Plasma exchange and intravenous immunoglobulin in the treatment of antibody-mediated rejection after kidney transplantation: a single-center historic cohort study.

BACKGROUND: Antibody-mediated rejection (AMR) of a kidney graft has been increasingly recognized as an important cause of graft failure. Our historic cohort study sought to analyze its treatment and outcomes at our center. METHODS: All patients with AMR between 2005 and 2011 were treated with plasma exchange (PE), intravenous low-dose cytomegalovirus (CMV) hyperimmune globulin, and adjustment of basal immunosuppression. We analyzed data regarding baseline characteristics, rejection treatment with focus on PE, complications, and 1-year outcomes. RESULTS: Twenty-three AMRs occurred in 23 patients (10 male, 13 female) of mean age 41 ± 16 years, all recipients of deceased-donor kidneys with a median of 3 HLA mismatches. The subjects had a median peak panel-reactive antibodies (PRA) of 7% (interquartile range [IQR] 1%-10%). Basal serum creatinine was 174 ± 84 µmol/L estimated glomerular filtration rate (eGFR) (eGFR 42 ± 22 mL/min/1.73 m(2)), while 3 patients were dialysis- dependent. Median period between transplantation and rejection was 38 months (IQR 1.5-88.5). Concomitant T-cell-mediated rejection was treated in 78% of cases. Median number of PE procedures per patient was 10 (range, 5-17). Treatment was estimated to be successful in 83%. Donor-specific antibodies documented in 12 patients (52%) disappeared or showed reduced titers in 7/10 patients with repeated measurements. An infection was present during treatment in 7 (30%) patients. Among 237 PE, there was 1 (0.4%) mild allergic reaction to fresh frozen plasma and significant metabolic alkalosis occurred after 7 (3%) procedures. One year after rejection the mean serum creatinine level was 144 ± 52 µmol/L and Kaplan-Meier estimated graft and patient survival rates were 62% and 95%, respectively. CONCLUSIONS: Intensive treatment with PE, intravenous immunoglobulin, and adjustment of basal immunosuppression were safe and effective to reverse AMR with improved graft function in the majority of patients. However, AMR was associated with markedly decreased 1-year graft survival and the optimal treatment remains uncertain.

Two cases of complications of the thrombolysis of right heart free-floating thrombi with pulmonary embolism: important role of echocardiographically based management.

We present two cases where successful thrombolysis of right heart thrombi and pulmonary embolism was accompanied by serious adverse events. In patient 1 with massive pulmonary thromboembolism, transesophageal ultrasound revealed large right atrial thrombus entrapped in a patent foramen ovale. Initial treatment with heparin was substituted with thrombolysis, which resulted in clinical improvement and dissolution of right heart thrombus but was followed by fatal intracerebral haemorrhage. In patient 2, thrombolysis caused mobilisation of thrombotic mass as evidenced by disappearance of thrombus on ultrasound. Massive pulmonary thromboembolism resulted in circulatory collapse. Short cardiopulmonary resuscitation restored spontaneous circulation and the patient recovered completely.

Optimizing timing of ventricular defibrillation.

OBJECTIVE: Our intent was to evolve a prognosticator that would predict the likelihood that an electrical shock would restore a perfusing rhythm. Such a prognosticator was to be based on conventional electrocardiographic signals but without constraints caused by artifacts resulting from precordial compression. The adverse effects of "hands off" intervals for rhythm analyses would therefore be minimized. Such a prognosticator was further intended to reduce the number of electrical shocks and the total energy delivered and thereby minimize postresuscitation myocardial dysfunction. DESIGN: Observational study. SUBJECTS: Medical research laboratory of a university-affiliated research and educational institute. SUBJECTS: Domestic pigs. INTERVENTIONS: Ventricular fibrillation was induced in an established porcine model of cardiac arrest. Recordings of scalar lead 2 over the frequency range of 4-48 Hz were utilized. The area under the curve representing the amplitude and frequency was defined as the amplitude spectrum area (AMSA). MEASUREMENTS AND MAIN RESULTS: A derivation group of 55 animals yielded a threshold value of AMSA that uniformly predicted successful resuscitation. A separate group of 10 animals, a validation group, confirmed that an AMSA value of 21 mV.Hz predicted restoration of perfusing rhythm after 7 of 8 electrical shocks and failure of electrical conversion in 21 of 23 electrical shocks, yielding sensitivity and specificity of about 90%. The negative predictive value of AMSA was 95% and statistically equivalent to that of coronary perfusion pressure, mean amplitude, and median frequency. The positive predictive value that would prompt continuation of cardiopulmonary resuscitation without interruption for an unsuccessful defibrillation attempt was greatly improved with AMSA (78%) as compared with coronary perfusion pressure (42%), mean amplitude (32%), and median frequency (29%). CONCLUSION: AMSA has the potential for guiding more optimal timing of defibrillation without adverse interruption of cardiopulmonary resuscitation or the delivery of unsuccessful high energy electrical shocks that contribute to postresuscitation myocardial injury.

K(ATP) channel activation reduces the severity of postresuscitation myocardial dysfunction.

Postresuscitation myocardial dysfunction has been recognized as a leading cause of the high postresuscitation mortality rate. We investigated the effects of ischemic preconditioning and activation of ATP-sensitive K(+) (K(ATP)) channels on postresuscitation myocardial function. Ventricular fibrillation (VF) was induced in 25 Sprague-Dawley rats. Cardiopulmonary resuscitation (CPR), including mechanical ventilation and precordial compression, was initiated after 4 min of untreated VF. Defibrillation was attempted after 6 min of CPR. The animals were randomized to five groups treated with 1) ischemic preconditioning, 2) K(ATP) channel opener, 3) ischemic preconditioning with K(ATP) channel blocker administered 1 min after VF, 4) K(ATP) channel blocker administered 45 min before induction of ischemic preconditioning, and 5) placebo. Postresuscitation myocardial function, as measured by the rate of left ventricular pressure increase at 40 mmHg, the rate of left ventricular decline, cardiac index, and duration of survival, was significantly improved in both preconditioned and K(ATP) channel opener-treated animals. K(ATP) channel blocker administered 45 min before induction of ischemic preconditioning completely abolished the myocardial protective effects of preconditioning. We conclude that ischemic preconditioning significantly improved post-CPR myocardial function and survival. These results also provide evidence that the myocardial protective effects of ischemic preconditioning are mediated by K(ATP) channel activation.

End-tidal carbon dioxide as a noninvasive indicator of cardiac index during circulatory shock.

OBJECTIVE: To document the relationships between cardiac index and end-tidal carbon dioxide tension (PetCO2 during diverse low-flow states of circulatory shock. DESIGN: Randomized, prospective, controlled studies on animal models of hemorrhagic, septic, and cardiogenic shock. SETTING: University-affiliated research laboratory. SUBJECTS: Sixteen anesthetized domestic pigs weighing 35-45 kg. INTERVENTIONS: Hemorrhagic shock was induced in five pigs by bleeding followed by reinfusion of shed blood. Septic shock was induced in five pigs by infusion of live Escherichia coli. Cardiogenic shock followed an interval of global myocardial ischemia after inducing and reversing ventricular fibrillation in six pigs. MEASUREMENTS AND MAIN RESULTS: PetCO2 was continuously measured. Cardiac index was measured intermittently by using conventional thermodilution techniques. Cardiac index was correlated with PetCO2 by polynomial regression and Bland-Altman analyses. PetCO2 was highly correlated with cardiac index during hemorrhagic shock (r2 = .69, p < .01), septic shock (r2 = .65, p < .01), and cardiogenic shock (r2 = .81, p < .01). PetCO2 predicted thermodilution cardiac index with bias of -11+/-27 (+/-2 SD) mL/min/kg during hemorrhagic shock, 1.3+/-20.4 (+/- 2 SD) mL/min/kg during septic shock, and -1+/-12 (+/-2 SD) mL/min/kg during cardiogenic shock. CONCLUSIONS: Cardiac output and PetCO2 were highly related in diverse experimental models of circulatory shock in which cardiac output was reduced by >40% of baseline values. Therefore, measurement of PetCO2 is a noninvasive alternative for continuous assessment of cardiac output during low-flow circulatory shock states of diverse causes.

Atrial function during cardiac arrest caused by ventricular fibrillation.

OBJECTIVES: To report observations on preserved regular atrial electrical and mechanical systole during ventricular fibrillation (VF) and to quantitate blood flow generated by atrial contractions in this setting. METHODS: In 10 rats, right atrial pressure pulses were continuously recorded before and for an interval of 8 min after inducing VF. In 3 isolated, perfused rat hearts, epicardial right atrial electrograms were recorded after inducing VF. In 15 pigs, transesophageal echo-Doppler measurements were obtained with pulsed and color-Doppler visualization of flow across the mitral valve after onset of VF. RESULTS: In each rat, regular right atrial pressure pulses were documented during VF. These persisted over an average interval of 7.5 min. In isolated, perfused hearts, right atrial contractions were accompanied by regular atrial depolarizations. In pigs, regular atrial contractions generated atrial stroke volumes of approximately 12 mL, or 25% of prearrest values during the first minute after onset of VF, but those declined to approximately 6 mL after 10 min of untreated cardiac arrest. Blood flow from the left atrium into the left ventricle failed to advance significantly into the systemic circuit. During atrial diastole, we observed reversal of flow into the left atrium. CONCLUSIONS: Atrial contractions are preserved during the initial 8 min or more after cardiac arrest due to VF. Substantial forward flow into the left ventricle failed to advance through the outflow tract but regurgitated into the atrium during atrial diastole.

The effects of biphasic and conventional monophasic defibrillation on postresuscitation myocardial function.

OBJECTIVES: The purpose of this study was to compare the effects of biphasic defibrillation waveforms and conventional monophasic defibrillation waveforms on the success of initial defibrillation, postresuscitation myocardial function and duration of survival after prolonged ventricular fibrillation (VF). BACKGROUND: We have recently demonstrated that the severity of postresuscitation myocardial dysfunction was closely related to the magnitude of the electrical energy of the delivered defibrillation shock. In the present study, the effects of fixed 150-J low-energy biphasic waveform shocks were compared with conventional monophasic waveform shocks after prolonged VF. METHODS: Twenty anesthetized, mechanically ventilated domestic pigs were investigated. VF was induced with an AC current delivered to the right ventricular endocardium. After either 4 or 7 min of untreated ventricular fibrillation (VF), the animals were randomized for attempted defibrillation with up to three 150-J biphasic waveform shocks or conventional sequence of 200-, 300- or 360-J monophasic waveform shocks. If VF was not reversed, a 1-min interval of precordial compression preceded a second sequence of up to three shocks. The protocol was repeated until spontaneous circulation was restored or for a total of 15 min. RESULTS: Monophasic waveform defibrillation after 4 or 7 min of untreated VF resuscitated eight of 10 pigs. All 10 pigs treated with biphasic waveform defibrillation were successfully resuscitated. Transesophageal echo-Doppler, arterial pressure and heart rate measurements demonstrated significantly less impairment of cardiovascular function after biphasic defibrillation. CONCLUSIONS: Lower-energy biphasic waveform shocks were as effective as conventional higher energy monophasic waveform shocks for restoration of spontaneous circulation after 4 and 7 min of untreated VF. Significantly better postresuscitation myocardial function was observed after biphasic waveform defibrillation.

Effects of hyper- and hypoventilation on gastric and sublingual PCO(2).

We investigated the effects of hyper- and hypoventilation on gastric (Pg(CO(2))) and sublingual (Psl(CO(2))) tissue PCO(2) before, during, and after reversal of hemorrhagic shock. Pg(CO(2)) was measured with ion-sensitive field-effect transistor sensor and Psl(CO(2)) with a CO(2) microelectrode. Under physiological conditions and during hemorrhagic shock, decreases in arterial (Pa(CO(2))) and end-tidal (PET(CO(2))) PCO(2) induced by hyperventilation produced corresponding decreases in Pg(CO(2)) and Psl(CO(2)). Hypoventilation produced corresponding increases in Pa(CO(2)), PET(CO(2)), Pg(CO(2)), and Psl(CO(2)). Accordingly, acute decreases and increases in Pa(CO(2)) and PET(CO(2)) produced statistically similar decreases and increases in Pg(CO(2)) and Psl(CO(2)). No significant changes in the tissue PCO(2)-Pa(CO(2)) gradients were observed during hemorrhagic shock in the absence or in the presence of hyper- or hypoventilation. Acute changes in Pg(CO(2)) and Psl(CO(2)) should, therefore, be interpreted in relationship with concurrent changes in Pa(CO(2)) and/or PET(CO(2)).

Electrocardiographic prediction of the success of cardiac resuscitation.

OBJECTIVES: To identify a method for predicting the success or failure of a defibrillatory shock such as to avoid potentially detrimental interruptions of cardiopulmonary resuscitation (CPR). Such a method would also guide more optimal programming of automated external defibrillators. DESIGN: Prospective, observational animal study. SETTING: Medical research laboratory in a university-affiliated research and educational foundation. SUBJECTS: Domestic pigs. INTERVENTIONS: Ventricular fibrillation (VF) was electrically induced in 66 domestic pigs. After an interval of between 3 and 5 mins of untreated VF, precordial compression was begun. Electrocardiographic lead 2 was monitored and artifacts produced during precordial compression were removed by digital filtering. MEASUREMENTS AND MAIN RESULTS: In the derivation study, electrical defibrillation restored spontaneous circulation in 30 of the 66 animals. Successfully resuscitated animals had significantly greater coronary perfusion pressure, maximum VF amplitude, mean VF amplitude, and dominant VF frequency. No animals were resuscitated if the coronary perfusion pressure was <8 mm Hg, maximum amplitude was <0.48 mV, mean amplitude was <0.25 mV, or dominant frequency <9.9 Hz independently of the duration of untreated VF. When mean amplitude and dominant frequency were combined, the predictability was further improved. In an additional validation study of 14 animals, consecutive defibrillations were uniformly unsuccessful if the combination of mean amplitude and dominant frequency did not exceed the threshold values obtained in derivation study. CONCLUSION: Mean VF amplitude alone or in combination with dominant frequency of VF was expressed as a numerical score. It served as an objective noninvasive measurement on a par with that of coronary perfusion pressure for predicting the success of defibrillation. As such, it minimizes the detriment of repetitively interrupting mechanical interventions during CPR for electrical defibrillation when an electrical shock predictably fails to restore an effective rhythm.

Are insulin metabolism and night-time blood pressure related to left ventricular hypertrophy?

Essential hypertensives in whom blood pressure does not fall during sleep (non-dippers) are thought to be at greater risk of cardiovascular morbidity. Insulin resistance is also suggested to be a risk factor for cardiovascular morbidity. The purpose of the present study was to evaluate the relationship of insulin metabolism to left ventricular hypertrophy in dippers and non-dippers. Thirty male, non-diabetic out-patients with newly diagnosed arterial hypertension were included in the study: 21 dippers (mean age 45+/-13 years; body mass index 28.2+/-4.0 kg/m2) and nine non-dippers (mean age 48+/-10 years, body mass index 28.6+/-3.9 kg/m2). Patients were subdivided into dippers and non-dippers on the basis of 24-h ambulatory blood pressure monitoring. Insulin and glucose responses to an oral glucose load have been evaluated. C-peptide levels were determined. Left ventricular mass was assessed by echocardiography. Non-dippers had significantly higher mean night-time systolic (non-dippers: 148+/-9; dippers: 123+/-16 mmHg; P<0.001), diastolic blood pressure (non-dippers: 90+/-8; dippers: 77+/-8 mmHg; P<0.001) and non-significantly higher left ventricular mass (279+/-92 g) and left ventricular mass index (135+/-46 g/m2). No significant difference was found between C-peptide, insulin, glucose levels and incremental areas between the two groups. Night-time blood pressure, insulin, C-peptide and glucose did not correlate with left ventricular mass in non-dippers. Dippers showed a positive correlation between fasting C-peptide and left ventricular mass (r=0.48, P=0.02) and between glucose and left ventricular mass (r=0.42, P=0.05). Our data indicate that night-time blood pressure and insulin are not related to left ventricular hypertrophy in patients with essential hypertension.

Diastolic function and insulin resistance in essential hypertension.

We studied the relationship of insulin metabolism to diastolic function in 41 hypertensive patients and 24 healthy subjects. They underwent a 75-g oral glucose tolerance test. Integrated response of insulin to the glucose load was calculated as the area under the curve of insulin (AUC-I) and glucose (AUC-G). The ratio AUC-I/AUC-G was taken as an index of insulin resistance. Echocardiographic examination was performed to measure left ventricular mass. We used pulsed Doppler technique to assess the ratio of early to late transmitral peak velocity (E/A). The hypertensives had higher fasting insulin concentrations, insulin levels at 60 min and at 120 min after oral glucose load. They had higher AUC-I and higher index of insulin resistance compared to normotensives. Patients with hypertension had a lower E/A ratio in comparison to normotensive volunteers. In all subjects, the E/A ratio was negatively correlated with fasting insulin and insulin concentrations at 30, at 60 and at 120 min, AUC-I and insulin resistance index. Multiple regression analysis was performed to evaluate the above relationships, when the effects of confounding factors such as age, heart rate and systolic blood pressure were taken into account. We found that E/A ratio is negatively correlated to insulin concentrations at 120 min and to AUC-I in hyperinsulinemic subgroup of subjects (fasting insulin> 10). We conclude, that insulin metabolism and E/A ratio, which reflects diastolic function of the left ventricle, are related in hypertension.

Heart conduction disturbances and cardiovascular collapse after disopyramide and low-dose metoprolol in a patient with hypertrophic obstructive cardiomyopathy.

Disopyramide as an antiarrhythmic can be prescribed to patients with atrial fibrillation and, owing to its negative inotropic effect, to patients with hypertrophic obstructive cardiomyopathy. It is known that in patients with cardiac conduction disturbances and heart failure, disopyramide can adversely affect heart rhythm and conduction and induce cardiovascular collapse. A patient with hypertrophic obstructive cardiomyopathy and paroxysms of atrial fibrillation is described who was treated with disopyramide and also, during the 5 days before admission, with metoprolol. In spite of normal cardiac conduction and function before disopyramide, this treatment was followed by hypotension, bradycardia, and cardiac conduction disturbances. Our case shows the potential for disopyramide, especially when combined with metoprolol, to induce grave adverse effects even in patients with normal cardiac conduction and ventricular function.