Fasting mimicking diet in mice delays cancer growth and reduces immunotherapy-associated cardiovascular and systemic side effects.

Immune checkpoint inhibitors cause side effects ranging from autoimmune endocrine disorders to severe cardiotoxicity. Periodic Fasting mimicking diet (FMD) cycles are emerging as promising enhancers of a wide range of cancer therapies including immunotherapy. Here, either FMD cycles alone or in combination with anti-OX40/anti-PD-L1 are much more effective than immune checkpoint inhibitors alone in delaying melanoma growth in mice. FMD cycles in combination with anti-OX40/anti-PD-L1 also show a trend for increased effects against a lung cancer model. As importantly, the cardiac fibrosis, necrosis and hypertrophy caused by immune checkpoint inhibitors are prevented/reversed by FMD treatment in both cancer models whereas immune infiltration of CD3+ and CD8+ cells in myocardial tissues and systemic and myocardial markers of oxidative stress and inflammation are reduced. These results indicate that FMD cycles in combination with immunotherapy can delay cancer growth while reducing side effects including cardiotoxicity.

The variability of cerebrovascular reactivity with posture and time.

Transcranial Doppler (TCD) ultrasonography has been used in a variety of clinical contexts to assess cerebrovascular reserve by measuring carbon dioxide reactivity. Reproducibility with time and altered position of the patient is examined in the present study. Carbon dioxide reactivity was determined in 10 healthy volunteers using TCD. Hypocarbia was produced by voluntary hyperventilation, and hypercarbia was produced by rebreathing from a circuit primed with 7% carbon dioxide. Each patient was studied in the supine position twice (1 week apart) and once in the seated position. Carbon dioxide reactivity was determined from linear regression analysis of paired middle cerebral artery flow velocity and end-tidal carbon dioxide values. Analysis of covariance for repeated measures was used for statistical analysis. Both the absolute slope and the relative slope (absolute slope expressed as a percentage of flow velocity at 40 mm Hg) were compared. In the supine position, flow velocity, absolute and relative slopes, and mean arterial pressure were similar from one week to the next at all carbon dioxide levels. In contrast, flow velocity, mean arterial pressure (adjusted for hydrostatic gradient), and absolute slope were decreased in the seated position (p < 0.05). No difference was observed when the relative slope was used for comparison. We conclude that absolute carbon dioxide reactivity is reproducible over time but may be influenced by position. Relative reactivity (relative slope), however, was both time and position independent.

Rocuronium versus succinylcholine-atracurium for tracheal intubation and maintenance relaxation during propofol anesthesia.

STUDY OBJECTIVES: To compare the onset and offset time (clinical duration), and intubating conditions obtained with rocuronium bromide 0.6 mg/kg and succinylcholine 1.0 mg/kg after induction with propofol and fentanyl; and to compare rocuronium with atracurium for maintenance during propofol anesthesia. DESIGN: Prospective, open-label, parallel group comparative, randomized study. SETTING: Operating rooms of a university hospital. PATIENTS: 30 ASA physical status I and II adult patients scheduled for elective surgeries with general anesthesia. INTERVENTIONS: Patients premedicated with midazolam 2 mg were anesthetized with fentanyl 2 microg/kg followed by propofol 2.5 mg/kg and muscle relaxants. Group 1 (n = 15) received succinylcholine 1.5 mg/kg and Group 2 (n = 16) received rocuronium bromide 0.6 mg/kg. Intubation was performed 60 seconds after the administration of muscle relaxant. Patients in Group 1 received atracurium and patients in Group 2 received rocuronium for maintenance if required. MEASUREMENTS: The ease of intubation was scored using a scale of 1 to 4. Onset and offset time monitored with evoked twitch response of the adductor pollicis were recorded. MAIN RESULTS: Intubation was successful in all patients and there was no difference in scores between the two groups. Although onset time was shorter with succinylcholine than with rocuronium, neuromuscular blockade was successfully antagonized in both groups, and the recovery profile was not different between the two groups. CONCLUSIONS: Rocuronium bromide at a dose of 0.6 mg/kg, when used with propofol and fentanyl for induction, provides intubating conditions similar to succinylcholine 1.0 mg/kg at 1 minute. The actual onset time and offset time, however, are significantly longer with rocuronium. There was no difference between atracurium and rocuronium as a maintenance drug. Rocuronium is suitable for surgical procedures greater than 30 minutes, eliminating the need for an additional relaxant to succinylcholine.

Graded hypercapnia and cerebral autoregulation during sevoflurane or propofol anesthesia.

BACKGROUND: Hypercapnia abolishes cerebral autoregulation, but little is known about the interaction between hypercapnia and autoregulation during general anesthesia. With normocapnia, sevoflurane (up to 1.5 minimum alveolar concentration) and propofol do not impair cerebral autoregulation. This study aimed to document the level of hypercapnia required to impair cerebral autoregulation during propofol or sevoflurane anesthesia. METHODS: Eight healthy subjects received a remifentanil infusion and were anesthetized with propofol (140 microg. kg-1. min-1) and sevoflurane (1.0-1.1% end tidal) in a randomized crossover study. Ventilation was adjusted to achieve incremental increases in arterial carbon dioxide partial pressure (Paco2) until autoregulation was impaired. Cerebral autoregulation was tested by increasing the mean arterial pressure (MAP) from 80 to 100 mmHg with phenylephrine while measuring middle cerebral artery flow velocity by transcranial Doppler. The autoregulation index, which has a value ranging from 0 to 1, representing absent to perfect autoregulation, was calculated, and an autoregulation index of 0.4 or less represented significantly impaired autoregulation. RESULTS: The threshold Paco2 to significantly impair cerebral autoregulation ranged from 50 to 66 mmHg. The threshold averaged 56 +/- 4 mmHg (mean +/- SD) during sevoflurane anesthesia and 61 +/- 4 mmHg during propofol anesthesia (P = 0.03). Carbon dioxide reactivity measured at a MAP of 100 mmHg was 30% greater than that at a MAP of 80 mmHg. CONCLUSIONS: Even mild hypercapnia can significantly impair cerebral autoregulation during general anesthesia. There is a significant difference between propofol anesthesia and sevoflurane anesthesia with respect to the effect of hypercapnia on cerebral autoregulation. This difference occurs at clinically relevant levels of Paco2. When inducing hypercapnia, carbon dioxide reactivity is significantly affected by the MAP.

Craniotomy procedures are associated with less analgesic requirements than other surgical procedures.

UNLABELLED: The conventional wisdom that neurosurgical patients experience minimal postoperative pain and require little analgesia has been challenged. To address this, we reviewed our anesthesia and postanesthesia care unit (PACU) records for 1995 and compared pain management in patients undergoing major intracranial and selected extracranial procedures. We recorded patient weight, operative time, time in the PACU, intraoperative and postoperative opioid use, PACU pain scores, and level of consciousness in patients who had undergone open fixation of mandible or maxilla (Group E), clipping of aneurysms or excision of tumors (Group I), or lumbar laminectomy (Group L). Group I (n = 78) patients received less fentanyl in the operating room (0.016 microg x kg(-1) x min(-1) versus 0.023 microg x kg(-1) x min(-1) for Group E [n = 134] and 0.023 microg x kg(-1) x min(-1) for Group L [n = 21]; P < 0.05), received less morphine in the PACU (0.0004 vs 0.0013 vs 0.0015 mg kg(-1) x min(-1); P < 0.005), reported lower pain scores (0.76 vs 2.5 vs 2.4; P < 0.05), and spent less time in the PACU (89.5 vs 109 vs 105 min; P < 0.05) than Group E or L patients. Our results were similar when only patients with Glasgow Coma Scale scores > or = 14 were used in a subset analysis. We conclude that patients suffer less pain and use fewer opioids in the PACU after intracranial surgery than after facial reconstruction or lumbar laminectomy. Our results confirm that the average craniotomy patient has less postoperative pain than patients who undergo other surgical procedures, although patients who undergo frontal craniotomy may require more aggressive pain management. IMPLICATIONS: This study compares the pain report and analgesic use in patients after intracranial versus extracranial surgery. The results confirm the commonly held but recently challenged belief that neurosurgery patients suffer less pain postoperatively than other patients. In this study, we found that most patients report minimal pain after intracranial surgery but that a small subset of patients, many of whom have undergone frontal craniotomies, require aggressive treatment of postoperative pain.

Cerebral autoregulation in children during sevoflurane anaesthesia.

INTRODUCTION: Little is known about cerebral autoregulation in children. The aim of this study was to examine cerebral autoregulation in children. METHODS: Cerebral autoregulation testing was performed during less than 1 MAC sevoflurane anaesthesia in children (from 6 months to 14 yr) and in adults (18-41 yr). Mean middle cerebral artery flow velocities (V(MCA)) were measured using transcranial Doppler ultrasonography. Mean arterial pressure (MAP) was increased to whichever was greater: 20% above baseline or (i) 80 mm Hg for less than 9 yr, (ii) 90 mm Hg for 9-14 yr, and (iii) 100 mm Hg for adults. Cerebral autoregulation was considered intact if the autoregulatory index was > or =0.4. RESULTS: There were 13 subjects less than 2 yr old (Group 1), 13 subjects 2-5 yr (Group II), 14 subjects 6-9 yr (Group III), 12 subjects 10-14 yr (Group IV), and 12 adults (Group V; control group). All subjects had an autoregulatory index > or =0.4. There was no difference in autoregulatory index between children in Groups I-IV or between children and adults. DISCUSSION: We found no age-related differences in autoregulatory capacity during low-dose sevoflurane anaesthesia. We report no differences in autoregulatory capacity between children and adults.