Nitrous oxide uptake during spontaneous and controlled ventilation

The rate of uptake of nitrous oxide was studied in 40 orthopaedic patients anaesthetised with either enflurane or isoflurane in nitrous oxide and with either spontaneous or controlled ventilation. A variant of the Douglas bag method was used in combination with low fresh gas flows to a circle system. There were no significant differences in nitrous oxide uptake between the groups and the uptake rates followed'the square root of time concept', with an overall best fit curve of 1080.t^-0.505 ml.70 kg^-1.min^-1. During spontaneous ventilation, the nitrous oxide uptake rate was similar or even higher than the corresponding rate during controlled ventilation, in spite of lower minute volumes.     

Interstitial fluid accumulation does not influence oxygen uptake in the rabbit small intestine

Crystalloid resuscitation increases interstitial fluid volume. Intestinal ischemia and impaired barrier function may contribute to the precipitation of multiple organ failure. Accordingly, the intestine was chosen as target organ to test whether interstitial oedema impairs oxygen extraction by the tissue.
The portal vein in anaesthetized rabbits was partially obstructed for 30 min along with an intravenous infusion of 0.9% saline 60–90 ml kg^-1 (oedema group, n = 7). Total water content of the small intestine increased from 3.4 ml g^-1 dry weight in control (n = 8) to 3.9 ml g^-1 in the oedema group ( P = 0.049). Small intestinal O₂ uptake was calculated from the arteriovenous O₂ content and electromagnetic flow measurements in the superior mesenteric artery. Mesenteric flow was reduced stepwise by a snare occluder around the artery. Intestinal oxygen-ation was monitored indirectly as well, by means of mesenteric venous lactate, arterial base excess and by mucosal pH (pH_i) assessed tonometrically.
The oxygen extraction ratios were similar in the oedema and control group at similar oxygen supplies. After a 45 min flow reduction to 15% of baseline mesenteric venous lactate and pH_i did not differ between the groups. pH; averaged 7.31 and fell to 6.74. Below an intestinal O₂ uptake of 2.5 ml min^-1, pH_i correlated somewhat better with O₂ uptake (r=0.66) than did arterial base excess (r=0.50).
The results indicate that acute elevation of extracellular volume to the extent in the present study, does not impede oxygen uptake in the gut.     

The Venturi Anaesthesia Circuit II Carbon Dioxide Production and Gas Flow Requirements

Carbon dioxide production was measured in 20 adult patients undergoing alloplastic operation of the hip. Body weight ranged from 40 to 81 kg. Anaesthesia consisted of lumbar plexus block, i. v. diazepam, pethidine, pavulon and N₂O/O₂ under controlled ventilation. CO₂ production was 2.13 ml kg^-1 min^-1 (interquartile range 2.09-2.23). A fresh gas flow rate of about 30 ml kg^-1 min^-1 was required for the elimination of CO₂ produced when using the Venturi system for inhalation anaesthesia.     

Differential effects of dobutamine, dopamine, and noradrenaline on splanchnic haemodynamics and oxygenation in the pig

Supranormal oxygen (O₂) transport may benefit critically ill patients. Catecholamines are clinically employed for this purpose. However, their effects on splanchnic haemodynamics and oxygenation are not well defined. The effects of dobutamine (DOBU), dopamine (DOPA), and noradrenaline (NA) on splanchnic blood flows (electromagnetic flow probes), O₂ deliveries and uptakes (catheterisation of portal and hepatic veins) were studied in nine anaesthetised (ketamine/flunitrazepam), ventilated, paralysed, and laparotomised pigs. All three catecholamines (DOPA at 15 μg·kg^-1 · min^-1, DOBU at 13 μg · kg^-1 · min^-1, NA at 0.4 μg · kg^-1 · min^-1) significantly ( P <0.05) increased cardiac output and systemic O₂ delivery. Only DOPA increased small intestinal and total hepatic blood flows, and O₂ deliveries, and decreased O₂ extractions. The same parameters did not change during DOBU. During NA, total hepatic blood flow and O₂ delivery decreased, and hepatic O₂ extraction increased. During all three catecholamines, small intestinal and total hepatic O₂ uptakes did not change significantly. Whereas hepatic arterial blood flow decreased during both DOPA and NE, portal venous flow increased during DOPA. These data suggest that in the experimental model used splanchnic O₂ supply and O₂ reserve capacity appear improved by DOPA, unaffected by DOBU, and impaired by NA.     

Cardiovascular effects of moderate normovolaemic haemodilution during enflurane–nitrous oxide anaesthesia in man

The cardiovascular effects of mild normovolaemic haemodilution during enflurane–nitrous oxide anaesthesia were studied in 20 patients with normal cardiac function before, during and after total hip replacement. After induction of anaesthesia, patients were randomly allocated to one control group (C), or one haemodiluted group (H) where Hct was decreased to 30% by replacement of blood volume by an identical volume of hydroxyethyl starch 200/0.5. Each patient was monitored with a pulmonary artery catheter allowing the measurement of right ventricular ejection fraction. During haemodilution, stroke index and right ventricular end–diastolic volume index increased from 33.1 7.9 to 39.3 7.1 ml M^-2 and from 73.8 20.3 to 94.9 18.5 mlM^-2 respectively (mean s.d., both P <0.05). However, heart rate decreased so that cardiac index did not change. O₂ delivery decreased significantly (from 389 70 to 31163 ml–min^-1 –m^-2; P <0.05), but was not different to the control group. O₂ consumption was maintained by an increase in O₂ extraction. During the surgical procedure, cardiac index was higher in the haemodiluted group than in the control group, so that O₂ delivery was similar in the two groups. O₂ consumption tended to be greater in the haemodiluted group.     

Haemodynamics during inhalation of a 50% nitrous-oxide-in-oxygen mixture with and without hypovolaemia

Background: Inhalation of a gas mixture containing 50% nitrous oxide in oxygen (N₂O/O₂) is widely used for pain relief in emergency situations, which may also be associated with blood loss. The aim of this study was to evaluate the haemodynamic effects of this gas mixture in normo- and hypovolaemic subjects.
Methods: Six healthy males were studied during inhalation of N₂O/O₂ before and after withdrawal of 900 ml of blood. On each occasion, we measured systemic and pulmonary arterial pressures, cardiac output, blood gases, extravascular lung water, and the blood flow and oxygen consumption in the whole body, liver and kidneys.
Results: Inhalation of N₂O/O₂ reduced the stroke volume and increased peripheral resistance. Oxygen uptake decreased in the liver (-30%) and in the whole body (-23%). Blood withdrawal reduced the pulmonary arterial and central venous pressures (-30 to -50%) and further decreased stroke volume and the blood flows to the liver and the kidney (-15%). The extravascular lung water tended to increase both during inhalation of N₂O/O₂ and during hypovolaemia.
Conclusion: N₂O/O₂ aggravated the hypokinetic circulation induced by hypovolaemia. However, the oxygen consumption decreased only during inhalation of N₂O/O₂. This opens up the possibility that the cardiodepression associated with N₂O/O₂ is caused by a change in metabolic demands.     

Hemodynamic and Cardiometabolic Effects of Prenalterol in Patients with Gram Negative Septic Shock

The hernodynamic eflects of prenalterol, a new inotropic agent, were investigated in 10 patients with gram negative septic shock. In four of the patients, coronary sinus blood flow (CSF) and myocardial oxygen and lactate extraction were also determined. After baseline hemodynamic measurements, prenalterol was infused intravenously over a 10-min period to a total dose of 150 pg/kg. All patients responded within 15 min after completion of prenalterol infusion by increasing mean arterial pressure from 57±11 to 75 ± 20 mmHg (7.58f 1.46 to 9.97±2.66 kPa), (+32%), ( P<0.01 ) and cardiac index from 2.65±0.40 to 3.80±0.47 l min^-l m^-2 (+44%) ( P < 0.001). There was no change in heart rate or systemic vascular resistance, nor were any arrhythmias recorded. The urinary output increased significantly. After prenalterol, CSF increased from 185kl 4 to 246±14 ml.min-¹, (+33%), (P<0.001) and myocardial oxygen and lactate extraction rose from 19.8±2.1to26.6±2.1 ml O₂.min^-1, (+ 34%) (P<0.00l) andfrom33.2±2.3 to44.7k2.1 μmol.min^-1, (+35%), (P<0.001), respectively. The total body oxygen consumption increased from 287f 13 to 348±23 ml O₂.min^-1, (+21 %), ( P<0.01 ) and the arterial lactate concentration decreased from 5.61±0.55 to 3.94±0. 16 mmol.l^-1, (- 30%), (P<0.01), suggesting improved tissue perfusion. The results demonstrate that prenalterol is a potent, highly selective inotropic agent inducing the same magnitude of increase in blood pressure and cardiac output as reported for dopamine in septic shock.     

Recovery characteristics of propofol anaesthesia, with and without nitrous oxide: a comparison with halothane/nitrous oxide anaesthesia in children

Few studies have examined whether nitrous oxide influences the recovery characteristics of propofol anaesthesia. The present study examined the effect of nitrous oxide on the recovery characteristics of propofol anaesthesia, and compared these data with those for halothane/nitrous oxide anaesthesia. Sixty children aged 3–12 years were assigned at random to receive one of three maintenance regimens: propofol with or without nitrous oxide (70%) or halothane/nitrous oxide (70%). During propofol/N₂O anaesthesia, the infusion rate of propofol (180±39 μg·kg⁻¹·min⁻¹) required to maintain the mean arterial pressure and heart rate within 20% of the baseline values was significantly less than that during propofol/O₂ (220±37 μg·kg⁻¹·min⁻¹; P <0.005). The time from discontinuation of anaesthesia to eye-opening (11±6 min), to response to commands (12±6 min), and to return of full wakefulness (21±10 min) after propofol/N₂O were similar to those after propofol/O₂, but significantly less (by approximately 30%) than those after halothane ( P <0.05). The overall incidence of emesis after propofol/N₂O (53%) was greater than that after propofol/O₂ (17%, P <0.05) and comparable to that after halothane/N₂O (58%). These data suggest that N₂O has little effect on the rate of recovery after propofol, but significantly increases the incidence of postoperative emesis, thereby attenuating one of the main attributes of propofol anaesthesia.     

Effects of induced hypotension on arterial blood–gases under spontaneous breathing

The effects of deliberate hypotension on both Pao₂ and Paco₂ were investigated under isoflurane anaesthesia with spontaneous breathing from a laryngeal mask. Lumbar epidural block was introduced; anaesthesia was induced with thiamylal (4 mg kg^-1) and maintained with 0.5% isoflurane in nitrous oxide (4 1 min^-1) and oxygen (2 1 min^-1) under spontaneous breathing. After that nitroglycerin, trimetaphan or prostaglandin E₁ were used to induce a hypotension of 70% of control. All three drugs significantly decreased Pao₂, from 19.9 ± 3.3, 19.2 ±2.7, and 19.6 ± 3.1 kPa to 14.6 ± 1.9, 16.6 ± 2.2, and 16.2 ± 2.4kPa (mean ± s.d.), respectively; none of them increased Paco₂. In spite of the sparing of functional residual capacity under spontaneous breathing, the levels of reduction of Pao₂ were the same as levels reported in paralyzed and mechanically ventilated subjects. In conclusion, under deliberate hypotension Pao₂ decreases to a considerable degree, even under spontaneous breathing, presumably not because of alveolar hypoventilation, but because of the suppression of hypoxic pulmonary vasoconstriction by the drugs used in this study.     

Aortic cross-clamping influences regional net release and uptake rates of tissue-type plasminogen activator in pigs

Background: The key regulator of intravascular fibrinolysis, tissue-type plasminogen activator (t-PA), is released from a dynamic endothelial storage pool. The aim of the study was to investigate regional t-PA net release and uptake rates in response to infra-renal aortic cross-clamping (AXC) and declamping (DC).
Results: Prior to AXC, we found a high net release rate of total t-PA across the preportal vascular bed (1700 ng.min^-1, P < 0.001), and a high hepatic net uptake (4900 ng.min^-1, P < 0.001), while coronary and pulmonary t-PA net fluxes were small and variable. AXC per se did not induce significant alterations in net fluxes of t-PA. Following DC, preportal and coronary net releases of total t-PA increased (to 2900 ng · min^-1 and 60 ngemin^-1, respectively). Despite an increase in hepatic net uptake of total t-PA (to 6100 ng.min^-1) after DC, a significant increase in hepatic venous total t-PA occurred.
Methods: Anesthetized pigs were studied during 5 min of AXC, followed by a 35-min declamping (DC) period. Arterio-venous concentration gradients of total and active t-PA, as well as respective plasma flows, were simultaneously obtained across the preportal, hepatic, coronary and pulmonary vascular beds. Plasma levels of total t-PA (ELISA with purified porcine t-PA as standard), and active t-PA (spectrophotometric functional assay) were determined.
Conclusions: The release and uptake of t-PA is indicated to be dynamic and organ-specific. DC induces an acute profibrinolytic reaction in preportal organs. The high hepatic t-PA uptake capacity restricts preportal profibrinolytic events to affect the systemic circulation.     

Low-flow anaesthesia at a fixed flow rate

Aims and Objectives: This study attempts to assess the safety of low-flow anaesthesia (LFA) at fixed flow rates with particular reference to the incidence of a decline in FiO₂ below safe levels of 0.3 and to determine whether LFA can be used safely in the absence of an FiO₂ monitor.
Methods: A total of 100 patients undergoing procedures under general anaesthesia at fresh gas flows of 300 ml/min of O₂ and 300 ml/min of N₂O were monitored while maintaining the dial setting of isoflurane at 1.5% for 2 h. The changes in gas composition were analysed and even a single recording of FiO₂ of <0.3 was considered sufficient to render the technique unsafe in the absence of gas monitors.
Results: The lowest recorded value of FiO₂ was 31% (v/v%). There was no incidence of adverse events necessitating the conversion from low flows to conventional flows.
Conclusions: We conclude that low flows of 300 ml/min of N₂O and 300 ml/min of oxygen can be used safely for a period of 2 h without the use of monitors for gas analysis of oxygen and agent in adult patients weighing between 40 and 75 kgs.     

Changes in CMRO2, EEG and concentration of etomidate in serum and brain tissue during craniotomy with continuous etomidate supplemented with N2O and fentanyl

Fourteen patients with supratentorial cerebral tumours were anaesthetized with continuous etomidate infusion (30 or 60 μg kg^-1 min^-1) supplemented with N₂O 67% and fentanyl. Peroperatively cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMR_O2) were measured twice by the Kety and Schmidt method. Simultaneously with the CBF measurements, blood for serum etomidate was sampled and EEG was recorded in 2-min periods in 12 patients. In 10 patients a brain biopsy for etomidate was taken peroperatively and correlated with the other data. The results indicate a dose-dependant increase in scrum etomidate and brain tissue etomidate, a decrease in CMR_o2 and suppression of EEG activity. In individual studies an increase in serum etomidate or a decrease in CMR_o2 correlated to a suppression of the EEG activity, and vice versa . However, the wide variations in these relationships within and between patients make any conclusion regarding CMR_o2 impossible from the EEG recording, infusion rate of etomidate or scrum concentration of etomidate.     

A simplified concept for controlling oxygen mixtures in the anaesthetic machine — better,cheaper and more user-friendly?

Modern anaesthetic machines are equipped with several safety components to prevent delivery of hypoxic mixtures. However, such a technical development has increased the complexity of the equipment. We report a reconstructed anaesthetic machine in which a paramagnetic oxygen analyzer has provided the means to simplify the apparatus. The new machine is devoid of several components conventionally included to prevent hypoxic mixtures: oxygen failure protection device, reservoir O₂ alarm, N₂O/air selector, and proportioning system for oxygen/nitrous oxide delivery. These devices have been replaced by a simple safety system using a paramagnetic oxygen analyzer at the common gas outlet, which in a feed-back system cuts off the supply of nitrous oxide whenever the oxygen concentration falls below 25%. The simplified construction of the anaesthetic machine has important consequences for safety, cost and user-friendliness. Reducing the complexity of the construction also simplifies the pre-use checkout procedure, and an efficient 5-point check list is presented for the new machine.     

Subcutaneous blood flow in man during sleep with continuous epidural anaesthesia

Background: Subcutaneous blood flow increases during sleep and we evaluated if this increase is affected by epidural anaesthesia.
Methods: Lower leg subcutaneous blood flow was determined by ¹³³Xenon clearance in ten subjects during continuous epidural anaesthesia at L₂-L₃ including eight hours of sleep, while the upper abdominal subcutaneous blood flow served as control.
Results: Epidural anaesthesia to the level of the umbilicus was followed by an increase in the lower leg subcutaneous blood flow from 3.4 (1.8-6.3) to 7.8 (3.6–16.9) ml min^-1 100 g^-1 (median and range; P <0.001) and returned to 3.5 (2.4–7.6) ml min^-1 100 g^-1 after 88 (45–123) min. In contrast, until the period of sleep the upper abdominal region blood flow remained at 5.2 (3.2–6.4) ml min^-1 100 g^-1. During sleep, lower leg subcutaneous blood flow did not change significantly, but the upper abdominal flow increased to 6.2 (5.2–7.2) ml min^-1 100 g^-1 after 34 (29–70) min ( P <0.01), and it remained elevated for 125 (100–164) min.
Conclusions: The results indicate that although epidural anaesthesia induced only a temporary increase in lower leg subcutaneous blood flow, it hindered the rise in subcutaneous blood flow normally manifest during early sleep.     

Haemodynamics and Oxygen Consumption in the Dog During High Epidural Block with Special Reference to the Splanchnic Region

High epidural block (Th I-IV) with bupivacaine was carried out in 16 dogs. Mean arterial blood pressure decreased to 52% of control value owing to nearly equal decreases in systemic vascular resistance and cardiac output. Portal venous blood flow decreased from 25.8 ± 8.6 to 16.7 ±7.2 ml/kg b.w. × min^-1 following epidural block, while hepatic arterial blood flow remained unchanged at 9.1 ± 3.1 ml/kg b.w. × min^-1 owing to a reduction in hepatic arterial resistance of 51 %. Hepatic oxygen uptake was maintained during the epidural block through increased oxygen extraction. However, total oxygen uptake decreased by 18 % and, in spite of this, arteriovenous oxygen content difference increased by 25%, indicating circulatory depression.     

Intestinal Vascular Responses to Dopamine During Fentanyl-Nitrous Oxide Anaesthesia, Supplemented with Dixyrazin

Intestinal haemodynamics in response to continuous i.v. administration of dopamine were investigated in cats anaesthetized with fentanyl-nitrous oxide either with or without supplement of dixyrazin. A dose-dependent vasodilatation was observed in the dopamine dose range 2.5–35 μg-kg^-1 min ^-1 and the subsequent maximal intestinal blood flow increase was 121%. No net intestinal vasoconstriction was evident even at the largest dopamine doses, although the vascular response reached a plateau at 17.5 μg-kg^-1 min^-1. Control experiments during chloralose anaesthesia gave similar results. Changes in mean arterial pressure and heart rate were small. Renal blood flow was virtually unchanged at dopamine doses below 10 μg-kg^-1 min^-1, while renal vasoconstriction was evident following dopamine doses above that level. The addition of i.v. dixyrazin (0.15-0.30 mg kg^-1) to the fentanyl-nitrous oxide anaesthesia substantially potentiated the intestinal vasodilator response to i.v. dopamine and the maximal blood flow increase was 183% at 10–15 μg kg^-1 min^-1. In vitro experiments using mesenteric resistance vessels from the rat demonstrated a dose-dependent relaxation to dopamine. At very large doses this response was counteracted, but not reversed into vasoconstriction by dopamine-induced a-adrenergic stimulation.     

Classes of tissue hypoxia

We identify eight causes of tissue hypoxia, falling into three classes, A, B, and C, depending upon the effect on the critical mixed venous p O₂ and the optimal oxygen consumption rate. The critical mixed venous p O₂ is the value above which the oxygen consumption rate is optimal and independent of the mixed venous p O₂ and below which the oxygen consumption rate decreases towards zero. Class A hypoxia: primary decrease in mixed venous p O₂. Causes: 1) ischaemic hypoxia (decrease in cardiac output), 2) low-extractivity hypoxia (decrease in oxygen extraction tension, p ₈). Class B hypoxia: primary increase in critical mixed venous p O₂. Causes: 1) shunt hypoxia (increased a-v shunting), 2) dysperfusion hypoxia (increased diffusion length from erythrocytes to mitochondria and/or decreased total capillary endothelial diffusion area, e. g., tissue oedema, microembolism), 3) histotoxic hypoxia (inhibition of the cytochrome chain). Class C hypoxia: primary increase in optimal oxygen consumption rate. Causes: 1) uncoupling hypoxia (uncoupling of the ATP formation associated with O₂ reduction), 2) hypermetabolic hypoxia (increased energy metabolism, e. g., due to hyperthermia).     

Effects of Ultrathin Silicone Coating of Porous Membrane on Gas Transfer and Hemolytic Performance

Abstract: To assess the effect of an ultrathin (0.2 μm) silicone-coated microporous membrane oxygenator on gas transfer and hemolytic performance, a silicone-coated capillary membrane oxygenator (Mera HP Excelung-prime, HPO-20H-C, Senko Medical Instrument Mfg. Co., Ltd. Tokyo, Japan) was compared with a noncoated polypropylene microporous membrane oxygenator of the same model and manufacturer using an in vitro test circuit. The 2 oxygenators showed little difference in the oxygen (O₂) transfer rate over a wide range of blood flow rates (1 L/min to 8 L/min). The carbon dioxide (CO₂) transfer rate was almost the same in both devices at low blood flow rates. but the silicone-coated oxygenator showed a decrease of more than 20% in the CO₂ transfer rate at higher blood flow rates. This loss in performance could be partly attenuated by increasing the gas/blood flow ratio from 0.5 or 1.0 to 2.0. In the hemolysis study, the silicone-coated membrane oxygenator showed a smaller increase in plasma free hemoglobin than the noncoated oxygenator. The pressure drop across both oxygenators was the same. These results suggest that the ultrathin silicone-coated porous membrane oxygenator may be a useful tool for long-term extracorporeal lung support while maintaining a sufficient gas transfer rate and causing less blood component damage.     

Air contamination of a closed anesthesia circuit

Closed-circuit anesthesia (CCA) has certain advantages such as decreased cost, decreased anesthetic gas pollution, improved in-halational gas humidity and temperature in comparison to conventional inhalational anesthesia using a high fresh gas flow, i.e. more than 2 L. min^-1, with a semi-closed breathing circuit. The main disadvantage of CCA is the possibility of hypoxic anesthetic gas delivery. This potentially lethal situation is caused by an insufficient oxygen flow rate for the body metabolism or by the accumulation of inactive gas, usually nitrogen, within the breathing circuit in spite of a sufficient oxygen concentration in the fresh gas supply to the breathing circuit. In the latter case, the accumulation of inactive gas may also lead an increased risk of awareness because of its dilution effect on the concentrations of inhalational anesthetics. We herein present a case of air contamination of the breathing circuit through a sampling line of an anesthetic gas monitor. The air caused a decrease in the oxygen concentration during closed circuit anesthesia.     

Intramuscular dexmedetomidine premedication—an alternative to midazolam-fentanyl-combination in elective hysterectomy?

Sedation, anxiolysis, intubation responses and fentanyl anaesthetic requirements were investigated in a double-blind, randomized study in twenty ASA I-II elective hysterectomy patients. Ten patients received dexmedetomidine 2.5 μg kg^-1 i.m. 60 min before induction and saline placebo i.v. 2 min prior to induction (= DP group). Ten patients received midazolam 0.08 mg kg^-1 i.m. 60 min and fentanyl 1.5 μg kg^-1 i.v. (= MF group) 2 min before induction of anaesthesia with thiopentone 4 mg kg^-1. Anaesthesia was maintained with 70% nitrous oxide in oxygen and with fentanyl 2 μg kg^-1 i.v. increments according to predetermined criteria. Both premedications induced sedation ( P < 0.01 in both groups) and anxiolysis ( P < 0.01 in DP vs <0.05 in MF group) without any differences between the groups. Haemodynamic changes following tracheal intubation did not significantly differ between the groups. Intraoperatively systolic and diastolic arterial pressure were 15% and 13% lower in DP group ( P < 0.01 and P < 0.05 for drug effect), the mean heart rate was approximately 9 beats min^-1 lower in DP group (n.s.). Fentanyl was required more often in MF group: median 3.5 (QD 1.5) vs. 2.5 (QD 0.5) times in DP group ( P < 0.05), the total amount being 57% smaller in DP group: 0.03 (QD 0.01) vs. 0.07 (QD 0.02) μg kg^-1 min^-1 ( P < 0.05). Postoperative course and analgesic requirements were similar in both groups. Dexmedetomidine premedication may offer an alternative to current anaesthesia practice in elective hysterectomy.