Current clinical application of dantrolene sodium

Dantrolene sodium (DS) was first introduced as an oral antispasmodic drug. However, in 1975, DS was demonstrated to be effective for managing malignant hyperthermia (MH) and was adopted as the primary therapeutic drug after intravenous administration. However, it is difficult to administer DS intravenously to manage MH. MH is life-threatening, pharmacogenomically related, and induced by depolarizing neuromuscular blocking agents or inhalational anesthetics. All anesthesiologists should know the pharmacology of DS. DS suppresses Ca2+ release from ryanodine receptors (RyRs). RyRs are expressed in various tissues, although their distribution differs among subtypes. The anatomical and physiological functions of RyRs have also been demonstrated as effective therapeutic drugs for cardiac arrhythmias, Alzheimer’s disease, and other RyR-related diseases. Recently, a new formulation was introduced that enhanced the hydrophilicity of the lipophilic DS. The authors summarize the pharmacological properties of DS and comment on its indications, contraindications, adverse effects, and interactions with other drugs by reviewing reference articles.

Chronic exposure to dexamethasone may not affect sugammadex reversal of rocuronium-induced neuromuscular blockade: an in vivo study on rats

Background@#Chronic glucocorticoid exposure is associated with resistance to nondepolarizing neuromuscular blocking agents. Therefore, we hypothesized that sugammadex-induced recovery would occur more rapidly in subjects exposed to chronic dexamethasone compared to those who were not exposed. This study evaluated the sugammadex-induced recovery profile after neuromuscular blockade (NMB) in rats exposed to chronic dexamethasone. @*Methods@#Sprague–Dawley rats were allocated to three groups (dexamethasone, control, and pair-fed group) for the in vivo study. The mice received daily intraperitoneal dexamethasone injections (500 μg/kg) or 0.9% saline for 15 days. To achieve complete NMB, 3.5 mg/kg rocuronium was administered on the sixteenth day. The recovery time to a train-of-four ratio ≥ 0.9 was measured to evaluate the complete recovery following the sugammadex injection. @*Results@#Among the groups, no significant differences were observed in the recovery time to a train-of-four ratio ≥ 0.9 following sugammadex administration (P = 0.531). The time to the second twitch of the train-of-four recovery following rocuronium administration indicated that the duration of NMB was significantly shorter in Group D than that in Groups C and P (P = 0.001). @*Conclusions@#Chronic exposure to dexamethasone did not shorten the recovery time of sugammadex-induced NMB reversal. However, the findings of this study indicated that no adjustments to sugammadex dosage or route of administration is required, even in patients undergoing long-term steroid treatment.

Anesthetic care for electroconvulsive therapy

Counselling and medication are often thought of as the only interventions for psychiatric disorders, but electroconvulsive therapy (ECT) has also been applied in clinical practice for over 80 years. ECT refers to the application of an electric stimulus through the patient’s scalp to treat psychiatric disorders such as treatment-resistant depression, catatonia, and schizophrenia. It is a safe, effective, and evidence-based therapy performed under general anesthesia with muscle relaxation. An appropriate level of anesthesia is essential for safe and successful ECT; however, little is known about this because of the limited interest from anesthesiologists. As the incidence of ECT increases, more anesthesiologists will be required to better understand the physiological changes, complications, and pharmacological actions of anesthetics and adjuvant drugs. Therefore, this review focuses on the fundamental physiological changes, management, and pharmacological actions associated with various drugs, such as anesthetics and neuromuscular blocking agents, as well as the comorbidities, indications, contraindications, and complications of using these agents as part of an ECT procedure through a literature review and our own experiences.

Adverse events of sugammadex that occurred in a Korean population

With increasing use, the incidence of adverse events associated with sugammadex, a neuromuscular blockade reverser, is increasing. This study aimed to identify and analyze cases of adverse events caused by sugammadex reported in Korean population. Methods: Out of a total of 12 cases detected using various keywords in the Korean Journal of Anesthesia, Anesthesia and Pain Medicine (Seoul), KoreaMed, PubMed, EMBASE, Web of Science, and The Cochrane Library-CENTRAL from 2013 to December 2020, 10 cases directly associated with sugammadex were selected. Results: Adverse events included five cases of anaphylaxis, one case of cardiac arrest, one case of profound bradycardia, one case of negative pressure pulmonary edema, and two cases of incomplete recovery. Three patients had American Society of Anesthesiologists physical status ≥ 3, two had emergency surgery, and two had a history of allergic reaction. Neuromuscular monitoring was applied in nine cases. The average dose of sugammadex was 2.87 mg/kg, and there were six cases in which one full vial was used, regardless of the state of neuromuscular recovery. Sugammadex was administered immediately after surgery in two cases, at train of four (TOF) 0 in four cases, at TOF 3 in one case, and after evaluation of the clinical signs only with no neuromuscular monitoring in one case. Conclusions: Even with neuromuscular monitoring, an excessive dose of sugammadex was observed. Given that adverse events tend to occur within 10 min of administration, continuous monitoring is important even after administration.

Effects of hydrocortisone-presensitized sugammadex on recovery from neuromuscular blockade induced by rocuronium: a rodent in vivo study

Sugammadex is a specific antagonist of aminosteroidal neuromuscular blocking agents with 1:1 binding to guest molecules. Sugammadex can also bind to other drugs having a steroid component in its chemical structure. In this in vivo experiment, we investigated the differences in the recovery of rocuronium-induced neuromuscular blockade using sugammadex pre-exposed with two different concentrations of hydrocortisone. Methods: The sciatic nerves and tibialis anterior muscles of 30 adult Sprague–Dawley rats were prepared for the experiment. The sciatic nerves were stimulated using a train-of-four (TOF) pattern with indirect supramaximal stimulation at 20 s intervals. After 15 min of stabilization, a 250 μg loading dose and 125 μg booster doses of rocuronium were serially administered until > 95% depression of the first twitch tension of TOF stimulation (T1) was confirmed. The study drugs were prepared by mixing sugamadex with the same volume of three different stock solutions (0.9% normal saline, 10 mg/ml hydrocortisone, and 100 mg/ ml hydrocortisone). The recovery of rats from neuromuscular blockade was monitored by assessing T1 and the TOF ratio (TOFR) simultaneously until T1 was recovered to > 95% and TOFR to > 0.9. Results: In the group injected with sugammadex premixed with a high concentration of hydrocortisone, statistically significant intergroup differences were observed in the recovery progression of T1 and TOFR (P < 0.050). Conclusions: When sugammadex was pre-exposed to a high dose of hydrocortisone only, recovery from neuromuscular blockade was delayed. Delayed recovery from neuromuscular blockade is not always plausible when sugammadex is pre-exposed to steroidal drugs.

The senior anesthesiologists and their medical profession in Korea: based on a survey

Background@#The number of aging physicians is increasing as the global population ages. With aging, anesthesiologists would be expected to experience changes in their professional position. Therefore, we aimed to investigate the current professional status of Korean anesthesiologists aged over 60 years. @*Methods@#Registered anesthesiologists aged over 60 years in Korea were invited for a survey. The questionnaire addressed 10 subjects with 40 questions that focused on demographics, practical activities, work conditions, difficulties experienced due to physical changes caused by aging, and economic status. @*Results@#In total, 122 anesthesiologists responded to the survey (response rate: 15.7%). Of them, 30.3% were working in honorary and advisory positions at tertiary hospitals, while 19.7% were working as pain physicians. Majority of the respondents were working for 5 days a week (41.8%) and 6–8 hours/day (48.4%). Majority of them (79.5%) were generally satisfied with their present life. @*Conclusions@#Majority of the senior anesthesiologists were working at general hospitals and they reported being “satisfied” with the current status of their life. However, the clinical practice and retirement strategies of senior anesthesiologists need to be evaluated systematically to prepare for the continuing gradual increase in the number of senior anesthesiologists.

The senior anesthesiologists and their medical profession in Korea: based on a survey

Background@#The number of aging physicians is increasing as the global population ages. With aging, anesthesiologists would be expected to experience changes in their professional position. Therefore, we aimed to investigate the current professional status of Korean anesthesiologists aged over 60 years. @*Methods@#Registered anesthesiologists aged over 60 years in Korea were invited for a survey. The questionnaire addressed 10 subjects with 40 questions that focused on demographics, practical activities, work conditions, difficulties experienced due to physical changes caused by aging, and economic status. @*Results@#In total, 122 anesthesiologists responded to the survey (response rate: 15.7%). Of them, 30.3% were working in honorary and advisory positions at tertiary hospitals, while 19.7% were working as pain physicians. Majority of the respondents were working for 5 days a week (41.8%) and 6–8 hours/day (48.4%). Majority of them (79.5%) were generally satisfied with their present life. @*Conclusions@#Majority of the senior anesthesiologists were working at general hospitals and they reported being “satisfied” with the current status of their life. However, the clinical practice and retirement strategies of senior anesthesiologists need to be evaluated systematically to prepare for the continuing gradual increase in the number of senior anesthesiologists.

Nasotracheal intubation for airway management during anesthesia

Nasotracheal intubation is used as a basic method for airway management, along with orotracheal intubation under anesthesia and intensive care. It has become an effective alternative method to orotracheal intubation with increased benefits of offering better mobility and surgical field in oral and maxillofacial surgery and possibly in trauma and critically ill patients. Nasotracheal intubation is performed through a relatively narrow nasal cavity; therefore, additional precautions are needed. Accordingly, nasotracheal intubation methods have evolved over the years with accumulated clinical experience and improved instruments to facilitate safe intubation with reduced complications. Therefore, in this review article, we summarize the basic anatomy of the nasal airways to clarify the precautions, delineate the history and development of various methods and instruments, and describe the indications, contraindications, complications, and preventive methods of nasotracheal intubation.

Effects of different sugammadex doses on the train of four ratio recovery progression during rocuronium induced neuromuscular blockade in the rat phrenic nerve hemidiaphragm / 대한마취과학회지

Background@#In this study, we used an ex-vivo model to investigate the recovery pattern of both the train-of-four (TOF) ratio and first twitch tension of TOF (T1), and determined their relationship during recovery from rocuronium-induced neuromuscular blockade at various concentrations of sugammadex. @*Methods@#Tissue specimens of the phrenic nerve-hemidiaphragm were obtained from 60 adult Sprague-Dawley rats. Each specimen was immersed in an organ bath filled with Krebs buffer solution and stimulated with the TOF pattern using indirect supramaximal stimulation at 20-second intervals. After a 30-minute stabilization period, rocuronium loading and booster doses were serially administered at 10-minute intervals in each sample until > 95% depression of T1 was confirmed. Specimens were randomly allocated to either the control group (washout) or to one of five sugammadex concentration groups (0.75, 1, 2, 4, or 8 times equimolar doses of rocuronium to produce >95% T1 depressions; SGX0.75, SGX1, SGX2, SGX4, and SGX8, respectively). Recovery from neuromuscular blockade was monitored using T1 and the TOF ratio simultaneously until the recovery of T1 to > 95% and the TOF ratio to > 0.9. @*Results@#Statistically significant intergroup differences were observed between the recovery patterns of T1 and the TOF ratio (TOFR, p<0.050), except between SGX2 and SGX4 groups. TOFR/T1 values were maintained at nearly 1 in the control, SGX0.75, and SGX1 groups; however, they were exponentially decayed in the SGX2, SGX4, and SGX8 groups. @*Conclusions@#Recovery of the TOF ratio may be influenced by the sugammadex dose, and a TOF ratio of 1.0 may be achieved before full T1 recovery if administration of sugammadex exceeds that of rocuronium.

Analysis of perioperative cardiac arrest in a rural hospital in Korea

Background@#Perioperative cardiac arrest has been studied in many countries but few related studies have been conducted in Korea. Previous studies were not applicable to rural hospitals due to differences in the demographics between the regions. In the present study, the incidence, mortality, and related factors of perioperative cardiac arrest in a hospital in Youngdong province were analyzed and compared with previous research. @*Methods@#A retrospective study was conducted from the January 1, 2012, to December 31, 2018, on patients who underwent both anesthesia and surgery in our hospital. Patients who received local anesthesia were not included in the study. The collected data included the patient characteristics, anesthesia methods, the American Society of Anesthesiologists physical status, surgical department, emergency status, traumatic status, pre- and post-cardiac arrest medical records, and patient outcomes. @*Results@#A total of 57,746 patients received anesthesia and underwent surgery during the study period, and 28 patients (4.85 per 10,000 anesthesia cases) received cardiopulmonary cerebral resuscitation (CPCR) during or within 24 hours of surgery. Eight patients survived and twenty patients died (3.46 per 10,000 anesthesia cases). There were three anesthesia-related arrests and all of these patients survived. When limiting the analysis to patients with intraoperative CPCR, the incidence and mortality were 1.56, and 1.39 per 10,000 anesthesia cases, respectively. @*Conclusions@#The incidence and mortality of perioperative cardiac arrest in our hospital were higher than those in a recent study in Seoul, demonstrating a regional gap in Korea.

Malignant hyperthermia and dantrolene sodium / 대한마취과학회지

No abstract available.

Effects of dexamethasone and hydrocortisone on rocuronium-induced neuromuscular blockade and reversal by sugammadex in phrenic nerve-hemidiaphragm rat model / 대한마취과학회지

BACKGROUND@#The facilitator effects of steroids on neuromuscular transmission may cause resistance to neuromuscular blocking agents. Additionally, steroids may hinder sugammadex reversal of neuromuscular blockade, but these findings remain controversial. Therefore, we explored the effect of dexamethasone and hydrocortisone on rocuronium-induced neuromuscular blockade and their inhibitory effect on sugammadex.@*METHODS@#We explored the effects of steroids, dexamethasone and hydrocortisone, in vitro using a phrenic nerve-hemidiaphragm rat model. In the first phase, an effective dose of rocuronium was calculated, and in the second phase, following sugammadex administration, the recovery of the train-of-four (TOF) ratio and T1 was evaluated for 30 minutes, and the recovery index was calculated in dexamethasone 0, 0.5, 5, and 50 μg/ml, or hydrocortisone 0, 1, 10, or 100 μg/ml.@*RESULTS@#No significant effect of steroids on the effective dose of rocuronium was observed. The TOF ratios at 30 minutes after sugammadex administration were decreased significantly only at high experimental concentrations of steroids: dexamethasone 50 μg/ml and hydrocortisone 100 μg/ml (P < 0.001 and P = 0.042, respectively). There were no statistical significances in other concentrations. No differences were observed in T1. Recovery index was significantly different only in 100 μg/ml of hydrocortisone (P = 0.03).@*CONCLUSIONS@#Acute exposure to steroids did not resist the neuromuscular blockade caused by rocuronium. And inhibition of sugammadex reversal on rocuronium-induced neuromuscular blockade is unlikely at typical clinical doses of dexamethasone and also hydrocortisone. Conclusively, we can expect proper effects of rocuronium and sugammadex when dexamethasone or hydrocortisone is used during general anesthesia.

Serratus anterior plane block combined with monitored anesthesia care for surgery of lateral side of breast: a case report / 대한마취과학회지

BACKGROUND@#In breast surgery, regional anesthesia rather than primary anesthesia has been mainly used for postoperative analgesia. Serratus anterior plane block is a new method for ultrasound-guided thoracic wall block. It is less invasive and relatively safer than conventional regional anesthetic techniques.CASE: We report a case of breast surgery under serratus anterior plane block as primary anesthesia with monitored anesthesia for a 78-year-old patient with a medical history of cardiopulmonary resuscitation due to stress-induced cardiomyopathy caused by pneumonia.@*CONCLUSIONS@#Serratus anterior plane block might be simple and effective technique for breast surgery when a lesion is located on lateral side.

Effects of dexamethasone and hydrocortisone on rocuronium-induced neuromuscular blockade and reversal by sugammadex in phrenic nerve-hemidiaphragm rat model / 대한마취과학회지

BACKGROUND: The facilitator effects of steroids on neuromuscular transmission may cause resistance to neuromuscular blocking agents. Additionally, steroids may hinder sugammadex reversal of neuromuscular blockade, but these findings remain controversial. Therefore, we explored the effect of dexamethasone and hydrocortisone on rocuronium-induced neuromuscular blockade and their inhibitory effect on sugammadex. METHODS: We explored the effects of steroids, dexamethasone and hydrocortisone, in vitro using a phrenic nerve-hemidiaphragm rat model. In the first phase, an effective dose of rocuronium was calculated, and in the second phase, following sugammadex administration, the recovery of the train-of-four (TOF) ratio and T1 was evaluated for 30 minutes, and the recovery index was calculated in dexamethasone 0, 0.5, 5, and 50 μg/ml, or hydrocortisone 0, 1, 10, or 100 μg/ml. RESULTS: No significant effect of steroids on the effective dose of rocuronium was observed. The TOF ratios at 30 minutes after sugammadex administration were decreased significantly only at high experimental concentrations of steroids: dexamethasone 50 μg/ml and hydrocortisone 100 μg/ml (P < 0.001 and P = 0.042, respectively). There were no statistical significances in other concentrations. No differences were observed in T1. Recovery index was significantly different only in 100 μg/ml of hydrocortisone (P = 0.03). CONCLUSIONS: Acute exposure to steroids did not resist the neuromuscular blockade caused by rocuronium. And inhibition of sugammadex reversal on rocuronium-induced neuromuscular blockade is unlikely at typical clinical doses of dexamethasone and also hydrocortisone. Conclusively, we can expect proper effects of rocuronium and sugammadex when dexamethasone or hydrocortisone is used during general anesthesia.

Serratus anterior plane block combined with monitored anesthesia care for surgery of lateral side of breast: a case report / 대한마취과학회지

BACKGROUND: In breast surgery, regional anesthesia rather than primary anesthesia has been mainly used for postoperative analgesia. Serratus anterior plane block is a new method for ultrasound-guided thoracic wall block. It is less invasive and relatively safer than conventional regional anesthetic techniques. CASE: We report a case of breast surgery under serratus anterior plane block as primary anesthesia with monitored anesthesia for a 78-year-old patient with a medical history of cardiopulmonary resuscitation due to stress-induced cardiomyopathy caused by pneumonia. CONCLUSIONS: Serratus anterior plane block might be simple and effective technique for breast surgery when a lesion is located on lateral side.

Current use of neuromuscular blocking agents and antagonists in Korea: a 2018 survey

BACKGROUND: Neuromuscular blocking agents (NMBAs) and neuromuscular monitoring in anesthetic management are integral for endotracheal intubation, better visualization of the surgical field, and prevention of residual neuromuscular blockade and pulmonary complications. Sugammadex is a drug that reduces risk of residual neuromuscular blockade, with more rapid recovery compared to anticholinesterase. The purpose of this study was to investigate current usage status of NMBAs and antagonist with neuromuscular monitoring, among anesthesiologists in Korea.METHODS: Anesthesiologists working in Korea were invited to participate in an online survey via email January 2–February 28, 2018. The questionnaire consisted of 45 items, including preferred NMBAs, antagonists, neuromuscular monitoring, and complications related to the use sugammadex. A total of 174 responses were analyzed.RESULTS: Rocuronium was a commonly used NMBA for endotracheal intubation (98%) of hospitals, and maintenance of anesthesia (83.3%) in of hospitals. Sugammadex, pyridostigmine, and neostigmine were used in 89.1%, 87.9%, and 45.4% of hospitals. Neuromuscular monitoring was employed in 79.3% of hospitals; however only 39.7% of hospitals used neuromuscular monitoring before antagonist administration. Usual dosage range of sugammadex was 2.1–4 mg/kg in 35.1% of hospitals, within 2 mg/kg in 34.5% of hospitals, and 1 vial regardless of body weight in 22.4% of hospitals. Sugammadex-related complications were encountered by 14.9% of respondents.CONCLUSIONS: This survey indicates several minor problems associated with the use of antagonists and neuromuscular monitoring. However, most anesthesiologists appear to have appropriate information regarding the usage of NMBAs and sugammadex.

The effect of magnesium sulfate concentration on the effective concentration of rocuronium, and sugammadex-mediated reversal, in isolated left phrenic nerve hemi-diaphragm preparations from the rat / 대한마취과학회지

BACKGROUND: Perioperative magnesium sulfate (MgSO4) is used for analgesic, anti-arrhythmic, and obstetric purposes. The effects of MgSO4 on the neuromuscular blockade (NMB) induced by rocuronium, and the sugammadex reversal thereof, have not been clearly quantified. We investigated the effect of various MgSO4 concentrations on the NMB by rocuronium, and sugammadex reversal, in isolated left phrenic nerve hemi-diaphragm (PNHD) preparations from the rat. METHODS: Rat PNHD preparations were randomly allocated to one of four groups varying in terms of MgSO4 concentration (1, 2, 3, and 4 mM, each n = 10, in Krebs solution). The train-of-four (TOF) and twitch height responses were recorded mechanomyographically. The preparations were treated with incrementally increasing doses of rocuronium and each group’s effective concentration (EC)50, EC90, and EC95 of rocuronium were calculated via nonlinear regression. Then, sugammadex was administered in doses equimolar to rocuronium. The recovery index, time to T1 height > 95% of control, and the time to a TOF ratio > 0.9 after sugammadex administration were measured. RESULTS: The EC50, EC90, and EC95 of rocuronium fell significantly as the magnesium level increased. The EC50, EC90, and EC95 of rocuronium did not differ between the 3 and 4 mM groups. The recovery index, time to T1 height > 95% of control, and time to a TOF ratio > 0.9 after sugammadex administration did not differ among the four groups. CONCLUSIONS: Increases in the magnesium concentration in rat PNHD preparations proportionally enhanced the NMB induced by rocuronium but did not affect reversal by equimolar amounts of sugammadex.

Effects of adenosine receptor agonist on the rocuronium-induced neuromuscular block and sugammadex-induced recovery / 대한마취과학회지

BACKGROUND: Several types of receptors are found at neuromuscular presynaptic membranes. Presynaptic inhibitory A1 and facilitatory A2A receptors mediate different modulatory functions on acetylcholine release. This study investigated whether adenosine A1 receptor agonist contributes to the first twitch tension (T1) of train-of-four (TOF) stimulation depression and TOF fade during rocuronium-induced neuromuscular blockade, and sugammadex-induced recovery. METHODS: Phrenic nerve-diaphragm tissues were obtained from 30 adult Sprague-Dawley rats. Each tissue specimen was randomly allocated to either control group or 2-chloroadenosine (CADO, 10 μM) group. One hour of reaction time was allowed before initiating main experimental data collection. Loading and boost doses of rocuronium were sequentially administered until > 95% depression of the T1 was achieved. After confirming that there was no T1 twitch tension response, 15 min of resting time was allowed, after which sugammadex was administered. Recovery profiles (T1, TOF ratio [TOFR], and recovery index) were collected for 1 h and compared between groups. RESULTS: There were statistically significant differences on amount of rocuronium (actually used during experiment), TOFR changes during concentration-response of rocuronium (P = 0.04), and recovery profiles (P < 0.01) of CADO group comparing with the control group. However, at the initial phase of this experiment, dose-response of rocuronium in each group demonstrated no statistically significant differences (P = 0.12). CONCLUSIONS: The adenosine A1 receptor agonist (CADO) influenced the TOFR and the recovery profile. After activating adenosine receptor, sugammadex-induced recovery from rocuronium-induced neuromuscular block was delayed.

Effects of sugammadex on the coronary circulation: direct effects on coronary vessels or hypersensitivity (Kounis syndrome)? / 대한마취과학회지

No abstract available.

Factors that affect the onset of action of non-depolarizing neuromuscular blocking agents / 대한마취과학회지

Neuromuscular blockade plays an important role in the safe management of patient airways, surgical field improvement, and respiratory care. Rapid-sequence induction of anesthesia is indispensable to emergency surgery and obstetric anesthesia, and its purpose is to obtain a stable airway, adequate depth of anesthesia, and appropriate respiration within a short period of time without causing irritation or damage to the patient. There has been a continued search for new neuromuscular blocking drugs (NMBDs) with a rapid onset of action. Factors that affect the onset time include the potency of the NMBDs, the rate of NMBDs reaching the effect site, the onset time by dose control, metabolism and elimination of NMBDs, buffered diffusion to the effect site, nicotinic acetylcholine receptor subunit affinity, drugs that affect acetylcholine (ACh) production and release at the neuromuscular junction, drugs that inhibit plasma cholinesterase, presynaptic receptors responsible for ACh release at the neuromuscular junction, anesthetics or drugs that affect muscle contractility, site and methods for monitoring neuromuscular function, individual variability, and coexisting disease. NMBDs with rapid onset without major adverse events are expected in the next few years, and the development of lower potency NMBDs will continue. Anesthesiologists should be aware of the use of NMBDs in the management of anesthesia. The choice of NMBD and determination of the appropriate dosage to modulate neuromuscular blockade characteristics such as onset time and duration of neuromuscular blockade should be considered along with factors that affect the effects of the NMBDs. In this review, we discuss the factors that affect the onset time of NMBDs.