Effect of dexamethasone administration for postoperative nausea and vomiting prophylaxis on glucose levels in adults with diabetes undergoing elective surgery: a systematic review with meta-analysis.

OBJECTIVE: The objective of this review was to evaluate the effect of intravenous dexamethasone given intraoperatively for postoperative nausea and vomiting prophylaxis on maximal blood glucose level within the initial 24 hours following elective surgery for patients with diabetes. INTRODUCTION: Postoperative nausea and vomiting is a prevalent adverse effect of anesthesia that leads to morbidity, increased health care costs, and unanticipated hospital admissions. Dexamethasone is an effective prophylactic agent that confers secondary analgesic and anti-inflammatory benefits. However, its use in patients with diabetes remains controversial due to the potential for increased postoperative blood glucose levels. INCLUSION CRITERIA: This review considered studies with participants 18 years of age or older with type 1 or 2 diabetes undergoing an elective surgical procedure. Eligible studies reported postoperative blood glucose levels in adults with diabetes after receiving a single 4-10 mg prophylactic dose of intravenous dexamethasone intraoperatively for postoperative nausea and vomiting. The primary outcome was maximum blood glucose level in the first 24 hours after surgery. All study designs were eligible for inclusion. Studies were excluded if they lacked a control group with diabetes or if they did not report maximum blood glucose values in both groups. METHODS: A search of MEDLINE, CINAHL Complete, Embase, Web of Science, TRIP database, and the Cochrane Database of Systematic Reviews was completed in October 2021. Gray literature resources were also searched. No date or language restrictions were applied. Methodological quality was assessed using JBI appraisal tools for randomized controlled trials, cohort studies, and case-control studies. A meta-analysis of maximal postoperative blood glucose level within 24 hours of surgery was performed, as well as subgroup analyses by dexamethasone dose, insulin treatment, and study design type. RESULTS: Eleven studies (4 randomized controlled trials, 6 cohort studies, and 1 case-control study) were included in this review, with 1 study excluded from meta-analysis and results reported narratively. The total sample size of studies included in meta-analysis was 2567. The administration of dexamethasone significantly increased maximal blood glucose levels in the 24 hours immediately following surgery compared with control groups with diabetes, as demonstrated by randomized controlled trials (mean difference [MD] 39.56 mg/dL; 95% CI 16.18 to 62.94; P < 0.001; I2 = 87%) and observational studies (MD 26.31 mg/dL; 95% CI 7.10 to 45.52; P = 0.007; I2 = 92%). This increase in blood glucose was significant for all doses of dexamethasone: 4 mg (MD 40.81 mg/dL; 95% CI 2.42 to 79.19; P = 0.001; I2 = 91%), 8 mg (randomized controlled trials only; MD 39.45 mg/dL; 95% CI 15.32 to 63.58; P = 0.001; I2 = 86%), and mixed 4-10 mg dose (MD 30.82 mg/dL; 95% CI 6.75 to 54.88; P < 0.012; I2 = 93%). Postoperative hyperglycemia persisted in studies using insulin treatment as well as those not using insulin protocols. The overall certainty of the findings ranged from very low for outcomes that included cohort studies to moderate when outcomes from randomized controlled trials were analyzed separately. However, the quantitative findings of the experimental and observational studies were clinically similar. Risk of bias presented minimal concerns in all included studies. CONCLUSIONS: Dexamethasone leads to transient postoperative hyperglycemia in patients with diabetes undergoing elective surgery when given as a single 4-10 mg intravenous dose for postoperative nausea and vomiting prophylaxis. The clinical relevance of hyperglycemia is debatable given its small magnitude and transient nature. Without more tightly controlled data, methodological consistency, and baseline blood glucose values, it is impossible to test causal links between hyperglycemia and pre-existing patient factors (eg, hemoglobin A1C levels) or postoperative complications. REVIEW REGISTRATION: PROSPERO CRD42020185607.

Exploratory proteomic analysis of hypobaric hypoxia and acute mountain sickness in humans.

Our objective in this exploratory study was to identify novel biomarkers of importance for acute mountain sickness (AMS) using discovery-based proteomic methods. Peripheral blood samples were collected and AMS symptoms were assessed in 20 healthy volunteers prior to [-15 h (baseline) and 0 h; 1,609 m; barometric pressure = 625 mmHg] and after a 9-h exposure to hypobaric hypoxia (9 h; 4,875 m; barometric pressure = 425 mmHg). AMS status was assessed using the Lake Louise Questionnaire. Plasma samples were pooled according to AMS status at each time point. Protein composition of the samples was determined by a GeLC-MS/MS approach using two analytical platforms (LTQ-XL linear ion trap mass spectrometer and a LTQ-FT ultra hybrid mass spectrometer) for technical replication. Spectral counting was used to make semiquantitative comparisons of protein abundance between AMS-susceptible (AMS) and AMS-resistant (AMS·R) subjects with exposure to hypobaric hypoxia. After 9 h of hypoxia, the abundance of proteins with antioxidant properties (i.e., peroxiredoxin 6, glutathione peroxidase, and sulfhydryl oxidase 1) rose in AMS but not AMS·R. Our exploratory analyses suggest that exposure to hypobaric hypoxia enhances enzymatic antioxidant systems in AMS vs. AMS·R, which, we propose, may be an overcompensation for hypoxia-induced oxidant production. On the basis of our findings we 1) speculate that quenching oxidant activity may have adverse downstream effects that are of pathophysiological importance for AMS such as interrupting oxidant-sensitive cell signaling and gene transcription and 2) question the existing assumption that increased oxidant production in AMS is pathological.

A simple method to clamp end-tidal carbon dioxide during rest and exercise.

Carbon dioxide regulates ventilation and cerebral blood flow during exercise. There are significant limitations in breathing systems designed to control end-tidal gas concentrations when used during high-intensity exercise. We designed a simple, inexpensive breathing system which controls end-tidal carbon dioxide (PET CO2) during exercise from rest to peak work capacity (W(max)). The system is operated by an investigator who, in response to breath-by-breath PET CO2, titrates flow of a 10 % CO(2), 21 % O(2) mixture into an open-ended 5-L inspiratory reservoir. To demonstrate system efficacy, nine fit male subjects performed two maximal, incremental exercise tests (25 W min(-1) ramp) on a cycle ergometer: a poikilocapnic control trial in which PET CO2 varied with work intensity, and an experimental trial, in which we planned to clamp PET CO2 at 50 mmHg. With our breathing system, we maintained PET CO2 at 51 ± 2 mmHg throughout exercise (rest, 50 ± 2; W(max), 52 ± 5 mmHg; mean ± SD) despite large changes in ventilation (range 27-65 at rest, 134-185 L min(-1) BTPS at W (max)) and carbon dioxide production (range 0.3-0.7 at rest, 4.5-5.5 L min(-1) at W (max)). This simple, inexpensive system achieves PET CO2 control at rest and throughout exercise.

Does cerebral oxygen delivery limit incremental exercise performance?

Previous studies have suggested that a reduction in cerebral oxygen delivery may limit motor drive, particularly in hypoxic conditions, where oxygen transport is impaired. We hypothesized that raising end-tidal Pco(2) (Pet(CO(2))) during incremental exercise would increase cerebral blood flow (CBF) and oxygen delivery, thereby improving peak power output (W(peak)). Amateur cyclists performed two ramped exercise tests (25 W/min) in a counterbalanced order to compare the normal, poikilocapnic response against a clamped condition, in which Pet(CO(2)) was held at 50 Torr throughout exercise. Tests were performed in normoxia (barometric pressure = 630 mmHg, 1,650 m) and hypoxia (barometric pressure = 425 mmHg, 4,875 m) in a hypobaric chamber. An additional trial in hypoxia investigated effects of clamping at a lower Pet(CO(2)) (40 Torr) from ∼75 to 100% W(peak) to reduce potential influences of respiratory acidosis and muscle fatigue imposed by clamping Pet(CO(2)) at 50 Torr. Metabolic gases, ventilation, middle cerebral artery CBF velocity (transcranial Doppler), forehead pulse oximetry, and cerebral (prefrontal) and muscle (vastus lateralis) hemoglobin oxygenation (near infrared spectroscopy) were monitored across trials. Clamping Pet(CO(2)) at 50 Torr in both normoxia (n = 9) and hypoxia (n = 11) elevated CBF velocity (∼40%) and improved cerebral hemoglobin oxygenation (∼15%), but decreased W(peak) (6%) and peak oxygen consumption (11%). Clamping at 40 Torr near maximal effort in hypoxia (n = 6) also improved cerebral oxygenation (∼15%), but again limited W(peak) (5%). These findings demonstrate that increasing mass cerebral oxygen delivery via CO(2)-mediated vasodilation does not improve incremental exercise performance, at least when accompanied by respiratory acidosis.

Acute mountain sickness, inflammation, and permeability: new insights from a blood biomarker study.

The pathophysiology of acute mountain sickness (AMS) is unknown. One hypothesis is that hypoxia induces biochemical changes that disrupt the blood-brain barrier (BBB) and, subsequently, lead to the development of cerebral edema and the defining symptoms of AMS. This study explores the relationship between AMS and biomarkers thought to protect against or contribute to BBB disruption. Twenty healthy volunteers participated in a series of hypobaric hypoxia trials distinguished by pretreatment with placebo, acetazolamide (250 mg), or dexamethasone (4 mg), administered using a randomized, double-blind, placebo-controlled, crossover design. Each trial included peripheral blood sampling and AMS assessment before (-15 and 0 h) and during (0.5, 4, and 9 h) a 10-h hypoxic exposure (barometric pressure = 425 mmHg). Anti-inflammatory and/or anti-permeability [interleukin (IL)-1 receptor agonist (IL-1RA), heat shock protein (HSP)-70, and adrenomedullin], proinflammatory (IL-6, IL-8, IL-2, IL-1ß, and substance P), angiogenic, or chemotactic biomarkers (macrophage inflammatory protein-1ß, VEGF, TNF-α, monocyte chemotactic protein-1, and matrix metalloproteinase-9) were assessed. AMS-resistant subjects had higher IL-1RA (4 and 9 h and overall), HSP-70 (0 h and overall), and adrenomedullin (overall) compared with AMS-susceptible subjects. Acetazolamide raised IL-1RA and HSP-70 compared with placebo in AMS-susceptible subjects. Dexamethasone also increased HSP-70 and adrenomedullin in AMS-susceptible subjects. Macrophage inflammatory protein-1ß was higher in AMS-susceptible than AMS-resistant subjects after 4 h of hypoxia; dexamethasone minimized this difference. Other biomarkers were unrelated to AMS. Resistance to AMS was accompanied by a marked anti-inflammatory and/or anti-permeability response that may have prevented downstream pathophysiological events leading to AMS. Conversely, AMS susceptibility does not appear to be related to an exaggerated inflammatory response.

Effects of acetazolamide and dexamethasone on cerebral hemodynamics in hypoxia.

Previous attempts to detect global cerebral hemodynamic differences between those who develop headache, nausea, and fatigue following rapid exposure to hypoxia [acute mountain sickness (AMS)] and those who remain healthy have been inconclusive. In this study, we investigated the effects of two drugs known to reduce symptoms of AMS to determine if a common cerebral hemodynamic mechanism could explain the prophylactic effect within individuals. With the use of randomized, placebo-controlled, double-blind, crossover design, 20 healthy volunteers were given oral acetazolamide (250 mg), dexamethasone (4 mg), or placebo every 8 h for 24 h prior to and during a 10-h exposure to a simulated altitude of 4,875 m in a hypobaric chamber, which included 2 h of exercise at 50% of altitude-specific VO(2max). Cerebral hemodynamic parameters derived from ultrasound assessments of dynamic cerebral autoregulation and vasomotor reactivity were recorded 15 h prior to and after 9 h of hypoxia. AMS symptoms were scored using the Lake Louise Questionnaire (LLQ). It was found that both drugs prevented AMS in those who became ill on placebo (~70% decrease in LLQ), yet a common cerebral hemodynamic mechanism was not identified. Compared with placebo, acetazolamide reduced middle cerebral artery blood flow velocity (11%) and improved dynamic cerebral autoregulation after 9 h of hypoxia, but these effects appeared independent of AMS. Dexamethasone had no measureable cerebral hemodynamic effects in hypoxia. In conclusion, global cerebral hemodynamic changes resulting from hypoxia may not explain the development of AMS.

Cerebral blood flow and oxygenation at maximal exercise: the effect of clamping carbon dioxide.

During exercise, as end-tidal carbon dioxide (P(ET)(CO2)) drops after the respiratory compensation point (RCP), so does cerebral blood flow velocity (CBFv) and cerebral oxygenation. This low-flow, low-oxygenation state may limit work capacity. We hypothesized that by preventing the fall in P(ET)(CO2) at peak work capacity (W(max)) with a newly designed high-flow, low-resistance rebreathing circuit, we would improve CBFv, cerebral oxygenation, and W(max). Ten cyclists performed two incremental exercise tests, one as control and one with P(ET)(CO2) constant (clamped) after the RCP. We analyzed , middle cerebral artery CBFv, cerebral oxygenation, and cardiopulmonary measures. At W(max), when we clamped P(ET)(CO2) (39.7 ± 5.2 mmHg vs. 29.6 ± 4.7 mmHg, P < 0.001), CBFv increased (92.6 ± 15.9 cm/s vs. 73.6 ± 12.5 cm/s, P < 0.001). However, cerebral oxygenation was unchanged (ΔTSI -21.3 ± 13.1% vs. -24.3 ± 8.1%, P = 0.33), and W(max) decreased (380.9 ± 20.4W vs. 405.7 ± 26.8 W, P < 0.001). At W(max), clamping P(ET)(CO2) increases CBFv, but this does not appear to improve W(max).

Effects of acute hypoxia on cerebral and muscle oxygenation during incremental exercise.

To determine if fatigue at maximal aerobic power output was associated with a critical decrease in cerebral oxygenation, 13 male cyclists performed incremental maximal exercise tests (25 W/min ramp) under normoxic (Norm: 21% Fi(O2)) and acute hypoxic (Hypox: 12% Fi(O2)) conditions. Near-infrared spectroscopy (NIRS) was used to monitor concentration (microM) changes of oxy- and deoxyhemoglobin (Delta[O2Hb], Delta[HHb]) in the left vastus lateralis muscle and frontal cerebral cortex. Changes in total Hb were calculated (Delta[THb] = Delta[O2Hb] + Delta[HHb]) and used as an index of change in regional blood volume. Repeated-measures ANOVA were performed across treatments and work rates (alpha = 0.05). During Norm, cerebral oxygenation rose between 25 and 75% peak power output {Power(peak); increased (inc) Delta[O2Hb], inc. Delta[HHb], inc. Delta[THb]}, but fell from 75 to 100% Power(peak) {decreased (dec) Delta[O2Hb], inc. Delta[HHb], no change Delta[THb]}. In contrast, during Hypox, cerebral oxygenation dropped progressively across all work rates (dec. Delta[O2Hb], inc. Delta[HHb]), whereas Delta[THb] again rose up to 75% Power(peak) and remained constant thereafter. Changes in cerebral oxygenation during Hypox were larger than Norm. In muscle, oxygenation decreased progressively throughout exercise in both Norm and Hypox (dec. Delta[O2Hb], inc. Delta [HHb], inc. Delta[THb]), although Delta[O2Hb] was unchanged between 75 and 100% Power peak. Changes in muscle oxygenation were also greater in Hypox compared with Norm. On the basis of these findings, it is unlikely that changes in cerebral oxygenation limit incremental exercise performance in normoxia, yet it is possible that such changes play a more pivotal role in hypoxia.