Physical hypothermia has long been considered a promising neuroprotective treatment of ischemic stroke, but the treatment's various complications along with the impractical duration and depth of ...therapy significantly narrow its clinical scope. In the present study, the model of reversible right middle cerebral artery occlusion (MCAO) for 2 h was used. We combined hypothermia (33-35 °C for 1 h) with phenothiazine neuroleptics (chlorpromazine & promethazine) as additive neuroprotectants, with the aim of augmenting its efficacy while only using mild temperatures. We also investigated its therapeutic effects on the Phosphatidylinositol 3 kinase/Protein kinase B (PI3K/Akt) apoptotic pathway. The combination treatment achieved reduction in ischemic rat temperatures in the rectum, cortex and striatum significantly (P < 0.01) faster than hypothermia alone, accompanied by more obvious (P < 0.01) reduction of brain infarct volume and neurological deficits. The combination treatment remarkably (P < 0.05) increased expression of p-Akt and anti-apoptotic proteins (Bcl-2 and Bcl-xL), while reduced expression of pro-apoptotic proteins (AIF and Bax). Finally, the treatment's neuroprotective effects were blocked by a p-Akt inhibitor. By combining hypothermia with phenothiazines, we significantly enhanced the neuroprotective effects of mild hypothermia. This study also sheds light on the possible molecular mechanism for these effects which involves the PI3K/Akt signaling and apoptotic pathway.
Objectives:
To assess whether a weaning protocol reduces the mechanical ventilation (MV) duration compared to physician's judgement-based weaning in neurological patients and to determine whether ...patient consciousness influences this reduction.
Methods:
A randomised controlled trial was conducted in a neurological intensive care unit (NCU) of a tertiary hospital; 144 patients requiring MV for more than 24 hours were randomly allocated to protocol-directed (intervention) (n = 71) or physician-directed (control) group (n = 73).
Results:
The intervention group displayed a significantly shorter median weaning time than the control group (2.00 vs 5.07 days, P < 0.05). The median MV duration tended to be shorter in the intervention group (10.8 vs 14.2 days, P = 0.106). The median length of NCU stay was 19.0 and 26.1 days in the intervention and control groups, respectively (P = 0.063). The median NCU cost was 9.26 × 10
4
and 12.24 × 10
4
¥ in the intervention and control groups, respectively (P = 0.059). The unsuccessful weaning, ventilator-associated pneumonia (VAP) and mortality rates were similar between the groups. Among conscious patients, the median weaning time (2.00 vs 7.00 days, P < 0.05) and the median MV duration (8.8 vs 18.0 days, P = 0.017) were significantly reduced in the intervention group. Among unconscious patients, the intervention group displayed a reduced median weaning time (1.00 vs 3.10 days, P < 0.05), but not median MV duration (11.6 vs 11.1 days, P = 0.702), compared to the control group.
Conclusion:
Protocol-directed weaning reduces weaning time, MV duration, length of NCU stay and NCU cost in neurological patients, and these effects are more significant in conscious patients than in unconscious patients.
Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant demyelinating neuropathy characterized by an increased susceptibility to peripheral nerve injury from trauma, ...compression, or shear forces. Patients with this condition are unique, necessitating distinct considerations for anesthesia and surgical teams. This review describes the etiology, prevalence, clinical presentation, and management of HNPP and presents contemporary evidence and recommendations for optimal care for HNPP patients in the perioperative period. While the incidence of HNPP is reported at 7-16:100,000, this figure may be an underestimation due to underdiagnosis, further complicating medicolegal issues. With the subtle nature of symptoms associated with HNPP, patients with this condition may remain unrecognized during the perioperative period, posing significant risks. Several aspects of caring for this population, including anesthetic choices, intraoperative positioning, and monitoring strategy, may deviate from standard practices. As such, a tailored approach to caring for this unique population, coupled with meticulous preoperative planning, is crucial and requires a multidisciplinary approach.
Previous studies have demonstrated depressive or hibernation-like roles of phenothiazine neuroleptics combined chlorpromazine and promethazine (C + P) in brain activity. This ischemic stroke study ...aimed to establish neuroprotection by reducing oxidative stress and improving brain metabolism with post-ischemic C + P administration. Sprague-Dawley rats were subjected to transient (2 or 4 h) middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion, or permanent (28 h) MCAO without reperfusion. At 2 h after ischemia onset, rats received either an intraperitoneal (IP) injection of saline or two doses of C + P. Body temperatures, brain infarct volumes, and neurological deficits were examined. Oxidative metabolism and stress were determined by levels of ATP, NADH, and reactive oxygen species (ROS). Protein kinase C-δ (PKC-δ) and Akt expression were determined by Western blotting. C + P administration induced a neuroprotection in both transient and permanent ischemia models evidenced by significant reduction in infarct volumes and neurological deficits post-stroke. C + P induced a dose-dependent reduction in body temperature as early as 5 min post-ischemia and lasted up to 12 h. However, reduction in body temperature either only slightly or did not enhance C + P-induced neuroprotection. C + P therapy improved brain metabolism as determined by increased ATP levels and NADH activity, as well as decreased ROS production. These therapeutic effects were associated with alterations in PKC-δ and Akt protein expression. C + P treatments conferred neuroprotection in severe stroke models by suppressing the damaging cascade of metabolic events, most likely independent of drug-induced hypothermia. These findings further prove the clinical potential for C + P treatment and may direct us closer towards the development of an efficacious neuroprotective therapy.
•We investigated the neuroprotective effects of pharmacological hypothermia and local hypothermia in rat MCAO models.•The combination of the above methods enhances the efficiency of hypothermia.•The ...combination of the above methods enhances efficacy of hypothermia-induced neuroprotection following ischemic stroke.•PI3K/Akt apoptotic pathway is a possible mechanism for the combination therapy.
Hypothermia has demonstrated neuroprotection following ischemia in preclinical studies while its clinical application is still very limited. The aim of this study was to explore whether combining local hypothermia in ischemic territory achieved by intra-arterial cold infusions (IACIs) with pharmacologically induced hypothermia enhances therapeutic outcomes, as well as the underlying mechanism.
Sprague-Dawley rats were subjected to right middle cerebral artery occlusion (MCAO) for 2h using intraluminal hollow filament. The ischemic rats were randomized to receive: 1) pharmacological hypothermia by intraperitoneal (i.p.) injection of dihydrocapsaicin (DHC); 2) physical hypothermia by IACIs for 10min; or 3) the combined treatments. Extent of brain injury was determined by neurological deficit, infarct volume, and apoptotic cell death at 24h and/or 7d following reperfusion. ATP and ROS levels were measured. Expression of p-Akt, cleaved Caspase-3, pro-apoptotic (AIF, Bax) and anti-apoptotic proteins (Bcl-2, Bcl-xL) was evaluated at 24h. Finally, PI3K inhibitor was used to determine the effect of p-Akt.
DHC or IACIs each exhibited hypothermic effect and neuroprotection in rat MCAO models. The combination of pharmacological and physical approaches led to a faster and sustained reduction in brain temperatures and improved ischemia-induced injury than either alone (P<0.01). Furthermore, the combination treatment favorably increased the expression of anti-apoptotic proteins and decreased pro-apoptotic protein levels (P<0.01 or 0.05). This neuroprotective effect was largely blocked by p-Akt inhibition, indicating a potential role of Akt pathway in this mechanism (P<0.01 or 0.05).
The combination approach is able to enhance the efficiency of hypothermia and efficacy of hypothermia-induced neuroprotection following ischemic stroke. The findings here move us a step closer towards translating this long recognized TH from bench to bedside.
Ischemic stroke induces metabolic disarray. A central regulatory site, pyruvate dehydrogeanse complex (PDHC) sits at the cross-roads of 2 fundamental metabolic pathways: aerobic and anaerobic. In ...this study, we combined ethanol (EtOH) and normobaric oxygen (NBO) to develop a novel treatment to modulate PDHC and its regulatory proteins, namely pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase, leading to improved metabolism and reduced oxidative damage.
Sprague-Dawley rats were subjected to transient (2, 3, or 4 hours) middle cerebral artery occlusion followed by 3- or 24-hour reperfusion, or permanent (28 hours) middle cerebral artery occlusion without reperfusion. At 2 hours after the onset of ischemia, rats received either an intraperitoneal injection of saline, 1 dose of EtOH (1.5 g/kg) for 2- and 3-hour middle cerebral artery occlusion, 2 doses of EtOH (1.5 g/kg followed by 1.0 g/kg in 2 hours) in 4 hours or permanent middle cerebral artery occlusion, and EtOH+95% NBO (at 2 hours after the onset of ischemia for 6 hours) in permanent stroke. Infarct volumes and neurological deficits were examined. Oxidative metabolism and stress were determined by measuring ADP/ATP ratio and reactive oxygen species levels. Protein levels of PDHC, pyruvate dehydrogenase kinase, and pyruvate dehydrogenase phosphatase were assessed.
EtOH induced dose-dependent neuroprotection in transient ischemia. Compared to EtOH or NBO alone, NBO+EtOH produced the best outcomes in permanent ischemia. These therapies improved brain oxidative metabolism by decreasing ADP/ATP ratios and reactive oxygen species levels, in association with significantly raised levels of PDHC and pyruvate dehydrogenase phosphatase, as well as decreased pyruvate dehydrogenase kinase.
Both EtOH and EtOH+NBO treatments conferred neuroprotection in severe stroke by affecting brain metabolism. The treatment may modulate the damaging cascade of metabolic events by bringing the PDHC activity back to normal metabolic levels.
Although tremendous efforts have been made to explore the potential aetiologies of cryptogenic ischaemic cerebral vascular disease (CICVD), it remains a great challenge for neurologists to get a ...comprehensive picture of CICVD across the world. Part of the reason why is that the vast majority of studies have focussed on CICVD in young stroke patients while the underlying causes of CICVD in middle-aged or elderly stroke population have not been fully investigated. The focus of this paper has been dedicated to review the different studies that explore the aetiologies of CICVD cases in this patient population. While there is a set of heterogeneous causes that can lead to CICVD in middle-aged and elderly patients, our review reveals that emboli originated from or across occult places within the heart or produced by transient arrhythmias could possibly be the main culprit. Dislodged aortic plaques might also account for certain CICVD cases and in fewer cases, hereditary arteriopathy and thrombophilia can also play a role. The aforementioned factors have similar roles in middle-aged and elderly CICVD patients as in their younger counterparts. However, more studies are needed to explore the role of these factors in older patients.
Cerebral venous sinus thrombosis (CVST) is an uncommon subtype of stroke with highly variable clinical presentation. Although anticoagulation with heparin and/or warfarin remains the standard ...treatment for CVST, treatment failure is still common. This study aims to evaluate the safety and efficacy of Batroxobin in combination with anticoagulation on CVST control. In this retrospective study, a total of 61 CVST patients were enrolled and divided into Batroxobin (n = 23) and control (n = 38) groups. In addition to the same standard anticoagulation in control, patients in the treatment group received Batroxobin 5 BU intravenous infusion (10 BU for the first time) every other day, for a total of three infusions. A higher recanalization rate was found in Batroxobin group (adjusted OR 95% CI of 2.5 1.1–5.0,
p
= 0.028) compared to the control group, especially in patients with high levels of fibrinogen (adjusted OR 95% CI of 4.7 1.4–16.7,
p
= 0.015). Statistically significant differences between the two groups were seen regarding the levels of thrombin time, fibrinogen and
d
-dimer at each cut-off time point (all
p
< 0.01). Compared with baseline, NIHSS scores at discharge showed significant improvement in the Batroxobin group 0(0, 4.25)–5(2, 11),
p
= 0.036. No significant difference in mRS scores was found between the two groups at discharge or at 6-month outpatient follow-up (all
p
> 0.05). Additionally, Batroxobin did not increase the risk of intracranial hemorrhage. We conclude that Batroxobin is a potentially safe and effective adjunct therapeutic agent promoting CVST recanalization especially in patients with high level of fibrinogen.
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