Higher baseline heart rate variability in CCHS patients with progestin-associated recovery of hypercapnic ventilatory response.

After a fortuitous observation of two cases of chemosensitivity recovery in women with congenital central hypoventilation syndrome (CCHS) who took desogestrel, we aimed to evaluate the ventilatory response to hypercapnia of five CCHS patients with or without treatment consisting of desogestrel (DESO) or levonorgestrel (LEVO). Only two patients became responsive to hypercapnia under treatment, according to their basal vagal heart rate variability. These results suggest that heart rate variability may be promising tool to discriminate patients susceptible to become responsive to hypercapnia under DESO-LEVO treatment.Clinical Trials Identifier NCT01243697.

Comparison of Two Dexmedetomidine Administration Strategies on the Incidence of Postoperative Respiratory Complications: A Retrospective, Inverse Probability of Treatment Weighted Study.

Randomized controlled trials have shown a higher risk of postoperative hypoxemia and delayed extubation with opioid-free anesthesia (OFA), compared with opioid anesthesia. The practice of OFA is not standardized. The objective of this study is to investigate the association between the dexmedetomidine administration protocol used and the occurrence of postoperative respiratory complications. This work is a retrospective, propensity score-adjusted study (inverse probability of treatment weighting) conducted between January 2019 and September 2021 in a French tertiary care university hospital, including 180 adult patients undergoing major digestive surgery. Comparison of 2 anesthesia protocols: with a continuous intravenous maintenance dose of dexmedetomidine following a bolus (group B+M, n = 105) or with a bolus dose alone (group B, n = 75). The main outcome measure was a composite respiratory end point within 24 hours of surgery. There was no significant difference in the incidence of overall respiratory complications, as assessed by the primary end point. Nevertheless, there were more patients with postoperative hypercapnia in group B+M than in group B (16% vs 2.5%, P = .004). Patients in group B+M were extubated later than patients in group B (group B+M, median 40 minutes, IQR 20-74 minutes; group B, median 20 minutes, IQR 10-50 minutes; P = .004). Our study showed negative results for the primary end point. However, data on the increased risk of postoperative hypercapnia in patients receiving a maintenance dose of dexmedetomidine are new. Other prospective randomized studies with greater power are necessary to confirm these data and to make OFA safer, by reducing the prescribed doses of dexmedetomidine.

Use of Fluoxetine to Augment the Inter-Ictal Hypercapnic Ventilatory Response in Patients with Epilepsy: A Pilot Study.

Background: Severe peri-ictal respiratory dysfunction is a potential biomarker for high SUDEP risk and correlates with an attenuated hypercapnic ventilatory response (HCVR). Prior studies suggest a potential role for selective serotonergic reuptake inhibitors in modifying the HCVR, but this approach has not been studied in the epilepsy population. Objectives: To assess the feasibility of using fluoxetine to augment HCVR in epilepsy patients. Methods and Material: An inter-ictal HCVR was measured using a CO2 rebreathing technique in patients with epilepsy aged 18-75 years. Eligible participants were randomized to fluoxetine or placebo, and the HCVR was repeated at the end of week 4. Primary outcomes were recruitment and retention rate. Results: Of the 30 subjects enrolled, 22 were randomized (mean: 3.8 subjects/3 months), with a retention rate of 100% in fluoxetine and 95% in placebo. Conclusions: Our results demonstrate feasibility for a larger definitive future study to assess the efficacy of fluoxetine in augmenting HCVR.

Hypoxic and Hypercapnic Responses in Transgenic Murine Model of Alzheimer's Disease Overexpressing Human AßPP: The Effects of Pretreatment with Memantine and Rivastigmine.

Despite the severe respiratory problems reducing the quality of life for Alzheimer's disease (AD) patients, their causes are poorly understood. We aimed to investigate hypoxic and hypercapnic respiratory responses in a transgenic mouse model of AD (AßPP V717I) overexpressing AßPP and mimicking early-onset AD. The cholinesterase inhibitor rivastigmine and the NMDA receptor antagonist memantine were used to investigate the effects of drugs, used to treat AD cognitive dysfunction, on breathing in hypoxia and hypercapnia. We found a significant increase in the respiratory response to hypercapnia and no difference in the hypoxic response in APP+ mice, compared with the control group (APP-). Memantine had no effect on respiration in either group, including responses to hypoxia and hypercapnia. Rivastigmine depressed resting ventilation and response to hypercapnia irrespective of the mice genotype. Reduction in hypoxia-augmented ventilation by rivastigmine was observed only in APP+ mice, which exhibited lower acetylcholinesterase activity in the hippocampus. Treatment with rivastigmine reduced the enzyme activity in both groups equally in the hippocampus and brainstem. The increased ventilatory response to hypercapnia in transgenic mice may indicate alterations in chemoreceptive respiratory nuclei, resulting in increased CO2 sensitivity. Rivastigmine is a potent reductant of normoxic and hypercapnic respiration in APP+ and APP- mice.

Ventilatory Response to Hypercapnia as Experimental Model to Study Effects of Oxycodone on Respiratory Depression.

BACKGROUND: Opioid analgesics used to treat pain can cause respiratory depression. However, this effect has not been extensively studied, and life-threatening, opioid-induced respiratory depression remains difficult to predict. We tested the ventilatory response to hypercapnia for evaluating the pharmacodynamic effect of a drug on respiratory depression. METHODS: We conducted a randomized, placebo-controlled, double-blind, crossover study on 12 healthy adult males. Subjects received 2 treatments (placebo and immediate-release oxycodone 30 mg) separated by a 24-hour washout period. Subjects inhaled a mixture of 7% carbon dioxide, 21% oxygen, and 72% nitrogen for 5 minutes to assess respiratory depression. Minute ventilation, respiratory rate, tidal volume, flow rate, end-tidal CO2, and oxygen saturation were recorded continuously at pre-dose and 30, 60, 120, and 180 minutes post-dose. The primary endpoint was the effect on the ventilatory response to hypercapnia at 60 minutes post-dose, as assessed by the slope of the linear relationship between minute ventilation and end-tidal CO2. RESULTS: At 60 minutes post-dose, subjects had a mean slope of 2.4 in the oxycodone crossover period, compared to 0.1 in the placebo period (mean difference, 2.3; 95% CI: 0.2 to 4.5; p = 0.035). Statistical significance was likewise achieved at the secondary time points (30, 120, and 180 minutes post-dose, p <0.05). CONCLUSIONS: This model for testing ventilatory response to hypercapnia discriminated the effect of 30 mg of oxycodone vs. placebo for up to 3 hours after a single dose. It may serve as a method to predict the relative effect of a drug on respiratory depression.

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of "Tail Wags Dog" Experiments.

(-)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated ß-arrestin recruitment assays). "Body" and "tail" interactions with opioid receptors (a subset of Portoghese's message-address theory) were used for molecular modeling and simulations, where the "address" can be considered the "body" of the hydromorphone molecule and the "message" delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/µ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.

Importancia del dióxido de carbono en el paciente crítico: implicaciones a nivel celular y clínico / Importance of carbon dioxide in the critical patient: Implications at the cellular and clinical levels

En los últimos años han surgido importantes descubrimientos sobre el papel del dióxido de carbono (CO2) a nivel celular y molecular, y sobre los efectos de la hipercapnia. Esta última puede tener efectos beneficiosos en pacientes con patología pulmonar aguda, como la reducción de la inflamación pulmonar y del daño oxidativo alveolar, la regulación de la inmunidad innata, la defensa del huésped y la inhibición de la expresión de citoquinas inflamatorias. Sin embargo, otros estudios sugieren que el CO2 puede tener efectos nocivos en el pulmón, como retraso en la reparación alveolar tras la injuria pulmonar, disminución de las tasas de reabsorción del fluido alveolar e inhibición de la proliferación de células alveolares. Por lo tanto, la hipercapnia tiene efectos tanto beneficiosos como nocivos y es importante determinar el efecto neto en condiciones específicas. El propósito de esta revisión es describir los efectos fisiológicos e inmunomoduladores de la hipercapnia, considerando sus potenciales consecuencias en el paciente con insuficiencia respiratoria aguda

Important recent insights have emerged regarding the cellular and molecular role of carbon dioxide (CO2) and the effects of hypercapnia. The latter may have beneficial effects in patients with acute lung injury, affording reductions in pulmonary inflammation, lessened oxidative alveolar damage, and the regulation of innate immunity and host defenses by inhibiting the expression of inflammatory cytokines. However, other studies suggest that CO2 can have deleterious effects upon the lung, reducing alveolar wound repair in lung injury, decreasing the rate of reabsorption of alveolar fluid, and inhibiting alveolar cell proliferation. Clearly, hypercapnia has both beneficial and harmful consequences, and it is important to determine the net effect under specific conditions. The purpose of this review is to describe the immunological and physiological effects of carbon dioxide, considering their potential consequences in patients with acute respiratory failure

Inhibition of the hypercapnic ventilatory response by adenosine in the retrotrapezoid nucleus in awake rats.

The brain regulates breathing in response to changes in tissue CO2/H+ via a process called central chemoreception. Neurons and astrocytes in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors. The role of astrocytes in this process appears to involve CO2/H+-dependent release of ATP to enhance activity of chemosensitive RTN neurons. Considering that in most brain regions extracellular ATP is rapidly broken down to adenosine by ectonucleotidase activity and since adenosine is a potent neuromodulator, we wondered whether adenosine signaling contributes to RTN chemoreceptor function. To explore this possibility, we pharmacologically manipulated activity of adenosine receptors in the RTN under control conditions and during inhalation of 7-10% CO2 (hypercapnia). In urethane-anesthetized or unrestrained conscious rats, bilateral injections of adenosine into the RTN blunted the hypercapnia ventilatory response. The inhibitory effect of adenosine on breathing was blunted by prior RTN injection of a broad spectrum adenosine receptor blocker (8-PT) or a selective A1-receptor blocker (DPCPX). Although RTN injections of 8PT, DPCPX or the ectonucleotidase inhibitor ARL67156 did not affected baseline breathing in either anesthetized or awake rats. We did find that RTN application of DPCPX or ARL67156 potentiated the respiratory frequency response to CO2, suggesting a portion of ATP released in the RTN during high CO2/H+ is converted to adenosine and serves to limit chemoreceptor function. These results identify adenosine as a novel purinergic regulator of RTN chemoreceptor function during hypercapnia.

¿Ventilación no invasiva en pacientes con neumonía sin EPOC? Efectos beneficiosos y aspectos a tener en cuenta para evitar potenciales complicaciones / Non-Invasive Ventilation In Non-COPD Subjects With Pneumonia: Benefits And Potential Complications

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Pharmacokinetics and Pharmacodynamics of Nebulized and Intratracheal Milrinone in a Swine Model of Hypercapnia Pulmonary Hypertension.

OBJECTIVES: Milrinone pulmonary administration is used currently for the treatment of pulmonary hypertension. Several methods are available: simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization. The aim of this study was to explore the concentration-effect relationship of milrinone for each of these methods. DESIGN: Observational open-label pharmacokinetic/pharmacodynamics cohort study. SETTING: Single-center, hospital animal laboratory. PARTICIPANTS: Twelve swine. INTERVENTIONS: After hypercapnia pulmonary hypertension, swine were administered equivalent inhaled milrinone doses of 15 or 50 µg/kg through simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization. MEASUREMENTS AND MAIN RESULTS: Blood and urine samples were taken up to 360 minutes postadministration. The ratio of mean systemic arterial pressure to mean pulmonary arterial pressure was monitored continuously. Right heart echographies were taken before and after hypercapnia and after drug administration. Mean elimination half-lives were similar for the 4 administrations. Mean percent changes in the ratio were of 37 (60%), 18 (31%), 17 (36%), and 20 (20%), for simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization, respectively. Mean maximum plasma concentrations for intratracheal administrations were reached at 8 and 45 min for atomization and instillation, respectively. Significant increases in right atrial diameter and right ventricular end-diastolic area were witnessed during pulmonary hypertension as well as a return to baseline values after milrinone administration. CONCLUSIONS: The intratracheal methods, particularly intratracheal atomization, showed less hemodynamic effect than nebulizations and, in the case of intratracheal instillation, unpredictable drug exposure. Nebulization methods on the other hand, especially simple jet nebulization, suggest better efficacy and sensitivity but are less fit for emergency situations.

UBC-Nepal expedition: The use of oral antioxidants does not alter cerebrovascular function at sea level or high altitude.

NEW FINDINGS: What is the central question of the study? Does the use of antioxidants alter cerebrovascular function and blood flow at sea level (344 m) and/or high altitude (5050 m)? What is the main finding and its importance? This is the first study to investigate whether antioxidant administration alters cerebrovascular regulation and blood flow in response to hypercapnia, acute hypoxia and chronic hypoxia in healthy humans. We demonstrate that an acute dose of antioxidants does not alter cerebrovascular function and blood flow at sea level (344 m) or after 12 days at high altitude (5050 m). ABSTRACT: Hypoxia is associated with an increase in systemic and cerebral formation of free radicals and associated reactants that may be linked to impaired cerebral vascular function and neurological sequelae. To what extent oral antioxidant prophylaxis impacts cerebrovascular function in humans throughout the course of acclimatization to the hypoxia of terrestrial high altitude has not been examined. Thus, the purpose of the present study was to examine the influence of orally ingested antioxidants at clinically relevant doses (vitamins C and E and α-lipoic acid) on cerebrovascular regulation at sea level (344 m; n = 12; female n = 2 participants) and at high altitude (5050 m; n = 9; female n = 2) in a randomized, placebo-controlled and double-blinded crossover design. Hypercapnic and hypoxic cerebrovascular reactivity tests of the internal carotid artery (ICA) were conducted at sea level, and global and regional cerebral blood flow (CBF; i.e. ICA and vertebral artery) were assessed 10-12 days after arrival at 5050 m. At sea level, acute administration of antioxidants did not alter cerebral hypoxic cerebrovascular reactivity (pre versus post: 1.5 ± 0.7 versus 1.2 ± 0.8%∆CBF/-%∆SpO2; P = 0.96) or cerebral hypercapnic cerebrovascular reactivity (pre versus post: 5.7 ± 2.0 versus 5.8 ± 1.9%∆CBF/∆mmHg; P = 0.33). Furthermore, global CBF (P = 0.43) and cerebral vascular conductance (ICA P = 0.08; vertebral artery P = 0.32) were unaltered at 5050 m after antioxidant administration. In conclusion, these data show that an oral antioxidant cocktail known to attenuate systemic oxidative stress failed to alter cerebrovascular function at sea level and CBF during acclimatization to high altitude.

Oxygen Administration Improves Survival but Worsens Cardiopulmonary Functions in Chlorine-exposed Rats.

Chlorine is a highly reactive gas that can cause significant injury when inhaled. Unfortunately, its use as a chemical weapon has increased in recent years. Massive chlorine inhalation can cause death within 4 hours of exposure. Survivors usually require hospitalization after massive exposure. No countermeasures are available for massive chlorine exposure and supportive-care measures lack controlled trials. In this work, adult rats were exposed to chlorine gas (LD58-67) in a whole-body exposure chamber, and given oxygen (0.8 FiO2) or air (0.21 FiO2) for 6 hours after baseline measurements were obtained. Oxygen saturation, vital signs, respiratory distress and neuromuscular scores, arterial blood gases, and hemodynamic measurements were obtained hourly. Massive chlorine inhalation caused severe acute respiratory failure, hypoxemia, decreased cardiac output, neuromuscular abnormalities (ataxia and hypotonia), and seizures resulting in early death. Oxygen improved survival to 6 hours (87% versus 42%) and prevented observed seizure-related deaths. However, oxygen administration worsened the severity of acute respiratory failure in chlorine-exposed rats compared with controls, with increased respiratory acidosis (pH 6.91 ± 0.04 versus 7.06 ± 0.01 at 2 h) and increased hypercapnia (180.0 ± 19.8 versus 103.2 ± 3.9 mm Hg at 2 h). In addition, oxygen did not improve neuromuscular abnormalities, cardiac output, or respiratory distress associated with chlorine exposure. Massive chlorine inhalation causes severe acute respiratory failure and multiorgan damage. Oxygen administration can improve short-term survival but appears to worsen respiratory failure, with no improvement in cardiac output or neuromuscular dysfunction. Oxygen should be used with caution after massive chlorine inhalation, and the need for early assisted ventilation should be assessed in victims.

Aerosol furosemide for dyspnea: Controlled delivery does not improve effectiveness.

Aerosolized furosemide has been shown to relieve dyspnea; nevertheless, all published studies have shown great variability in response. This dyspnea relief is thought to result from the stimulation of slowly adapting pulmonary stretch receptors simulating larger tidal volume. We hypothesized that better control over aerosol administration would produce more consistent dyspnea relief; we used a clinical ventilator to control inspiratory flow and tidal volume. Twelve healthy volunteers inhaled furosemide (40mg) or placebo in a double blind, randomized, crossover study. Breathing Discomfort was induced by hypercapnia during constrained ventilation before and after treatment. Both treatments reduced breathing discomfort by 20% full scale. Effectiveness of aerosol furosemide treatment was weakly correlated with larger tidal volume. Response to inhaled furosemide was inversely correlated to furosemide blood level, suggesting that variation among subjects in the fate of deposited drug may determine effectiveness. We conclude that control of aerosol delivery conditions does not improve consistency of treatment effect; we cannot, however, rule out placebo effect.

Antioxidant and Antiamnestic Effects of Potassium Comenate and Comenic Acid under Conditions of Normobaric Hypoxia with Hypercapnia.

Potassium comenate and comenic acid exhibit manifest and virtually identical antioxidant activity under conditions of hypoxia with hypercapnia. The effects of these drugs on conditioned reflex training with positive reinforcement differ significantly. Potassium comenate promotes retention of the learning capacity and memory in hypoxic rats at the level of intact control, that is, exhibits a pronounced protective antiamnestic effect, while comenic acid only facilitates training of the conditioned reflex with positive reinforcement.

Hydrogen sulfide ameliorates prenatal cigarette smoke exposure-induced impairment of respiratory responses to hypercapnia in neonatal rats.

The present study was designed to investigate whether H2S could improve the respiratory responses to hypercapnia blunted by prenatal CSE in neonatal rats in vivo. Respiratory activities were recorded with head-out body plethysmography. The results showed that during baseline, respiratory frequency (FR), tidal volume (VT) and minute ventilation (VE) were similar among tested groups; frequency of spontaneous apnea (FSA), not post-sigh apnea (FPA), was significantly elevated by prenatal CSE. During hypercapnia, the increases in FR and VE were significantly reduced, but VT was not markedly different, in CSE group; both FSA and FPA were decreased, although FSA remained higher in CSE group. All the aforementioned effects induced by CSE on respiratory activities were relieved by NaHS (donor of H2S, 56µmol/kg by intraperitoneal injection). These data indicate that H2S could ameliorate the disruption of respiratory responses to hypercapnia induced by prenatal CSE in neonatal rats.

Erythropoietin in the Locus coeruleus attenuates the ventilatory response to CO2 in rats.

The Locus coeruleus (LC) is a pontine area that contributes to the CO2/pH chemosensitivity. LC cells express erythropoietin (Epo) receptors (EpoR), and Epo in the brainstem is a potent normoxic and hypoxic respiratory stimulant. However, a recent study showed that the intra-cisternal injection (ICI) of Epo antagonist does not alter the hypercapnic ventilatory response in mice. As ICI leads to a widespread dispersal of the product throughout the brainstem, in this work we evaluated the specific impact of Epo in the LC-mediated ventilatory response to CO2 (by whole body plethysmography) in juvenile male Wistar rats. Normocapnic and hypercapnic ventilation were evaluated before and after unilateral microinjection of Epo (1ng/100nL) into the LC. To evaluate the long-term effect of Epo, the HcVR was re-evaluated 24h later. Our results show that Epo attenuates the hypercapnic ventilation. We conclude that Epo in the LC tunes the hypercapnia-induced hyperpnea.

Disharmony between wake- and respiration-promoting activities: effects of modafinil on ventilatory control in rodents.

BACKGROUND: Modafinil is a wake-promoting drug and has been widely used for daytime sleepiness in patients with narcolepsy and other sleep disorders. A recent case series reported that daily oral modafinil alleviated hypercapnic respiratory failure in patients with COPD. However, the precise action of modafinil on respiration such as hypercapnic and/or hypoxic ventilatory responses remains unclear. The aim of this study is to clarify the effect of modafinil on the ventilatory control. METHODS: We investigated the hypothesis that modafinil enhances resting ventilation as well as the stimulatory ventilatory responses to hypercapnia and hypoxia. We addressed the issue by examining minute ventilation, respiratory rate and volume components using plethysmography, combined with a concurrent EEG monitoring of the level of wakefulness before and after administration of modafinil in two doses of 100 mg/kg and 200 mg/kg in unanesthetized mice. In addition, we monitored the effect of the lower dose of modafinil on mice locomotor activity in a freely moving condition by video-recording. RESULTS: Wakefulness, locomotor activity and variability of the breathing pattern in tidal volume were promoted by both doses of modafinil. Neither dose of modafinil increased the absolute values of resting ventilation or promoted the ventilatory responses to hypercapnia and hypoxia. Rather, higher dose of modafinil slightly suppressed respiratory rate in room air condition. CONCLUSIONS: Modafinil is conducive to the state of wakefulness but does not augment resting ventilation or the hyperventilatory responses to chemical stimuli in unanesthetized rodents.

Effect of Potassium Comenate on CNS Functional Status in Rodents Exposed to Combined Hypoxia and Hypercapnia in Comparison with Normally Ventilated Animals.

The effects of potassium comenate on functional state of CNS in mice and rats were studied in the open-field and hole-board tests under control conditions and after acute exposure to hypoxia-hypercapnia. The effects of potassium comenate on CNS were also studied in rodents subjected to propofol-induced sleep. Preliminary administration of 4 mg/kg potassium comenate for 3 days attenuated the posthypoxic changes in behavioral reactions (emotional anxiety/reactivity). The pronounced stress-protective effect of potassium comenate was observed both on days 1 and 14 after exposure to hypoxia-hypercapnia. Under normal conditions, potassium comenate moderated behavioral reactions and augmented somniferous effect of propofol. We hypothesized that the antihypoxic effect of potassium comenate is determined by its stress-protective and sedative potencies.

Isoflurane rescue therapy for bronchospasm reduces intracranial pressure in a patient with traumatic brain injury.

PRIMARY OBJECTIVE: To assess the unusual use of a volatile anaesthetic for treatment of life-threatening bronchospasm in a patient with traumatic brain injury (TBI). RESEARCH DESIGN: Case report. METHODS AND PROCEDURES: This study presents a previously healthy 30-year-old man with severe TBI and bronchospasm-induced acute hypercapnia. He was treated with inhaled isoflurane in combination with monitoring of intracranial pressure (ICP) and regional cerebral blood flow (rCBF). RESULTS: Three-day-long isoflurane treatment resolved drug-refractory bronchospasm, decreased airway pressure and improved gas exchange, even at a low end-tidal concentration (0.3-0.5 vol%). Although rCBF was increased by 18 ml min(-1) 100 g(-1) during isoflurane treatment, there was a significant decrease in ICP (21 (SD = 3) mmHg, 9 (SD = 5) mmHg, 2 (SD = 3) mmHg; during pre-treatment, treatment and post-treatment, respectively; p < 0.001). Improved autoregulation due to lower partial pressure of carbon dioxide, restoration of carbon dioxide reactivity, isoflurane-induced regional differences in rCBF and improved microcirculation may have been responsible for the prompt and long-lasting normalization of ICP. The patient had no TBI-related disability at 6 months post-injury. CONCLUSIONS: Isoflurane at a low dose can be an effective and safe treatment option for drug-refractory bronchospasm in a patient with traumatic intracranial hypertension, provided that multimodality neuromonitoring is used.