Irrigation is used in every brain surgery operation, yet the optimal temperature of irrigation fluid remains poorly defined and is a topic of debate among neurosurgeons. The majority of neurosurgeons who use warm irrigation cite maintaining normothermia and its perceived hemostatic benefit as their main reasons. However, basic science, neurophysiology, and clinical data challenge the rationale for warm irrigation and suggest that cold irrigation is more advantageous given its neuroprotective properties. Hyperthermia exacerbates neuronal injury, increases metabolic demand, lowers seizure threshold, and worsens outcomes following CNS injury. Conversely, hypothermia reduces intracranial pressure, decreases cerebral metabolism, limits oxidative damage, and improves outcomes in numerous injury models. This review synthesizes the available literature on irrigation temperature in cranial neurosurgery and argues that cold irrigation is superior because it is physiologically consistent with the principles of neuroprotection, metabolic suppression, and seizure prevention.

Salvage of the ischemic penumbra is critical for improving outcomes after stroke, yet effective molecular targets remain elusive. Therapeutic hypothermia (TH) is a promising neuroprotective strategy, but its precise mechanisms, particularly concerning penumbral salvage, are not fully understood. Here, we demonstrate that TH significantly reduces infarct volume and limits the expansion of the ischemic penumbra in a murine model of transient middle cerebral artery occlusion. Mechanistically, TH exerted its protective effects primarily by suppressing apoptosis rather than other forms of regulated cell death. We identified phosphatidylserine (PS) exposure-a key "eat-me" signal for apoptosis-as a critical target of TH. TH selectively attenuated ischemia-induced PS externalization in neurons both in vivo and in vitro. Furthermore, we found that TH downregulated the expression of the scramblase Xkr8, a major regulator of PS exposure. Inhibition of Xkr8 mimicked the neuroprotective effects of TH, reducing PS exposure and improving neuronal survival, whereas overexpression of Xkr8 mitigated TH-mediated protection in the mouse model. Collectively, our findings reveal that TH protects the ischemic penumbra by inhibiting Xkr8-dependent PS exposure and subsequent apoptotic neuronal death, highlighting Xkr8 as a novel therapeutic target for ischemic stroke.

A 62-year-old woman with a symptomatic Crawford extent II thoracoabdominal aortic aneurysm (maximum diameter 73 mm) presented with severe dysphagia and dyspnoea and was deemed at very high operative risk because of profound underweight (35 kg, 1.65 m; body mass index 12.9) and chronic obstructive pulmonary disease stage Gold III. As endovascular repair was unlikely to provide relief of compressive symptoms and would have required extensive aortic coverage, an open strategy was selected. To improve physiological reserve, a period of preoperative conditioning was undertaken with nutritional support (including percutaneous endoscopic gastrostomy feeding) and respiratory optimization, achieving 43 kg at surgery (body mass index 15.8). Repair was performed through a left thoraco-phreno-laparotomy using femoral arterial and right atrial venous cannulation, deep hypothermia (18°C), and hypothermic circulatory arrest (24 minutes) to facilitate a controlled proximal anastomosis in a fragile, ulcerated aorta. Because sequential distal clamping was unsafe, selective visceral and renal protection was applied during reconstruction and reimplantation. The postoperative course was prolonged due to respiratory complications requiring tracheostomy, but no other major complications were observed. At 6-month follow-up, compressive symptoms had resolved and the patient was living independently.

Tissue perfusion and oxygenation, key factors of renal ischemia-reperfusion injury (RIR), can be assessed using contrast-enhanced ultrasound (CEUS) and photoacoustic (PA) imaging. We hypothesized that early changes in renal perfusion and oxygenation caused by IRI, or protection by mild therapeutic hypothermia (mTH), could be detected and correlate with fibrosis. C57BL6 mice underwent 15-min unilateral renal ischemia, with or without mTH, followed by 1-month reperfusion. They were assigned to sham (n = 5), normothermic renal ischemia (IR-37°C, n = 7), mTH renal ischemia (IR-34°C, n = 7). The IR-37°C and IR-34°C groups had body temperature maintained at 37°C or 34°C during surgery. CEUS and PA were conducted at baseline, 20 min, and 1 month after reperfusion. Histological analysis was performed at 1 month. IRI induced renal atrophy and fibrosis at 1 month, prevented by mTH. CEUS revealed altered perfusion in IR-37°C at 20 min, sustained at 1 month, compared to Sham, while perfusion was preserved with mTH in IR-34°C. Oxygenation assessed by PA was not modified. However, oxygenation measured 20 min after IRI correlated with fibrosis at 1 month. CEUS and PA are promising tools for non-invasive assessment of renal IRI. IRI induced early and sustained perfusion alterations, while early assessment of oxygenation correlated with fibrosis. mTH prevented these alterations.

This review explores the heme oxygenase/carbon monoxide (HO/CO) pathway as a central integrator of thermoregulation and neuroenergetics during inflammatory and oxidative stress. Thermoregulation is framed not merely as a homeostatic process, but as a continuous problem of energy allocation where body temperature (Tb) serves as an indicator of an organism's bioenergetic capacity. The core mechanistic thesis identifies the HO/CO system as a state-dependent "coupling pathway" that links inflammatory and redox tone to mitochondrial performance and, through central autonomic hierarchies, to the selection of thermal phenotypes, such as fever, regulated hypothermia, or torpor-like states. While fever supports "resistance" at a high metabolic cost, regulated hypothermia aligns with "tolerance" by conserving energy when resources or oxygen delivery are constrained. Key knowledge gaps remain regarding the precise cell-type-specific roles of HO-1 in the central nervous system (CNS) and the context-dependent nature of CO signaling via soluble guanylyl cyclase (sGC) in vivo. Therapeutically, targeting the HO/CO pathway via inhaled CO, CO-releasing molecules (CORMs), or HO-1 induction offers prospects for modulating neuroinflammation and metabolic resilience. However, translational constraints include timing-dependent effects and the need for precision phenotyping to identify which patients might benefit from interventions. In conclusion, the HO/CO system is discussed as a sophisticated modulator that biases thermoregulatory strategy based on the immediate physiological constraints of oxygen delivery and energetic reserve.

Hypothermia and hypometabolism are important for hibernating animals to survive harsh environmental conditions. Induction of a hypothermic and hypometabolic state is considered an avenue to treat severe diseases, such as ischemic stroke. However, noninvasive and safe methods to achieve a long-lasting hypothermic and hypometabolic state remain limited. Here, we present data from preclinical and clinical studies to explore the feasibility and safety of drug-induced hypothermia by administration of chlorpromazine and promethazine (C+P). In mice, C+P treatment induced hypothermia and suppressed glucose metabolism in the brain. C+P treatment reduced infarct volumes and improved neurological deficit in a mouse middle cerebral artery occlusion model induced by suture insertion. Furthermore, C+P treatment reduced body temperature, suppressed metabolism, and exerted cerebroprotective effects in a rhesus monkey model of stroke. In a double-blind, phase 1 clinical trial (NCT06663631), a total of 32 patients diagnosed with acute ischemic stroke were enrolled, receiving either placebo or increasing doses of C+P treatment: 10, 20, 50, or 100 milligrams. All doses were safe and well tolerated. Only 100 milligrams of C+P resulted in a modest and transient reduction in body temperature. Plasma proteomic profiling revealed a down-regulation of markers associated with aerobic respiration and glucose metabolism. These findings highlight the translational potential of C+P treatment and warrant a larger trial to further investigate safety and efficacy of C+P.