Improving neurological outcomes post-cardiac arrest in a rat model: immediate hypothermia and quantitative EEG monitoring

OBJECTIVES: Therapeutic hypothermia (TH) after cardiac arrest (CA) improves outcomes in a fraction of patients. To enhance the administration of TH, we studied brain electrophysiological monitoring in determining the benefit of early initiation of TH compared to conventional administration in a rat model. METHODS: Using an asphyxial CA model, we compared the benefit of immediate hypothermia (IH, T=33 degrees C, immediately post-resuscitation, maintained 6h) to conventional hypothermia (CH, T=33 degrees C, starting 1h post-resuscitation, maintained 12h) via surface cooling. We tracked quantitative EEG using relative entropy (qEEG) with outcome verification by serial Neurological Deficit Score (NDS) and quantitative brain histopathological damage scoring (HDS). Thirty-two rats were divided into 4 groups based on CH/IH and 7/9-min duration of asphyxial CA. Four sham rats were included for evaluation of the effect of hypothermia on qEEG. RESULTS: The 72-h NDS of the IH group was significantly better than the CH group for both 7-min (74/63; median, IH/CH, p<0.001) and 9-min (54/47, p=0.022) groups. qEEG showed greater recovery with IH (p<0.001) and significantly less neuronal cortical injury by HDS (IH: 18.9+/-2.5% versus CH: 33.2+/-4.4%, p=0.006). The 1-h post-resuscitation qEEG correlated well with 72-h NDS (p<0.05) and 72-h behavioral subgroup of NDS (p<0.01). No differences in qEEG were noted in the sham group. CONCLUSIONS: Immediate but shorter hypothermia compared to CH leads to better functional outcome in rats after 7- and 9-min CA. The beneficial effect of IH was readily detected by neuro-electrophysiological monitoring and histological changes supported the value of this observation.     

Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats

Background and purpose:

The association between torcetrapib and its off-target effects on blood pressure suggested a possible class-specific effect. The effects of dalcetrapib (RO4607381/JTT-705) and torcetrapib on haemodynamics and the renin-angiotensin-aldosterone system (RAAS) were therefore assessed in a rat model.

Experimental approach:

Arterial pressure (AP) and heart rate were measured by telemetry in normotensive and spontaneously hypertensive rats (SHR) receiving torcetrapib 10, 40 or 80 mg·kg⁻¹·day⁻¹; dalcetrapib 100, 300 or 500 mg⁻¹·kg·day⁻¹; or vehicle (placebo) for 5 days. Expression of RAAS genes in adrenal gland, kidney, aorta and lung from normotensive rats following 5 days'' treatment with torcetrapib 40 mg·kg⁻¹·day⁻¹, dalcetrapib 500 mg·kg⁻¹·day⁻¹ or vehicle was measured by quantitative polymerase chain reaction.

Key results:

Torcetrapib transiently increased mean AP in normotensive rats (+3.7 ± 0.1 mmHg), whereas treatment in SHR resulted in a dose-dependent and sustained increase [+6.5 ± 0.6 mmHg with 40 mg·kg⁻¹·day⁻¹ at day 1 (P < 0.05 versus placebo)], which lasted over the treatment period. No changes in AP or heart rate were observed with dalcetrapib. Torcetrapib, but not dalcetrapib, increased RAAS-related mRNAs in adrenal glands and aortas.

Conclusions and implications:

In contrast to torcetrapib, dalcetrapib did not increase blood pressure or RAAS-related gene expression in rats, suggesting that the off-target effects of torcetrapib are not a common feature of all compounds acting on cholesteryl ester transfer protein.     

Management of brain injury after resuscitation from cardiac arrest

The devastating neurologic injury in survivors of cardiac arrest has been recognized since the development of modern resuscitation techniques. After numerous failed clinical trials, two trials showed that induced mild hypothermia can ameliorate brain injury and improve survival and functional neurologic outcome in comatose survivors of out-of-hospital cardiac arrest. This article provides a comprehensive review of the advances in the care of brain injury after cardiac arrest, with updates on the process of prognostication, the use of therapeutic hypothermia and adjunctive intensive care unit care for cardiac arrest survivors.     

Cerebral Vasculitis: Diagnosis and Follow-Up With Transcranial Doppler Ultrasonography

The authors report a patient with postpartum intracerebral hemorrhage associated with cerebral vasculitis. Cerebral circulation was assessed with transcranial Doppler (TCD) ultrasonography, magnetic resonance angiography, and conventional cerebral angiography. Initial TCD studies demonstrated bilateral patchy increased cerebral blood flow velocity (CBFV) in the anterior circulation with complete normalization during remission. This case report provides evidence that cerebral vasculitis leads to relevant CBFV changes and that the TCD technique may assist in diagnosis and follow-up of these patients.     

Sleep-Disordered Breathing in Recipients of Implantable Defibrillators

Study Objectives: To examine the prevalence and clinical significance of sleep-disordered breathing in patients with implantable cardioverter defibrillators (ICD).
Methods and Results: Overnight sleep studies were performed in 129 ICD recipients who had no history of sleep apnea. The mean left ventricular ejection fraction (LVEF) was 29 ± 11%. Mild, moderate, and severe sleep apnea was diagnosed in the presence of an apnea/hypopnea index (AHI) of 5–15/h, 15.1–30/h, and >30/h, respectively. No sleep apnea was present in 49 patients (38%), 57 (44%) had central sleep apnea (CSA), and 23 patients (18%) had obstructive sleep apnea (OSA). Mild, moderate, and severe sleep apnea were present in 25%, 31%, and 44% of patients with CSA, compared with 52%, 22%, and 26% of patients with OSA (P < 0.05). LVEF was similar in patients with versus without OSA or CSA. Patients with CSA were significantly older and had a higher prevalence of ischemic cardiomyopathy than patients without sleep apnea.
Conclusions: Previously undiagnosed CSA is common in ICD recipients. Severely disordered breathing during sleep was more prevalent among patients with CSA than patients with OSA. This prospective, observational study will examine the long-term clinical significance of sleep-disordered breathing in ICD recipients.     

Incidence of T Wave Alternation After Acute Myocardial Infarction and Correlation with Other Prognostic Parameters: Results of a Prospective Study

Tachycardia induced alternation of the T wave (TWA) has been associated with arrhythmia morbidity in mixed patient populations. However, less is known concerning the general incidence of TWA and its usefulness in risk stratification early after acute myocardial infarction (MI). TWA was prospectively and systematically assessed in 140 consecutive patients 15 +/- 6 days after acute MI and prior to discharge. Results of TWA measurements were compared to other noninvasive risk markers, LV function, and coronary angiography. Sustained TWA was present at rest or inducible during exercise in 27% of patients. The patient-specific heart rate for the onset of TWA was 98 +/- 9 beats/min. After multivariate analysis, TWA correlated with age (P = 0.02) and LV function (P = 0.002) and occurred more often in patients after nonanterior MI (P = 0.03). Acute results of Holter monitoring, late potentials by signal-averaged ECG, and heart rate variability were unrelated to the TWA status. During follow-up (451 +/- 210 days) two major arrhythmic events occurred. The incidence of TWA early after MI is about 25%. TWA is related to age and LV function but not to other common arrhythmia markers. Although TWA does not appear to be related to excessive cardiac morbidity, evaluation of the prognostic significance of TWA requires further study.