Cannabis Use and Inhalational Anesthesia Administration in Older Adults: A Propensity Matched Retrospective Cohort Study.

BACKGROUND: Cannabis use is associated with higher intravenous anesthetic administration. Similar data regarding inhalational anesthetics are limited. With rising cannabis use prevalence, understanding any potential relationship with inhalational anesthetic dosing is crucial. We compared average intraoperative isoflurane/sevoflurane minimum alveolar concentration equivalents between older adults with and without cannabis use. METHODS: The electronic health records of 22,476 surgical patients ≥65 years old at the University of Florida Health System between 2018-2020 were reviewed. The primary exposure was cannabis use within 60 days of surgery, determined via i) a previously published natural language processing algorithm applied to unstructured notes and ii) structured data, including International Classification of Disease codes for cannabis use disorders and poisoning by cannabis, laboratory cannabinoids screening results, and RxNorm codes. The primary outcome was the intraoperative time-weighted average of isoflurane/sevoflurane minimum alveolar concentration equivalents at one-minute resolution. No a priori minimally clinically important difference was established. Patients demonstrating cannabis use were matched 4:1 to non-cannabis use controls using a propensity score. RESULTS: Among 5,118 meeting inclusion criteria, 1,340 patients (268 cannabis users and 1,072 nonusers) remained after propensity score matching. The median and interquartile range (IQR) age was 69 (67, 73) years; 872 (65.0%) were male, and 1,143 (85.3%) were non-Hispanic White. The median (IQR) anesthesia duration was 175 (118, 268) minutes. After matching, all baseline characteristics were well-balanced by exposure. Cannabis users had statistically significantly higher average minimum alveolar concentrations than nonusers [mean±SD: 0.58±0.23 versus 0.54±0.22, respectively; mean difference=0.04; 95% confidence limits, 0.01 to 0.06; p=0.020]. CONCLUSION: Cannabis use was associated with administering statistically significantly higher inhalational anesthetic minimum alveolar concentration equivalents in older adults, but the clinical significance of this difference is unclear. These data do not support the hypothesis that cannabis users require clinically meaningfully higher inhalational anesthetics doses.

Cannabis use and acute postoperative pain outcomes in older adults: a propensity matched retrospective cohort study.

INTRODUCTION: Cannabis use is increasing among older adults, but its impact on postoperative pain outcomes remains unclear in this population. We examined the association between cannabis use and postoperative pain levels and opioid doses within 24 hours of surgery. METHODS: We conducted a propensity score-matched retrospective cohort study using electronic health records data of 22 476 older surgical patients with at least 24-hour hospital stays at University of Florida Health between 2018 and 2020. Of the original cohort, 2577 patients were eligible for propensity-score matching (1:3 cannabis user: non-user). Cannabis use status was determined via natural language processing of clinical notes within 60 days of surgery and structured data. The primary outcomes were average Defense and Veterans Pain Rating Scale (DVPRS) score and total oral morphine equivalents (OME) within 24 hours of surgery. RESULTS: 504 patients were included (126 cannabis users and 378 non-users). The median (IQR) age was 69 (65-72) years; 295 (58.53%) were male, and 442 (87.70%) were non-Hispanic white. Baseline characteristics were well balanced. Cannabis users had significantly higher average DVPRS scores (median (IQR): 4.68 (2.71-5.96) vs 3.88 (2.33, 5.17); difference=0.80; 95% confidence limit (CL), 0.19 to 1.36; p=0.01) and total OME (median (IQR): 42.50 (15.00-60.00) mg vs 30.00 (7.50-60.00) mg; difference=12.5 mg; 95% CL, 3.80 mg to 21.20 mg; p=0.02) than non-users within 24 hours of surgery. DISCUSSION: This study showed that cannabis use in older adults was associated with increased postoperative pain levels and opioid doses.

Dosing Cefazolin for Surgical Site Infection Prophylaxis in Adolescent Idiopathic Scoliosis Surgery: Intermittent Bolus or Continuous Infusion?-A Pilot Study.

Background: Cefazolin may minimize the risk of surgical site infection (SSI) following posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). Cefazolin dosing recommendations vary and there is limited evidence for achieved tissue concentrations. Methods: We performed a randomized, controlled, prospective pharmacokinetic pilot study of 12 patients given cefazolin by either intermittent bolus (30 mg/kg every 3 h) or continuous infusion (30 mg/kg bolus followed by 10/mg/kg per hour) during PSF for AIS. Results: Patients were well matched for demographic and perioperative variables. While total drug exposure, measured as area-under-the-curve (AUC), was similar in plasma for bolus and infusion dosing, infusion dosing achieved greater cefazolin exposure in subcutaneous and muscle tissue. Using the pharmacodynamic metric of time spent above minimal inhibitory concentration (MIC), both bolus and infusion dosing performed well. However, when targeting a bactericidal concentration of 32 µg/mL, patients in the bolus group spent a median of 1/5 and 1/3 of the typical 6 h operative time below target in subcutaneous and muscle tissue, respectively. Conclusions: We conclude that intraoperative determination of cefazolin tissue concentrations is feasible and both bolus and infusion dosing of cefazolin achieve concentrations in excess of typical MICs. Infusion dosing appears to more consistently achieve bactericidal concentrations in subcutaneous and muscle tissues.

Analyzing the value of IONM as a complex intervention: The gap between published evidence and clinical practice.

OBJECTIVE: Intraoperative neurophysiological monitoring (IONM) was investigated as a complex intervention (CI) as defined by the United Kingdom Medical Research Council (MRC) in published studies to identify challenges and solutions in estimating IONM's effects on postoperative outcomes. METHODS: A scoping review to April 2022 of the influence of setting on what was implemented as IONM and how it influenced postoperative outcomes was performed for studies that compared IONM to no IONM cohorts. IONM complexity was assessed with the iCAT_SR tool. Causal graphs were used to represent this complexity. RESULTS: IONM implementation depended on the surgical procedure, institution and/or surgeon. "How" IONM influenced neurologic outcomes was attributed to surgeon or institutional experience with the surgical procedure, surgeon or institutional experience with IONM, co-interventions in addition to IONM, models of IONM service delivery and individual characteristics of the IONM provider. Indirect effects of IONM mediated by extent of tumor resection, surgical approach, changes in operative procedure, shorter operative time, and duration of aneurysm clipping were also described. There were no quantitative estimates of the relative contribution of these indirect effects to total IONM effects on outcomes. CONCLUSIONS: IONM is a complex intervention whose evaluation is more challenging than that of a simple intervention. Its implementation and largely indirect effects depend on specific settings that are usefully represented in causal graphs. SIGNIFICANCE: IONM evaluation as a complex intervention aided by causal graphs and multivariable analysis could provide a valuable framework for future study design and assessments of IONM effectiveness in different settings.

Intergenerational Perioperative Neurocognitive Disorder.

Accelerated neurocognitive decline after general anesthesia/surgery, also known as perioperative neurocognitive disorder (PND), is a widely recognized public health problem that may affect millions of patients each year. Advanced age, with its increasing prevalence of heightened stress, inflammation, and neurodegenerative alterations, is a consistent contributing factor to the development of PND. Although a strong homeostatic reserve in young adults makes them more resilient to PND, animal data suggest that young adults with pathophysiological conditions characterized by excessive stress and inflammation may be vulnerable to PND, and this altered phenotype may be passed to future offspring (intergenerational PND). The purpose of this narrative review of data in the literature and the authors' own experimental findings in rodents is to draw attention to the possibility of intergenerational PND, a new phenomenon which, if confirmed in humans, may unravel a big new population that may be affected by parental PND. In particular, we discuss the roles of stress, inflammation, and epigenetic alterations in the development of PND. We also discuss experimental findings that demonstrate the effects of surgery, traumatic brain injury, and the general anesthetic sevoflurane that interact to induce persistent dysregulation of the stress response system, inflammation markers, and behavior in young adult male rats and in their future offspring who have neither trauma nor anesthetic exposure (i.e., an animal model of intergenerational PND).

Intergenerational Perioperative Neurocognitive Disorder in Young Adult Male Rats with Traumatic Brain Injury.

BACKGROUND: The authors tested the hypothesis that the effects of traumatic brain injury, surgery, and sevoflurane interact to induce neurobehavioral abnormalities in adult male rats and in their offspring (an animal model of intergenerational perioperative neurocognitive disorder). METHODS: Sprague-Dawley male rats (assigned generation F0) underwent a traumatic brain injury on postnatal day 60 that involved craniectomy (surgery) under 3% sevoflurane for 40 min followed by 2.1% sevoflurane for 3 h on postnatal days 62, 64, and 66 (injury group). The surgery group had craniectomy without traumatic brain injury, whereas the sevoflurane group had sevoflurane only. On postnatal day 90, F0 males and control females were mated to generate offspring (assigned generation F1). RESULTS: Acutely, F0 injury rats exhibited the greatest increases in serum corticosterone and interleukin-1ß and -6, and activation of the hippocampal microglia. Long-term, compared to controls, F0 injury rats had the most exacerbated corticosterone levels at rest (mean ± SD, 2.21 ± 0.64 vs. 7.28 ± 1.95 ng/ml, n = 7 - 8; P < 0.001) and 10 min after restraint (133.12 ± 33.98 vs. 232.83 ± 40.71 ng/ml, n = 7 - 8; P < 0.001), increased interleukin-1ß and -6, and reduced expression of hippocampal glucocorticoid receptor (Nr3c1; 0.53 ± 0.08 fold change relative to control, P < 0.001, n = 6) and brain-derived neurotrophic factor genes. They also exhibited greater behavioral deficiencies. Similar abnormalities were evident in their male offspring, whereas F1 females were not affected. The reduced Nr3c1 expression in F1 male, but not female, hippocampus was accompanied by corresponding Nr3c1 promoter hypermethylated CpG sites in F0 spermatozoa and F1 male, but not female, hippocampus. CONCLUSIONS: These findings in rats suggest that young adult males with traumatic brain injury are at an increased risk of developing perioperative neurocognitive disorder, as are their unexposed male but not female offspring.

Frailty Assessment and Prehabilitation Before Complex Spine Surgery in Patients With Degenerative Spine Disease: A Narrative Review.

Degenerative spine disease increases in prevalence and may become debilitating as people age. Complex spine surgery may offer relief but becomes riskier with age. Efforts to lessen the physiological impact of surgery through minimally invasive techniques and enhanced recovery programs mitigate risk only after the decision for surgery. Frailty assessments outperform traditional tools of perioperative risk stratification. The extent of frailty predicts complications after spine surgery such as reoperation for infection and 30-day mortality, as well as elements of social cost such as hospital length of stay and discharge to an advanced care facility. Symptoms of spine disease overlap with phenotypic markers of frailty; therefore, different frailty assessment tools may perform differently in patients with degenerative spine disease. Beyond frailty, however, cognitive decline and psychosocial isolation may interact with frailty and affect achievable surgical outcomes. Prehabilitation, which has reduced perioperative risk in colorectal and cardiac surgery, may benefit potential complex spine surgery patients. Typical prehabilitation includes physical exercise, nutrition supplementation, and behavioral measures that may offer symptomatic relief even in the absence of surgery. Nonetheless, the data on the efficacy of prehabilitation for spine surgery remains sparse and barriers to prehabilitation are poorly defined. This narrative review concludes that a frailty assessment-potentially supplemented by an assessment of cognition and psychosocial resources-should be part of shared decision-making for patients considering complex spine surgery. Such an assessment may suffice to prompt interventions that form a prehabilitation program. Formal prehabilitation programs will require further study to better define their place in complex spine care.

Transcranial Motor Evoked Potential Monitoring in a Patient With a Deep Brain Stimulator: A Case Report.

SUMMARY: A major complication of surgical scoliosis correction is permanent injury of the spinal cord. Intraoperative neuromonitoring continually evaluates spinal cord function through monitoring sensory and corticospinal motor tracts. There is no literature or manufacturer recommendation on whether transcranial motor evoked potential (tcMEP) monitoring can be performed safely in the presence of a deep brain stimulator (DBS) system. A 17-year-old adolescent boy with severe neuromuscular scoliosis presented for a posterior spinal fusion. The patient suffered from generalized dystonia treated with a DBS terminating in the left and right globus pallidus internus. The competing goals of monitoring motor function during the spinal fusion and preserving the integrity of the DBS system were discussed preoperatively. The DBS system was deactivated for the duration of surgery, and tcMEPs were used sparingly at the lowest suitable stimulation voltage. Intraoperative management focused on facilitating neurophysiologic monitoring through a total intravenous anesthetic of propofol, methadone, and remifentanil. The tcMEPS remained unchanged throughout the operation and the patient emerged able to move his lower extremities to command. Postoperatively, the DBS system was turned back on and showed retained settings, normal functioning, and unchanged impedance of the DBS leads. Neither the patient nor his parents reported any subjective changes in the symptoms of dystonia. The authors conclude that monitoring tcMEPs in the presence of a DBS implant may be done safely, when the clinical circumstances suggest that the added information gained from tcMEPs outweighs the theoretical risk to the DBS system and the course of the medical condition treated by the DBS.

Methadone and a Clinical Pathway in Adolescent Idiopathic Scoliosis Surgery: A Historically Controlled Study.

STUDY DESIGN: Historically controlled clinical trial. OBJECTIVES: Patients presenting for correction of adolescent idiopathic scoliosis (AIS) by posterior spinal fusion may benefit from structured clinical pathways. We studied the effects of implementing a published clinical pathway for the perioperative care of patients with AIS that required intraoperative use of methadone at our institution. METHODS: We performed a historically controlled clinical trial of patients undergoing posterior spinal fusion for AIS by comparing a retrospectively collected control group of 25 patients with a prospective experimental group of 14 patients receiving methadone, gabapentin, propofol, and remifentanil as part of a new clinical pathway. RESULTS: Use of the pathway decreased average pain scores evaluated by the Numeric Rating Scale in the 24 hours following surgery (4.8 [4-6] to 3.4 [2-4], P = .03 [-2.6 to -0.2; t = -2.3]) and postoperative opioid consumption by 76% (41 [29-51] mg to 10 [4-17] mg, P < .001 [-45 to -15; Welch's t = 4.9]) during the same period. Improved analgesia and reduced reliance on opioids facilitated other postoperative elements of the clinical pathway and shortened the average hospital length of stay by 1 day (4 [3-6] days to 3 [3-5] days, P = .001 [-2 to -1; U = 67, Z = -3.3]). CONCLUSIONS: Multimodal analgesia and a clinical pathway add value in the perioperative care of patients undergoing posterior spinal fusion for AIS by improving analgesia and shortening hospitalization. The prospective arm of the trial was registered at clinicaltrials.gov under NCT02481570.

Proof of principle: Preoperative cognitive reserve and brain integrity predicts intra-individual variability in processed EEG (Bispectral Index Monitor) during general anesthesia.

BACKGROUND: Preoperative cognitive reserve and brain integrity may explain commonly observed intraoperative fluctuations seen on a standard anesthesia depth monitor used ubiquitously in operating rooms throughout the nation. Neurophysiological variability indicates compromised regulation and organization of neural networks. Based on theories of neuronal integrity changes that accompany aging, we assessed the relative contribution of: 1) premorbid cognitive reserve, 2) current brain integrity (gray and white matter markers of neurodegenerative disease), and 3) current cognition (specifically domains of processing speed/working memory, episodic memory, and motor function) on intraoperative neurophysiological variability as measured from a common intraoperative tool, the Bispectral Index Monitor (BIS). METHODS: This sub-study included participants from a parent study of non-demented older adults electing unilateral Total Knee Arthroplasty (TKA) with the same surgeon and anesthesia protocol, who also completed a preoperative neuropsychological assessment and preoperative 3T brain magnetic resonance imaging scan. Left frontal two-channel derived EEG via the BIS was acquired preoperatively (un-medicated and awake) and continuously intraoperatively with time from tourniquet up to tourniquet down. Data analyses used correlation and regression modeling. RESULTS: Fifty-four participants met inclusion criteria for the sub-study. The mean (SD) age was 69.5 (7.4) years, 54% were male, 89% were white, and the mean (SD) American Society of Anesthesiologists score was 2.76 (0.47). We confirmed that brain integrity positively and significantly associated with each of the cognitive domains of interest. EEG intra-individual variability (squared deviation from the mean BIS value between tourniquet up and down) was significantly correlated with cognitive reserve (r = -.40, p = .003), brain integrity (r = -.37, p = .007), and a domain of processing speed/working memory (termed cognitive efficiency; r = -.31, p = .021). Hierarchical regression models that sequentially included age, propofol bolus dose, cognitive reserve, brain integrity, and cognitive efficiency found that intraoperative propofol bolus dose (p = .001), premorbid cognitive reserve (p = .008), and current brain integrity (p = .004) explained a significant portion of intraoperative intra-individual variability from the BIS monitor. CONCLUSIONS: Older adults with higher premorbid reserve and less brain disease were more stable intraoperatively on a depth of anesthesia monitor. Researchers need to replicate findings within larger cohorts and other surgery types.

Neurophysiological monitoring and spinal cord integrity.

An integral part of a major spine surgery is the intraoperative neurophysiological monitoring (IONM). By providing continuous functional assessment of specific anatomic structures, IONM allows the rapid detection of neuronal compromise and the opportunity for corrective action before an insult causes permanent neurological damage. Thus, IONM functions not just as a diagnostic tool but may also improve surgical outcomes. Effective clinical application requires a thorough understanding of the scope and limitations of IONM modalities not only by the monitoring team but also by the surgeon and anesthesiologist. Intraoperatively, collaboration and communication between monitorist, surgeon, and anesthesiologist are critical to the effectiveness of IONM. In this study, we review specific monitoring modalities, focusing on the relevant anatomy, physiology, and mechanisms of neuronal injury during major spine surgery. We discuss how these factors interact with anesthetic and surgical management. This review concludes with the current controversies surrounding the evidence in support of IONM and directions of future research.

A prospective time-series quality improvement trial of a standardized analgesia protocol to reduce postoperative pain among neurosurgery patients.

OBJECTIVE The inclusion of the pain management domain in the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey now ties patients' perceptions of pain and analgesia to financial reimbursement for inpatient stays. Therefore, the authors wanted to determine if a quality improvement initiative centered on a standardized analgesia protocol could significantly reduce postoperative pain among neurosurgery patients. METHODS The authors implemented a 10-month, prospective, interrupted time-series trial of a quality improvement initiative. The intervention consisted of a multimodal, interdepartmental, standardized analgesia protocol with process improvements from preadmission to discharge. All neurosurgical-floor patients participated in the quality improvement intervention, with data collected on a systematically randomly sampled subset of 96 patients for detailed analysis. Patient-reported numeric rating scale pain on the first postoperative day (POD) served as the primary outcome. RESULTS Implementation of the analgesia protocol resulted in improved preoperative and postoperative documentation of pain (p < 0.001) and improved use of multimodal analgesia, including use of NSAIDs (p < 0.009) and gabapentin (p < 0.027). This intervention also correlated with a 32% reduction in reported pain on the 1st POD for all neurosurgical patients (mean pain scale scores 4.31 vs 2.94; p = 0.000) and a 43% reduction among spinal surgery patients (mean pain scale scores 5.45 vs 3.10; p = 0.036). After controlling for covariates, implementation of the protocol was a significant predictor of lowered postoperative pain (p = 0.05) on the 1st POD. This reduction in pain correlated with protocol compliance (p = 0.028), and a significant decrease in the monthly number of naloxone doses suggests improved safety (mean dose ± SD 1.5 ± 1.0 vs 0.33 ± 0.5; p = 0.04). Furthermore, a significant and persistent reduction in the pain management component of the HCAHPS scores suggests a durability of results extending beyond the life of the study (72.1% vs 82.0%; p = 0.033). CONCLUSIONS The implementation of a standardized analgesia protocol can significantly reduce postoperative pain among neurosurgical patients while increasing safety. Given the current climate of patient-centered outcomes, this study has broad implications for the continuum of care model proposed in the Affordable Care Act. Clinical trial registration no.: NCT01693588 ( clincaltrials.gov ).

Role of Steroids in Hyperexcitatory Adverse and Anesthetic Effects of Sevoflurane in Neonatal Rats.

UNLABELLED: Recent studies have demonstrated that long-term developmental effects of neonatal anesthesia were more prominent in males. We tested whether steroids, in general, and sex steroids, in particular, are involved in the mediation of sevoflurane-caused paradoxical cortical seizures during the early postnatal period. METHODS: Cortical electroencephalograms, hippocampal synaptic activity, serum levels of steroids and the loss of the righting reflex (LORR), a marker of anesthetic effect, were measured on postnatal days 4-6 in Sprague Dawley rats of both genders exposed to 2.1% sevoflurane. RESULTS: Episodes of seizures, persistent spikes in electroencephalograms and increases in serum corticosterone were similar in both genders. In the order of increasing potency, the corticosteroid receptor antagonist RU 28318, the estradiol receptor antagonist ICI 182780 and the estradiol synthesis inhibitor formestane decreased sevoflurane-induced seizures. Exogenous estradiol increased sevoflurane-caused seizures, spikes and serum levels of corticosterone. These estradiol-enhanced seizures and spikes were depressed by ICI 182780 and the NKCC1 inhibitor, bumetanide, while RU 28318 decreased seizures only. In hippocampal CA1 neurons, estradiol increased the amplitude, rise time and area under the curve of gamma-aminobutyric acid type A receptor (GABAAR)-mediated miniature postsynaptic currents. Exogenous estradiol shortened, while ICI 182780 and formestane lengthened the time needed for sevoflurane to induce LORR. CONCLUSION: These findings provide evidence for gender-independent acute electroencephalographic effects of sevoflurane at this age. Corticosterone and estradiol are involved in the mediation of sevoflurane-induced seizures. Estradiol, but not corticosterone, also contributes to sevoflurane-caused spikes, by enhancing GABAAR-mediated excitation in the cortex. By increasing GABAAR-mediated inhibition in more mature caudal regions of the brain, estradiol contributes to sevoflurane-induced LORR.

The effect of body inclination during prone positioning on intraocular pressure in awake volunteers: a comparison of two operating tables.

Visual loss is a rare, but catastrophic, complication of surgery in the prone position. The prone position increases intraocular pressure (IOP), which may lead to visual loss by decreasing perfusion of the anterior optic nerve. We tested whether the reverse Trendelenburg position ameliorates the increase in IOP caused by prone positioning. Furthermore, we compared two prone positioning set ups. The IOP of 10 healthy awake volunteers was measured in the prone position at 3 different degrees of inclination (horizontal, 10 degrees reverse Trendelenburg, and 10 degrees Trendelenburg) and in the sitting and supine positions in a randomized crossover study comparing the Jackson table and the Wilson frame. In a given eye, all prone IOP values (median [25th-75th percentile] exceeded those of the sitting (15.0 mm Hg [12.8-16.3 mm Hg]) and supine (16.8mm Hg [14.0-18.3 mm Hg]) positions. IOPs in the reverse Trendelenburg, horizontal, and Trendelenburg positions were 20.3 mm Hg (16.3-22.5 mm Hg), 22.5 mm Hg (19.8-25.3 mm Hg), and 23.8 mm Hg (21.5-26.3 mm Hg), respectively (P < 0.001 versus reverse Trendelenburg; dagger P < 0.001 versus horizontal). The reverse Trendelenburg position ameliorated the increase in IOP caused by the prone position. Furthermore, the reverse Trendelenburg position decreased the number of grossly abnormal IOP values (>23 mm Hg) by 50% and 75% compared with the prone horizontal and Trendelenburg positions, respectively. The prone positioning setups did not differ in their effect on IOP. The increase in IOP caused by prone positioning was ameliorated by the reverse Trendelenburg position and was aggravated by the Trendelenburg position. The short time period between changes in position and changes in IOP suggests an important role for ocular venous pressures in determining IOP. Therefore, IOP can be beneficially manipulated by operating table inclination in the prone position.

Contribution of I(K,ADO) to the negative dromotropic effect of adenosine.

OBJECTIVE: Despite the pathophysiological and therapeutic significance of the negative dromotropic effect of adenosine, its underlying ionic mechanism, and specifically the role of the adenosine-activated K(+) current (I(K,ADO)) is not experimentally defined. Therefore, we studied the contribution of I(K,ADO) to the negative dromotropic effect of adenosine. METHODS: Effects of adenosine on single atrioventricular nodal and left atrial myocytes from rabbits were studied using the whole cell configuration of the patch clamp technique. Complementary experiments were done in rabbit and guinea pig isolated hearts instrumented to measure the atrium-to-His bundle interval. RESULTS: In contrast to its effect in atrial myocytes, Ba(2+) selectively and completely blocked I(K,ADO) at membrane potentials from -70 to 0 mV in atrioventricular nodal myocytes and abolished the adenosine-induced leftward shift of the reversal membrane potential. Ba(2+) alone did not significantly prolong the A-H interval, but markedly attenuated the A-H interval prolongation caused by adenosine. In guinea pig heart, EC(50) values ( pD(2) +/- SEM) for adenosine-induced atrium-to-His bundle interval prolongation were 3.3 micromol/L (5.48 +/- 0.04) and 13.2 micromol/L (4.88 +/- 0.05, P < 0.001) in the absence and presence of Ba(2+), respectively. Despite species-dependent differences in sensitivities to adenosine (guinea pig > rabbit), the relative contribution of adenosine-activated K(+) current to the atrium-to-His bundle interval prolongation was nearly identical. In guinea pig hearts it ranged from 37.8 % (P = 0.013) to 72.5 % (P < 0.001) at 2 to 6 micromol/L adenosine, respectively. CONCLUSION: I(K,ADO) contributes significantly to the negative dromotropic effect of adenosine, but predominantly at relatively high concentrations of the nucleoside.

Potentiation of the negative dromotropic effect of adenosine by rapid heart rates: possible ionic mechanism.

Adenosine-induced slowing of atrioventricular nodal conduction is a rate-dependent process that is potentiated by the A(1)-adenosine receptor allosteric enhancer, PD 81,723. The ionic mechanisms underlying these phenomena were investigated in guinea pig isolated hearts and single atrial myocytes by measuring the atrium-to-His bundle (A-H) interval and using patch-clamp recordings, respectively.A decrease in atrial cycle length from 300 to 190 ms decreased the concentration of adenosine needed to cause atrioventricular nodal block from 7.8 +/- 1.0 to 2.6 +/- 0.7 micromol/L (P < 0.001). Ba(2+) (100 micromol/L), a selective blocker of the adenosine-activated inward rectifier K(+) current I(K,ADO) in the atrioventricular node, failed to abolish this rate-dependent effect of adenosine. PD 81,723 (5 micromol/L) potentiated the negative dromotropic effect of adenosine even after I(K,ADO) was blocked by Ba(2+) and after attenuation of I(Ca,L) by adenosine was prevented by 8-Br-cAMP (1.5 mmol/L). In atrial myocytes, adenosine augmented a time- and voltage-dependent K(+) current (Ado-I(K)). Ado-I(K) was more sensitive to adenosine than I(K,ADO) (EC(50) values, 0.8 versus 1.4 micromol/L, P < 0.01). PD 81,723 blocked I(K,ADO), but potentiated Ado-I(K). Ado-I(K) was insensitive to Ba(2+) (P = 0.98), whereas it was blocked by chromanol 293B (5 micromol/L, P < 0.001). Unlike I(K,ADO), Ado-I(K) increased during rapid stimulation of myocytes (P < 0.001). Adenosine augments a time- and voltage-dependent K(+) current, Ado-I(K). The pharmacological and kinetic properties of Ado-I(K) are consistent with it playing an important role in the negative dromotropic effect of adenosine at lower concentrations of the nucleoside, at fast heart rates and in the presence of PD 81,723.