The Latest Pharmacologic Ventilator

Cotten, Joseph F.

doi:10.1097/aln.0000000000000368

Cited by 11 publications

(20 citation statements)

References 5 publications

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“…1 Although the current results are encouraging, we still have a way to go before we uncork the champagne. Unfortunately, naloxone also reverses analgesia.…”

Section: Commentmentioning

confidence: 76%

Efficacy of Sugammadex for the Reversal of Moderate and Deep Rocuronium-Induced Neuromuscular Block in Patients Pretreated With Intravenous Magnesium

Czarnetzki

Tassonyi

Lysakowski

et al. 2015

Survey of Anesthesiology

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Clearly, this study confirms that neostigmine alone does not enhance respiratory safety and may actually be harmful when given in high doses (>60 μg/kg) and when given in the absence of neuromuscular transmission monitoring. Administering neostigmine to a patient who has spontaneously recovered from ND-NMBA may cause a depolarizing neuromuscular block with no TOF fade. In addition, incomplete reversal of deep neuromuscular blockade exposes the patient to a prolonged period of respiratory muscle weakness. It is unsafe to administer neostigmine to a patient who has spontaneously recovered from neuromuscular blockade because neostigmine dose-dependently affects respiratory muscle function and increases upper airway collapsibility. Indeed, both residual neuromuscular blockade and neostigmineinduced neuromuscular blockade cause upper airway dilator muscle dysfunction resulting in upper airway obstruction, which can produce negative-pressure pulmonary edema.The current investigators, who are affiliated with an excellent, highly respected institution, commented that despite the widespread availability of both qualitative and quantitative neuromuscular transmission monitoring in their hospital 1 of 5 patients who received an ND-NMBA did not have a single TOF count recorded! This overconfidence and overreliance on clinical intuition are grossly inappropriate in an era when we are admonished to practice evidence-based medicine. Unwarranted use of neostigmine and neostigmine administration without the guidance of appropriate monitoring tools can result in preventable respiratory morbidity in our patients. Surely, our patients deserve better "care." Comment by Kathryn E. McGoldrick, MD, FCAI(Hon) Disclosure: The author declares no conflict of interest.

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“…1 Although the current results are encouraging, we still have a way to go before we uncork the champagne. Unfortunately, naloxone also reverses analgesia.…”

Section: Commentmentioning

confidence: 76%

Efficacy of Sugammadex for the Reversal of Moderate and Deep Rocuronium-Induced Neuromuscular Block in Patients Pretreated With Intravenous Magnesium

Czarnetzki

Tassonyi

Lysakowski

et al. 2015

Survey of Anesthesiology

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“…Most effective non‐opioid agents developed to prevent or treat OIRD in humans include drugs that increase glutamatergic neurotransmission at brainstem respiratory centers (ampakines including CX717) and potassium channel blockers acting at the peripheral chemoreceptors of the carotid bodies (GAL021, doxapram, and almitrine) . Drugs acting at the peripheral chemoreceptors through blockade of K + ‐channels mimic the effect of hypoxia, which exclusively acts at the carotid bodies.…”

Section: Discussionmentioning

confidence: 99%

“…The PKPD analysis allows us to address a number of important issues. It will give an estimate of the speed of onset/offset of GAL021 in its ability to reverse OIRD, and it will provide insight in the possibility that GAL021's respiratory stimulation may hit a ceiling in efficacy because of the fact that the brainstem respiratory circuitry remains affected by the opioid at central sites …”

mentioning

confidence: 99%

Reversal of opioid‐induced respiratory depression by BK‐channel blocker GAL021: A pharmacokinetic‐pharmacodynamic modeling study in healthy volunteers

Roozekrans

Olofsen

Schrier

et al. 2015

Clin Pharma and Therapeutics

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Opioid-induced respiratory depression (OIRD) is a serious and potentially life-threatening complication of opioid overdose, abuse, and misuse. An option to avert OIRD is to treat patients on strong opioids with respiratory stimulants that do not interact with the opioid system and consequently do not compromise opioid analgesic efficacy. The BK-channel blocker GAL021 is a respiratory stimulant acting at K(+) -channels expressed on type 1 carotid body cells. The authors performed a population pharmacokinetic-pharmacodynamic (PKPD) analysis on the ability of GAL021 to reverse alfentanil-induced respiratory depression in 12 male volunteers using an isohypercapnic experimental design. The analysis showed that (1) GAL021 interacts in a multiplicative fashion with alfentanil and GAL021, which predicts that GAL021 efficacy is reduced at low ventilation levels; (2) GAL021 has a rapid onset/offset with a blood-effect site equilibration half-life not different from zero; and (3) GAL021 displays ceiling in its efficacy to reverse OIRD.

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“…[12][13][14] It is further important to realize that stimulation of respiration at the level of the CBs has a ceiling effect on the relief of respiratory depression, when the respiratory depression is due to an effect at the level of the brainstem. 15,16 We recently showed this for GAL021, a potassium channel blocker that stimulates breathing via the CB but does not increase CO. 15,17 Although at moderate levels of opioidinduced respiratory depression (alfentanil plasma concentration 40-80 ng/mL), GAL021 produced pronounced respiratory stimulation, our model analysis predicted that at deeper levels of opioid-induced respiratory depression (alfentanil concentration >100 ng/mL) the effect of GAL021 on respiration is small. Hence, we hypothesize that at deep levels of opioid-induced respiratory depression, doxapram will cause respiratory stimulation coupled to reduced analgesia, predominantly related to the decrease in plasma drug concentration.…”

Section: Study Highlightsmentioning

confidence: 96%

“…We hypothesize that because doxapram increases CO it may well affect PK (and consequently PD) through changes in distribution and elimination clearances of these drugs . It is further important to realize that stimulation of respiration at the level of the CBs has a ceiling effect on the relief of respiratory depression, when the respiratory depression is due to an effect at the level of the brainstem . We recently showed this for GAL021, a potassium channel blocker that stimulates breathing via the CB but does not increase CO .…”

mentioning

confidence: 99%

Doxapram‐mediated Increase in Cardiac Output Reduces Opioid Plasma Concentrations: A Pharmacokinetic/Pharmacodynamic–Pharmacokinetic/Pharmacodynamic Modeling Study in Healthy Volunteers

Roozekrans

Olofsen

Schrier

et al. 2017

Clin Pharma and Therapeutics

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Doxapram is an analeptic that induces ventilatory stimulation and increases blood pressure and cardiac output (CO). Its mechanism of action is the blockade of background K -channels expressed on type 1 carotid body cells. In the randomized controlled trial, the authors explored the role of the increase in CO by doxapram (plasma concentration (Cp) 1,000-3,500 ng/mL) on the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the potent opioid alfentanil (Cp 100-200 ng/mL). Population PK-PD analyses were performed on the doxapram PK-CO data and the alfentanil PK-antinociception data. The analyses showed that the doxapram-induced increase in CO explained the increase in alfentanil distribution and elimination clearances causing a significant reduction in plasma alfentanil Cp and antinociception. This novel approach in which one PK-PD model effectively drives another PK-PD model highlights the importance of physiological influences on PK and PD of a potent opioid with rapid onset of effect and low clinical margin of safety.

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The Latest Pharmacologic Ventilator

Cited by 11 publications

References 5 publications

Efficacy of Sugammadex for the Reversal of Moderate and Deep Rocuronium-Induced Neuromuscular Block in Patients Pretreated With Intravenous Magnesium

Efficacy of Sugammadex for the Reversal of Moderate and Deep Rocuronium-Induced Neuromuscular Block in Patients Pretreated With Intravenous Magnesium

Reversal of opioid‐induced respiratory depression by BK‐channel blocker GAL021: A pharmacokinetic‐pharmacodynamic modeling study in healthy volunteers

Doxapram‐mediated Increase in Cardiac Output Reduces Opioid Plasma Concentrations: A Pharmacokinetic/Pharmacodynamic–Pharmacokinetic/Pharmacodynamic Modeling Study in Healthy Volunteers

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