus formation by transesophageal echocardiography and multiple clinical, hemodynamic, and hemorheologic parameters in 70 patients with idiopathic dilated cardiomyopathy. Transesophageal echocardiography showed left atrial spontaneous echo contrast and left atrial thrombi in 33% and 19% of patients, respectively. Patients with left atrial spontaneous echo contrast had a lower cardiac index (2.1 +/- 0.9 versus 2.6 +/- 0.9 L/min/m2; p < 0.02), a lower left atrial (21 +/- 8 versus 38 +/- 10 cm/sec; p < 0.001) and left atrial appendage flow velocity (17 +/- 14 versus 39 +/- 13 cm/sec; p < 0.001), a larger left atrial diameter (53 +/- 6 versus 46 +/- 10 mm; p < 0.002), and more often presented with atrial fibrillation (62% versus 32%; p < 0.02). Plasma fibrinogen concentration (4.0 +/- 1.1 versus 3.5 +/- 0.7 gm/L; p < 0.02) and plasma viscosity (1.83 +/- 0.10 versus 1.76 +/- 0.15 mPa.sec; p < 0.05) were higher in patients with spontaneous echo contrast. Multivariate analysis revealed an association between the presence of spontaneous echo contrast and left atrial flow velocity p < 0.0001) and plasma viscosity (p < 0.01). In patients with left atrial (appendage) thrombus or a history of embolism, left atrial appendage flow velocity was lower (15.0 +/- 8.2 versus 29.6 +/- 14.5 cm/sec; p < 0.005) and spontaneous echo contrast was more frequently observed (52% versus 23%; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)