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Extreme heat caused by climate change is increasing the transmission of infectious diseases, resulting in a sharp rise in heat-related illness and mortality. Understanding the mechanistic link between heat, inflammation, and disease is thus important for public health. Thermal hyperpnea, and consequent respiratory alkalosis, is crucial in febrile seizures and convulsions induced by heat stress in humans. Here, we address what causes thermal hyperpnea in neonates and how it is affected by inflammation. Transient receptor potential cation channel subfamily V member 1 (TRPV1), a heat-activated channel, is sensitized by inflammation and modulates breathing and thus may play a key role. To investigate whether inflammatory sensitization of TRPV1 modifies neonatal ventilatory responses to heat stress, leading to respiratory alkalosis and an increased susceptibility to hyperthermic seizures, we treated neonatal rats with bacterial LPS, and breathing, arterial pH, in vitro vagus nerve activity, and seizure susceptibility were assessed during heat stress in the presence or absence of a TRPV1 antagonist (AMG-9810) or shRNA-mediated TRPV1 suppression. LPS-induced inflammatory preconditioning lowered the threshold temperature and latency of hyperthermic seizures. This was accompanied by increased tidal volume, minute ventilation, expired CO 2 , and arterial pH (alkalosis). LPS exposure also elevated vagal spiking and intracellular calcium concentrations in response to hyperthermia. TRPV1 inhibition with AMG-9810 or shRNA reduced the LPS-induced susceptibility to hyperthermic seizures and altered the breathing pattern to fast shallow breaths (tachypnea), making each breath less efficient and restoring arterial pH. These results indicate that inflammation exacerbates thermal hyperpnea-induced respiratory alkalosis associated with increased susceptibility to hyperthermic seizures, primarily mediated by TRPV1 localized to vagus neurons.

We tested the hypothesis that increasing the respiratory control systems' arterial PCO 2 equilibrium point via induced acute metabolic alkalosis by ingestion of sodium bicarbonate (NaHCO 3 , 0.3 g/kg) would decrease the ventilatory equivalent for CO 2 (V̇ E /V̇CO 2 ) at its lowest point ("nadir") during constant-load cycle exercise testing performed at 80 % of peak power output in 18 healthy young adults. Compared to the sodium chloride (4 g) control condition, ingestion of NaHCO 3 : increased arterialized venous pH, HCO 3 - and PCO 2 at rest by 0.05 ± 0.01 units (mean ± SE), 6.4 ± 0.4 mEq/L and 4.3 ± 0.7 mmHg, respectively (all p < 0.0001); and decreased the V̇ E /V̇CO 2 nadir during exercise by 9.4 % (p < 0.0001) secondary to a 4.7 ± 1.8 L/min decrease in V̇ E (p = 0.019). In conclusion, induced acute metabolic alkalosis by ingestion of NaHCO 3 decreased the V̇ E /V̇CO 2 response to strenuous exercise in healthy adults., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Respiratory acidosis and subsequent metabolic compensation are well-studied processes in fish exposed to elevated CO 2 (hypercapnia). Yet, such exposures in the marine environment are invariably accompanied by a return of environmental CO 2 to atmospheric baselines. This understudied phenomenon has the potential to cause a respiratory alkalosis that would necessitate base excretion. Here we sought to explore this question and the associated physiological mechanisms that may accompany base excretions using the red drum (Sciaenops ocellatus). As expected, when high pCO 2 (15,000 μatm CO 2 ) acclimated red drum were transferred to normal pCO 2 , their net H + excretion shifted from positive (0.157 ± 0.044 μmol g -1  h -1 ) to negative (-0.606 ± 0.116 μmol g -1  h -1 ) in the 2 h post-transfer period. Net H + excretion returned to control rates during the 3 to 24 h flux period. Gene expression and enzyme activity assays demonstrated that while the acidosis resulted in significant changes in several relevant transporters, no significant changes accompanied the alkalosis phase. Confocal microscopy was used to assess alkalosis-stimulated translocation of V-type H + ATPase to the basolateral membrane previously seen in other marine species; however, no apparent translocation was observed. Overall, these data demonstrate that fluctuations in environmental CO 2 result in both acidic and alkalotic respiratory disturbances; however, red drum maintain sufficient regulatory capacity to accommodate base excretion. Furthermore, this work does not support a role for basolateral VHA translocation in metabolic compensation from a systemic alkalosis in teleosts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The aim of this study was to investigate the effect of pre-induced inspiratory muscle fatigue (IMF) on race-paced swimming and acid-base status. Twenty-one collegiate swimmers performed two discontinuous 400-m race-paced swims on separate days, with (IMF trial) and without (control trial) pre-induced IMF. Swimming characteristics, inspiratory and expiratory mouth pressures, and blood parameters were recorded. IMF and expiratory muscle fatigue (P < 0.05) were evident after both trials and swimming time was slower (P < 0.05) from 150-m following IMF inducement. Pre-induced IMF increased pH before the swim (P < 0.01) and reduced bicarbonate (P < 0.05) and the pressure of carbon dioxide (PCO 2 ) (P < 0.05). pH (P < 0.05), bicarbonate (P < 0.01) and PCO 2 (P < 0.05) were lower during swimming in the IMF trial. Blood lactate was similar before both trials (P > 0.05) but was higher (P < 0.01) in the IMF trial after swimming. Pre-induced IMF induced respiratory alkalosis, reduced bicarbonate buffering capacity and slowed swimming speed. Pre-induced and propulsion-induced IMF reflected metabolic acidosis arising from dual role breathing and propulsion muscle fatigue.

The venous-arterial difference in CO 2 (ΔCO 2 ) has been proposed as an index of the adequacy of tissue perfusion in shock states. We hypothesized that the variation in PaCO 2 (hyper- or hypocapnia) could impact ΔCO 2 , partly through microcirculation adaptations. Fifteen healthy males volunteered to participate. For hypocapnia condition (hCO 2 ), the subjects were asked to hyperventilate, while they were asked to breathe a gas mixture containing 8 % CO 2 for hypercapnia condition (HCO 2 ). The 2 conditions were randomly assigned. Blood gases were measured at baseline before each condition, and after 5-7 min of either hCO 2 or HCO 2 condition. Microcirculation was assessed by the muscle reoxygenation slope measured with near infrared spectroscopy following a vascular occlusion test and by skin circulation with in vivo reflectance confocal microscopy. ΔCO 2 was significantly increased with hCO 2 while it tended to decrease with HCO 2 (non-significant). HCO 2 induced a moderate increase of the resaturation slope of NIRS oxygenation. Skin microcirculatory blood flow significantly dropped with hCO 2 , while it remained unchanged with hypercapnia. Our results warrant cautious interpretation of ΔCO 2 as an indicator of tissue perfusion during respiratory alkalosis.

Respiratory alkalosis, or primary hypocapnia, occurs when alveolar ventilation exceeds that required to eliminate the carbon dioxide produced by tissues. Concurrent decreases in Paco 2 , increases in pH, and compensatory decreases in blood HCO 3 - levels are associated with respiratory alkalosis. Respiratory alkalosis can be acute or chronic, with metabolic compensation initially consisting of cellular uptake of HCO 3 - and buffering by intracellular phosphates and proteins. Chronic respiratory alkalosis results in longer-lasting decreases in renal reabsorption of HCO 3 - ; the arterial pH can approach near-normal values., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The regulation of the acid-base balance and pH is critical for the organism. The most important buffer system is CO 2 / HCO 3 - . The kidney controls systemic bicarbonate and therefore the metabolic regulation and the lung is relevant for respiratory regulation by an effective CO 2 elimination. There are four acid-base disorders with two metabolic and two respiratory disorders (acidosis and alkalosis). The anion gap enables a further workup of metabolic acidosis., (© Georg Thieme Verlag KG Stuttgart · New York.)

This study compared the ventilation response to an incremental ergometer exercise at two altitudes: 633 mmHg (resident altitude = 1,600 m) and following acute decompression to 455 mmHg (≈4,350 m altitude) in eight male cyclists and runners. At 455 mmHg, the V E STPD at RER <1.0 was significantly lower and the V E BTPS was higher because of higher breathing frequency; at VO 2 max, both V E STPD and V E BTPS were not significantly different. As percent of VO 2 max, the V E BTPS was nearly identical and V E STPD was 30% lower throughout the exercise at 455 mmHg. The lower V E STPD at lower pressure differs from two classical studies of acclimatized subjects (Silver Hut and OEII), where V E STPD at submaximal workloads was maintained or increased above that at sea level. The lower V E STPD at 455 mmHg in unacclimatized subjects at submaximal workloads results from acute respiratory alkalosis due to the initial fall in HbO 2 (≈0.17 pHa units), reduction in PACO 2 (≈5 mmHg) and higher PAO 2 throughout the exercise, which are partially pre-established during acclimatization. Regression equations from these studies predict V E STPD from VO 2 and P B in unacclimatized and acclimatized subjects. The attainment of ventilatory acclimatization to altitude can be estimated from the measured vs. predicted difference in V E STPD at low workloads after arrival at altitude.

Unlabelled: Relatively long-lasting metabolic alkalizing procedures such as bicarbonate ingestion have potential for improving performance in long-sprint to middle-distance events. Within a few minutes, hyperventilation can induce respiratory alkalosis. However, corresponding performance effects are missing or equivocal at best., Purpose: To test a potential performance-enhancing effect of respiratory alkalosis in a 30-s Wingate Anaerobic Test (WAnT)., Methods: 10 men (mean ± SD age 26.6 ± 4.9 y, height 184.4 ± 6.1 cm, body-mass test 1 80.7 ± 7.7 kg, body-mass test 2 80.4 ± 7.2 kg, peak oxygen uptake 3.95 ± 0.43 L/min) performed 2 WAnTs, 1 with and 1 without a standardized 15-min hyperventilation program pre-WAnT in randomized order separated by 1 wk., Results: Compared with the control condition, hyperventilation reduced (all P < .01) pCO2 (40.5 ± 2.8 vs 22.5 ± 1.6 mm Hg) and HCO3 - (25.5 ± 1.7 vs 22.7 ± 1.6 mmol/L) and increased (all P < .01) pH (7.41 ± 0.01 vs 7.61 ± 0.03) and actual base excess (1.4 ± 1.4 vs 3.2 ± 1.6 mmol/L) pre-WAnT with an ergogenic effect on WAnT average power (681 ± 41 vs 714 ± 44 W) and total metabolic energy (138 ± 12 vs. 144 ± 13 kJ) based on an increase in glycolytic energy (81 ± 13 vs 88 ± 13 kJ)., Conclusion: Hyperventilation-induced respiratory alkalosis can enhance WAnT cycling sprint performance well in the magnitude of what is seen after successful bicarbonate ingestion.

Purpose: Acid-base disturbances were investigated in patients with cirrhosis in relation to hemodynamic derangement to analyze the hyperventilatory effects and the metabolic compensation., Methods: A total of 66 patients with cirrhosis and 44 controls were investigated during a hemodynamic study., Results: Hyperventilatory hypocapnia was present in all patients with cirrhosis and progressed from Child class A to C (P<0.01). Arterial pH increased significantly from class A to C (P<0.001) and was correlated inversely to the mean arterial blood pressure (r=-0.30, P<0.02), systemic vascular resistance (r=-0.25, P<0.05), indocyanine green clearance (r=-0.37, P<0.005), and serum sodium (r=-0.38, P<0.002). Metabolic compensation was shown by a reduced standard base excess in all patients (P<0.001). Standard base excess contained elements related to changes in serum albumin, water dilution, and effects of unidentified ions (all P<0.001). A significant hepatic component in the acid-base disturbances could not be identified., Conclusion: Hypocapnic alkalosis is related to disease severity and hyperdynamic systemic circulation in patients with cirrhosis. The metabolic compensation includes alterations in serum albumin and water retention that may result in a delicate acid-base balance in these patients.

Purpose: Hyperventilation, implemented during recovery of repeated maximal sprints, has been shown to attenuate performance decrement. This study evaluated the effects of hyperventilation, using strength exercises, on muscle torque output and EMG amplitude., Methods: Fifteen power-trained athletes underwent maximal isokinetic knee extensions consisting of 12 repetitions × 8 sets at 60°/s and 25 repetitions × 8 sets at 300°/s. The inter-set interval was 40 s for both speeds. For the control condition, subjects breathed spontaneously during the interval period. For the hyperventilation condition, subjects hyperventilated for 30 s before each exercise set (50 breaths/min, PETCO2: 20-25 mmHg). EMG was recorded from the vastus medialis and lateralis muscles to calculate the mean amplitude for each contraction., Results: Hyperventilation increased blood pH by 0.065-0.081 and lowered PCO2 by 8.3-10.3 mmHg from the control values (P < 0.001). Peak torque declined with repetition and set numbers for both speeds (P < 0.001), but the declining patterns were similar between conditions. A significant, but small enhancement in peak torque was observed with hyperventilation at 60°/s during the initial repetition phase of the first (P = 0.032) and fourth sets (P = 0.040). EMG amplitude also declined with set number (P < 0.001) for both speeds and muscles, which was, however, not attenuated by hyperventilation., Conclusion: Despite a minor ergogenic effect in peak torque at 60°/s, hyperventilation was not effective in attenuating the decrement in torque output at 300°/s and decrement in EMG amplitude at both speeds during repeated sets of maximal isokinetic knee extensions.

Normal cerebrovascular adaptation during pregnancy is poorly understood. We document a case study of progressively increased cerebrovascular reactivity to CO2, despite no change in resting blood flow, from prepregnancy to late gestation in a 36-year-old normotensive participant. Increased cerebral reactivity was related to progressive chronic respiratory alkalosis and specifically elevated pH and reduced HCO3(-). These novel data serve as important indicators of normative maternal cerebral adaptation and highlight novel areas of future study.

Background: In vitro and animal experiments have shown that the transport and signaling of β2-adrenergic agonists are pH-sensitive. Inhaled albuterol, a hydrophilic β2-adrenergic agonist, is widely used for the treatment of obstructive airway diseases. Acute exacerbations of obstructive airway diseases can be associated with changes in ventilation leading to either respiratory acidosis or alkalosis thereby affecting albuterol responsiveness in the airway. The purpose of this study was to determine if airway pH has an effect on albuterol-induced vasodilation in the airway., Methods: Ten healthy volunteers performed the following respiratory maneuvers: quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation (to dissociate the effect of pH from the effect of ventilation). During these breathing maneuvers, exhaled breath condensate (EBC) pH and airway blood flow response to inhaled albuterol (ΔQ̇aw) were assessed., Results: Mean ± SE EBC pH (units) and ΔQ̇aw (μl.min(-1).mL(-1)) were 6.4 ± 0.1 and 16.8 ± 1.9 during quiet breathing, 6.3 ± 0.1 and 14.5 ± 2.4 during eucapnic hyperventilation, 6.6 ± 0.2 and -0.2 ± 1.8 during hypocapnic hyperventilation (p = 0.02 and <0.01 vs. quiet breathing), and 5.9 ± 0.1 and 2.0 ± 1.5 during hypercapnic hyperventilation (p = 0.02 and <0.02 vs quiet breathing)., Conclusions: Albuterol responsiveness in the airway as assessed by ΔQ̇aw is pH sensitive. The breathing maneuver associated with decreased and increased EBC pH both resulted in a decreased responsiveness independent of the level of ventilation. These findings suggest an attenuated response to hydrophilic β2-adrenergic agonists during airway disease exacerbations associated with changes in pH., Trial Registration: Registered at clinicaltrials.gov: NCT01216748 .

In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch (PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (Δf(R)) was larger in hyperoxia (65% FiO2), smaller in 15% FiO2, and absent in 12% FiO2. Tidal volume changes (ΔV(T)) followed the same trend. The effect of hypoxia on Δf(R) was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO2). Δf(R) was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion, RTN neurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN., (Copyright © 2015 the authors 0270-6474/15/350527-17$15.00/0.)

For people unaccustomed to high altitude, exposure to height often leads to Acute Mountain Sickness, with headaches, difficulty breathing and gastrointestinal symptoms. Nausea and loss of appetite may result in less calorie intake and weight loss. At altitudes greater than 4000 m about 50-80% of people are affected. After only short exposure, gastrointestinal mucosal lesions can occur, potentially leading to gastrointestinal bleeding and lessened hunger. Patients with inflammatory bowel disorders may develop an acute exacerbation. At high altitude, an induction of numerous metabolic processes can be observed, including increased iron absorption. While the pathophysiology of hypobaric hypoxia has been well documented for the respiratory and cardiovascular system, this Mini-Review summarizes the current literature concerning the gastrointestinal function in high altitude.

Introduction: Exposures to natural and simulated altitudes entail reduced oxygen availability and thus hypoxia. Depending on the level of hypoxia, the duration of exposure, the individual susceptibility, and preexisting diseases, health problems of variable severity may arise. Although millions of people are regularly or occasionally performing mountain sport activities, are transported by airplanes, and are more and more frequently exposed to short-term hypoxia in athletic training facilities or at their workplace, e.g., with fire control systems, there is no clear consensus on the level of hypoxia which is generally well tolerated by human beings when acutely exposed for short durations (hours to several days)., Conclusions: Available data from peer-reviewed literature report adaptive responses even to altitudes below 2,000 m or corresponding normobaric hypoxia (F(i)O(2) > 16.4%), but they also suggest that most of exposed subjects without severe preexisting diseases can tolerate altitudes up to 3,000 m (F(i)O(2) > 14.5%) well. However, physical activity and unusual environmental conditions may increase the risk to get sick. Large interindividual variations of responses to hypoxia have to be expected, especially in persons with preexisting diseases. Thus, the assessment of those responses by hypoxic challenge testing may be helpful whenever possible.

Acidification has been reported to provide protective effects on force production in vitro. Thus, in this study, we tested if respiratory acid-base changes influence muscle function and excitability in vivo. Nine subjects performed strenuous, intermittent hand grip exercises (10 cycles of 15 s of work/45 s of rest) under respiratory acidosis by CO(2) rebreathing, alkalosis by hyperventilation, or control. The Pco(2), pH, K(+) concentration ([K(+)]), and Na(+) concentration were measured in venous and arterialized blood. Compound action potentials (M-wave) were elicited to examine the excitability of the sarcolemma. The surface electromyogram (EMG) was recorded to estimate the central drive to the muscle. The lowest venous pH during the exercise period was 7.24 ± 0.03 in controls, 7.31 ± 0.05 with alkalosis, and 7.17 ± 0.04 with acidosis (P < 0.001). The venous [K(+)] rose to similar maximum values in all conditions (6.2 ± 0.8 mmol/l). The acidification reduced the decline in contraction speed (P < 0.001) but decreased the M-wave area to 73.4 ± 19.8% (P < 0.001) of the initial value. After the first exercise cycle, the M-wave area was smaller with acidosis than with alkalosis, and, after the second cycle, it was smaller with acidosis than with the control condition (P < 0.001). The duration of the M-wave was not affected. Acidification diminished the reduction in performance, although the M-wave area during exercise was decreased. Respiratory alkalosis stabilized the M-wave area without influencing performance. Thus, we did not find a direct link between performance and alteration of excitability of the sarcolemma due to changes in pH in vivo.

Hyperventilation causes respiratory alkalosis. The nervous system is more excitable in alkalosis. This phenomenon can be observed as paraesthesia in fingers and toes as well as around the lips in anxious patients breathing rapidly. We wanted to test this phenomenon on already irritable nerves like the median nerve in carpal tunnel syndrome (CTS). We deployed 50 patients who came in to the day case unit for carpal tunnel decompression with electro-physiologically proven diagnosis. We devised a test whereby patients were made to hyperventilate under prescribed conditions and repeated Phalen's test and Tinel's sign for comparison. These were compared with a control group chosen randomly among hospital staff. 86% patients had a positive result which was just behind Phalen's test in sensitivity. It was also 100% specific as there were no false positives. Hyperventilation is a phenomenon which provokes carpal tunnel syndrome. Its clinical value remains to be seen due to cumbersome method and probable patient non-compliance but it is a new discovery. It may be useful in other irritable-nerve-syndromes as a test to add to our available armament. It may be an additional factor or a primary reason for nocturnal paraesthesias in CTS patients.

Purpose: Febrile seizures (FS) are the most common type of convulsive events in children. FS are suggested to result from a combination of genetic and environmental factors. However, the pathophysiologic mechanisms underlying FS remain unclear. Using an animal model of experimental FS, it was demonstrated that hyperthermia causes respiratory alkalosis with consequent brain alkalosis and seizures. Here we examine the acid-base status of children who were admitted to the hospital for FS. Children who were admitted because of gastroenteritis (GE), a condition known to promote acidosis, were examined to investigate a possible protective effect of acidosis against FS., Methods: We enrolled 433 age-matched children with similar levels of fever from two groups presented to the emergency department. One group was admitted for FS (n = 213) and the other for GE (n = 220). In the FS group, the etiology of fever was respiratory tract infection (74.2%), otitis media (7%), GE (7%), tonsillitis (4.2%), scarlet fever (2.3%) chickenpox (1.4%), urinary tract infection (1.4%), postvaccination reaction (0.9%), or unidentified (1.4%). In all patients, capillary pH and blood Pco(2) were measured immediately on admission to the hospital., Key Findings: Respiratory alkalosis was found in children with FS (pH 7.46 ± 0.04, [mean ± standard deviation] Pco(2) 29.5 ± 5.5 mmHg), whereas a metabolic acidosis was seen in all children admitted for GE (pH 7.31 ± 0.03, Pco(2) 37.7 ± 4.3 mmHg; p < 0.001 for both parameters). No FS were observed in the latter group. A subgroup (n = 15; 7%) of the patients with FS had GE and, notably, their blood pH was more alkaline (pH 7.44 ± 0.04) than in the GE-admitted group. During the enrollment period, eight of the patients were admitted on separate occasions because of FS or GE. Consistent with the view that generation of FS requires a genetic susceptibility in addition to acute seizure triggering factors, each of these patients had an alkalotic blood pH when admitted because of FS, whereas they had an acidotic pH (and no FS) when admitted because of GE (pH 7.47 ± 0.05 vs. pH 7.33 ± 0.03, p < 0.005)., Significance: The results show that FS are associated with a systemic respiratory alkalosis, irrespective of the severity of the underlying infection as indicated by the level of fever. The lack of FS in GE patients is attributable to low pH, which also explains the fact that children with a susceptibility to FS do not have seizures when they have GE-induced fever that is associated with acidosis. The present demonstration of a close link between FS and respiratory alkalosis may pave the way for further clinical studies and attempts to design novel therapies for the treatment of FS by controlling the systemic acid-base status., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Acid/base homeostasis is one of the most difficult subdisciplines of physiology for medical students to master. A different approach, where theory and practice are linked, might help students develop a deeper understanding of acid/base homeostasis. We therefore set out to develop a laboratory exercise in acid/base physiology that would provide students with unambiguous and reproducible data that clearly would illustrate the theory in practice. The laboratory exercise was developed to include both metabolic acidosis and respiratory alkalosis. Data were collected from 56 groups of medical students that had participated in this laboratory exercise. The acquired data showed very consistent and solid findings after the development of both metabolic acidosis and respiratory alkalosis. All results were consistent with the appropriate diagnosis of the acid/base disorder. Not one single group failed to obtain data that were compatible with the diagnosis; it was only the degree of acidosis/alkalosis and compensation that varied.

Although much research has investigated the types of exercise that are enhanced with sodium bicarbonate (NaHCO3) ingestion, to date, there has been limited research on the dosage and timing of ingestion that optimizes the associated ergogenic effects. This study investigated the effects of various NaHCO3 loading protocols on the time-dependent blood-buffering profile. Eight male volunteers (age, 22.4 +/- 5.7 yr; height, 179.8 +/- 9.6 cm, body mass, 76.3 +/- 14.1 kg) completed Part A, measures of alkalosis throughout 120 minutes after ingestion of various single NaHCO3 dosages (0.3 gxkg-1, 0.2 gxkg-1, 0.1 gxkg-1, and placebo); and Part B, similar profiles after alternative NaHCO3 loading protocols (single morning dosage [SMD], single evening dosage [SED], and dosages ingested on 3 consecutive evenings [CED]). Results from Part A are as follows. Blood buffering in the 0.1 gxkg-1 condition was significantly lower than the 0.2 g.kg-1 and 0.3 gxkg-1 conditions (p < 0.002), but there was no significant differences between the 0.2 gxkg -1and 0.3 g.kg-1 conditions (p = 0.34). Although the blood buffering was relatively constant in the 0.1 and 0.2 conditions, it was significantly higher at 60 minutes than at 100 minutes and 120 minutes in the 0.3 gxkg-1 condition (p < 0.05). Results from Part B are as follows. Blood buffering for SMD was significantly higher than for SED and CED (p < 0.05). Blood buffering in the SMD condition was significantly lower at 17:00 hours than at 11:00 hours (p = 0.007). The single 0.2 and 0.3 gxkg-1 NaHCO3 dosages appeared to be the most effective for increasing blood-buffering capacity. The 0.2 gxkg-1 dosage is best ingested 40 to 50 minutes before exercise and the 0.3 gxkg-1 dosage 60 minutes before exercise.

In acute pulmonary embolism, patients free from circulatory failure usually present a blood gas pattern consistent with respiratory alkalosis. We investigated whether the appearance of arterial base deficit in these patients indicates disease severity and diagnostic delay. Twenty-four consecutive patients with pulmonary embolism were retrospectively evaluated. Twelve patients had arterial base excess > or =0 mmol/L (Group 1), and 12 patients arterial base deficit <0 mmol/L (Group 2). No patient showed signs of circulatory failure. Group 1 was characterized by a mean base excess of 2.2 +/- 1.7 mmol/L, while in Group 2, the mean base deficit was -1.9 +/- 0.7 mmol/L (p < 0.0001). At 1 week since the embolism, 11 patients of Group 1 and 6 of Group 2 received a PE diagnosis (p < 0.05). The vascular obstruction index was more severe in Group 2 than in Group 1 (48 +/- 12 vs. 36 +/- 17%, respectively, p < 0.05). In Group 2, the PaCO(2) was lower (33 +/- 3 vs. 36 +/- 5 mmHg, respectively, p < 0.05), the arterial pH was decreased (7.442 +/- 0.035 vs. 7.472 +/- 0.050, respectively, p = 0.097), the Pv(50) was lower (28.3 +/- 1.7 vs. 29.8 +/- 1.6 mmHg, respectively, p < 0.05), the aHCO(3) (-) was lower (22.5 +/- 0.7 vs. 26.1 +/- 1.6 mmol/L, respectively; p < 0.0001), while between the Groups, O(2) delivery, O(2) mixed venous saturation, and O(2) extraction ratio were equivalent. Despite no signs of circulatory failure, an arterial Base deficit develops in patients with respiratory alkalosis subsequent to more severe pulmonary vascular obstruction. Diagnostic delay favors a base deficit. Depending on the degree of hypocapnia, there may be limitation of peripheral O(2) uptake despite adequate O(2) availability. Progressive bicarbonate deficit suggests an increased risk for underlying conditions such as cardio-respiratory disorders or cancer, and requires close control and treatment.

The effect of hyperventilation-induced hypocapnic alkalosis (Hypo) on the adjustment of pulmonary O2 uptake (VO2p) and leg femoral conduit artery ("bulk") blood flow (LBF) during moderate-intensity exercise (Mod) was examined in eight young male adults. Subjects completed four to six repetitions of alternate-leg knee-extension exercise during normal breathing [Con; end-tidal partial pressure of CO2 (PetCO2) approximately 40 mmHg] and sustained hyperventilation (Hypo; PetCO2 approximately 20 mmHg). Increases in work rate were made instantaneously from baseline (3 W) to Mod (80% estimated lactate threshold). VO2p was measured breath by breath by mass spectrometry and volume turbine, and LBF (calculated from mean femoral artery blood velocity and femoral artery diameter) was measured simultaneously by Doppler ultrasound. Concentration changes of deoxy (Delta[HHb])-, oxy (Delta[O2Hb])-, and total hemoglobin-myoglobin (Delta[HbTot]) of the vastus lateralis muscle were measured continuously by near-infrared spectroscopy (NIRS). The kinetics of VO2p, LBF, and Delta[HHb] were modeled using a monoexponential equation by nonlinear regression. The time constants for the phase 2 VO2p (Hypo, 49+/-26 s; Con, 28+/-8 s) and LBF (Hypo, 46+/-16 s; Con, 23+/-6 s) were greater (P<0.05) in Hypo compared with Con. However, the mean response time for the overall Delta[HHb] response was not different between conditions (Hypo, 23+/-5 s; Con, 24+/-3 s), whereas the Delta[HHb] amplitude was greater (P<0.05) in Hypo (8.05+/-7.47 a.u.) compared with Con (6.69+/-6.31 a.u.). Combined, these results suggest that hyperventilation-induced hypocapnic alkalosis is associated with slower convective (i.e., slowed femoral artery and microvascular blood flow) and diffusive (i.e., greater fractional O2 extraction for a given DeltaVO2p) O2 delivery, which may contribute to the hyperventilation-induced slowing of VO2p (and muscle O2 utilization) kinetics.

Febrile seizures (FS) are the most common type of convulsive events in children. FS have been extensively studied using animal models, where rat and mice pups are placed in a hyperthermic environment. Such work has largely focused on the consequences rather than on the mechanisms of experimental febrile seizures (eFS). We have recently shown that eFS are preceded by a dramatic rise in the rate of respiration. The consequent respiratory alkalosis affecting the brain and increasing neuronal excitability is a direct cause of the eFS [1]. If a similar mechanism contributes to human FS and other fever-related epileptiform syndromes, a number of factors operating at the molecular, cellular and systems level that have not been previously thought to be involved in their etiology must be considered. These include physiological and pathophysiological factors affecting CO(2) chemosensitivity as well as cellular and systemic mechanisms of acid-base regulation. Furthermore, a critical role for brain pH in FS points to novel types of susceptibility genes, which include genes coding pH-sensitive target proteins (e.g. neuronal ion channels) and pH-regulatory proteins. We will discuss these novel ideas and putative therapies based on them.

Background: In acute respiratory alkalosis, the severity of alkalaemia is ameliorated by a decrease in plasma [HCO(3)(-)] of 0.2 mEq/L for each 1 mmHg decrease in PaCO(2). Although hyperventilation in panic disorder patients is frequently encountered in outpatients, the drop in plasma [HCO(3)(-)] sometimes surpasses the expectation calculated from the above formula. The quantitative relationship between reduced PaCO(2) and plasma [HCO(3)(-)] in acute respiratory alkalosis has not been studied in panic disorder patients. Our objective was to provide reference data for the compensatory metabolic changes in acute respiratory alkalosis in panic disorder patients., Methods: In 34 panic disorder patients with hyperventilation attacks, we measured arterial pH, PaCO(2), plasma [HCO(3)(-)] and lactate on arrival at the emergency room., Results: For each decrease of 1 mmHg in PaCO(2), plasma [HCO(3)(-)] decreased by 0.41 mEq/L. During hypocapnia, panic disorder patients exhibited larger increases in serum lactate levels (mean +/- SD; 2.59 +/- 1.50 mmol/L, range; 0.78-7.78 mmol/L) than previously reported in non-panic disorder subjects. Plasma lactate accumulation was correlated with PaCO(2) (P < 0.001)., Conclusions: These results suggest that the compensatory metabolic response to acute respiratory alkalosis is exaggerated by increased lactic acid production in panic disorder patients. Here, we call attention to the diagnosis of acid-base derangements by means of plasma [HCO(3)(-)] and lactate concentration in panic disorder patients.

Objective: To determine whether Labrador Retrievers participating in field trials develop respiratory alkalosis and hypocapnia primarily in conditions of high ambient temperatures., Animals: 16 Labrador Retrievers., Procedures: At each of 5 field trials, 5 to 10 dogs were monitored during a test (retrieval of birds over a variable distance on land [1,076 to 2,200 m]; 36 assessments); ambient temperatures ranged from 2.2 degrees to 29.4 degrees C. For each dog, rectal temperature was measured and a venous blood sample was collected in a heparinized syringe within 5 minutes of test completion. Blood samples were analyzed on site for Hct; pH; sodium, potassium, ionized calcium, glucose, lactate, bicarbonate, and total CO2 concentrations; and values of PvO2 and PvCO2. Scatterplots of each variable versus ambient temperature were reviewed. Regression analysis was used to evaluate the effect of ambient temperature (< or = 21 degrees C and > 21 degrees C) on each variable., Results: Compared with findings at ambient temperatures < or = 21 degrees C, venous blood pH was increased (mean, 7.521 vs 7.349) and PvCO2 was decreased (mean, 17.8 vs 29.3 mm Hg) at temperatures > 21 degrees C; rectal temperature did not differ. Two dogs developed signs of heat stress in 1 test at an ambient temperature of 29 degrees C; their rectal temperatures were higher and PvCO2 values were lower than findings in other dogs., Conclusions and Clinical Relevance: When running distances frequently encountered at field trials, healthy Labrador Retrievers developed hyperthermia regardless of ambient temperature. Dogs developed respiratory alkalosis and hypocapnia at ambient temperatures > 21 degrees C.

In a study using a heated chamber for induction of experimental febrile seizures (eFS) in rat pups, ictal activity was shown to be precipitated by a respiratory alkalosis (Schuchmann et al., 2006). In sharp contrast to this, in a recent review Dubé et al., (2007) suggest that the respiratory alkalosis is model specific, and that no increase in respiratory rate is observed in the widely used "hair dryer model" of eFS. The data in the present work, based on well-established techniques for measuring respiratory rates in rat pups, show a pronounced increase in the "hair dryer model" with values that are slightly higher than those recorded in the heated chamber model. Hence, a temperature-evoked increase in respiration is a common feature of these two models of eFS.

Dimethylsulfoxide (DMSO) is a solvent commonly used for the cryopreservation of autologous peripheral blood stem cells (APBSC). Side effects upon infusion of DMSO-cryopreserved APBSC mainly consist of nausea, emesis, chills, rigors, and cardiovascular events, such as bradyarrhythmia or hypotension. We report the case of a patient who received DMSO-cryopreserved APBSC after myeloablative chemotherapy for a relapsing lymphoma. The patient developed a rare reaction during the infusion manifesting as transient global amnesia. The clinical course during the reaction is described and an explanation of the possible causes is discussed. This observation underlines the need for an adequate DMSO depletion to limit neurotoxicity or other adverse manifestations.

We examined the cardiovascular and cerebrovascular responses to acute isocapnic (IH) and poikilocapnic hypoxia (PH) in 10 men (25.7 +/- 4.2 yr, mean +/- SD). Heart rate (HR), mean arterial pressure (MAP), and mean peak middle cerebral artery blood flow velocity (Vp) were measured continuously during two randomized protocols of 20 min of step IH and PH (45 Torr). HR was elevated during both IH (P < 0.01) and PH (P < 0.01), with no differences observed between conditions. MAP was modestly elevated across all time points during IH but only became elevated after 5 min during PH. During IH, Vp was elevated from baseline throughout the exposure with a consistent hypoxic sensitivity of approximately 0.34 cm x s(-1).%desaturation(-1) (P < 0.05). The Vp response to PH was biphasic with an initial decrease from baseline occurring at 79 +/- 23 s, followed by a subsequent elevation, becoming equivalent to the IH response by 10 min. The nadir of the PH response exhibited a hypoxic sensitivity of -0.24 cm x s(-1) x % desaturation(-1). When expressed in relation to end-tidal Pco2, a sensitivity of -1.08 cm x s(-1).Torr(-1) was calculated, similar to previously reported sensitivities to euoxic hypocapnia. Cerebrovascular resistance (CVR) was not changed during IH. During PH, an initial increase in CVR was observed. However, CVR returned to baseline by 20 min of PH. These data show the cerebrovascular response to PH consists of an early hypocapnia-mediated response, followed by a secondary increase, mediated predominantly by hypoxia.

The effect of voluntary hyperventilation-induced hypocapnic alkalosis (RALK) on pulmonary O2 uptake (VO2) kinetics and muscle deoxygenation was examined in young male adults (n=8) during moderate-intensity exercise. Subjects performed five repetitions of a step-transition in work rate from 20 W cycling to a work rate corresponding to 90% of the estimated lactate threshold during control (CON; PET,CO2, approximately 40 mmHg) and during hyperventilation (RALK; PET,CO2, approximately 20 mmHg). was measured breath-by-breath and relative concentration changes in muscle deoxy- (DeltaHHb), oxy- (DeltaO2Hb) and total (DeltaHbtot) haemoglobin were measured continuously using near-infrared (NIR) spectroscopy (Hamamatsu, NIRO 300). The time constant for the fundamental, phase 2, VO2 response (tau VO2) was greater (P<0.05) in RALK (48+/-11 s) than CON (31+/-9 s), while tauHHb was similar between conditions (RALK, 12+/-4 s; CON, 11+/-4 s). The DeltaHb(tot) was lower (P<0.05) in RALK than CON, prior to (RALK, -3+/-5 micromol l(-1); CON, -1+/-4 micromol l(-1)) and at the end (RALK, 1+/-6 micromol l(-1); CON, 5+/-5 micromol l(-1)) of moderate-intensity exercise. Although slower adaptation of during RALK may be related to an attenuated activation of PDH (and other enzymes) and provision of oxidizable substrate to the mitochondria (i.e. metabolic inertia), the present findings also suggest a role for a reduction in local muscle perfusion and O2 delivery.

The purpose of this study was to determine if increased environmental heat leads to hyperthermic-induced hypocapnia and associated alkalosis during prolonged self-paced cycling. Nine male cyclists completed three 100 km stochastic time trials in hot (34 degrees C), neutral (22 degrees C) and cold (10 degrees C) environments. Intermittent measurements of rectal and skin temperature, expired gases, blood pH, PaCO(2), PaO(2), and bicarbonate were made throughout. Rectal temperature increased significantly throughout all trials (P < 0.001) and was significantly correlated with increases in the ventilatory equivalent for carbon dioxide (Ve/ VCo2; r = 0.77; P < 0.001) and blood pH (r = 0.69; P < 0.05). Rectal temperature was also negatively correlated with a reduction in PaCO(2) (r = -0.80; P < 0.001). PaO(2) and bicarbonate concentration remained constant throughout all trials. This study has shown that prolonged self-paced cycling is associated with a hyperthermic-induced hyperventilation, causing a decrease in arterialized carbon dioxide tension and consequential respiratory alkalosis.

Febrile seizures are frequent during early childhood, and prolonged (complex) febrile seizures are associated with an increased susceptibility to temporal lobe epilepsy. The pathophysiological consequences of febrile seizures have been extensively studied in rat pups exposed to hyperthermia. The mechanisms that trigger these seizures are unknown, however. A rise in brain pH is known to enhance neuronal excitability. Here we show that hyperthermia causes respiratory alkalosis in the immature brain, with a threshold of 0.2-0.3 pH units for seizure induction. Suppressing alkalosis with 5% ambient CO2 abolished seizures within 20 s. CO2 also prevented two long-term effects of hyperthermic seizures in the hippocampus: the upregulation of the I(h) current and the upregulation of CB1 receptor expression. The effects of hyperthermia were closely mimicked by intraperitoneal injection of bicarbonate. Our work indicates a mechanism for triggering hyperthermic seizures and suggests new strategies in the research and therapy of fever-related epileptic syndromes.

Background: To evaluate the relationship between hypobaric hypoxia acclimatization and intraocular pressure (IOP) during ascent, acclimatization, and descent between 2286 m and 5050 m., Methods: The following acclimatization-indicative physiological parameters were compared daily with IOP changes in eight healthy climbers of the 2003 Greek Karakorum expedition in altitude stages between 500 m and 5050 m: hemoglobin oxygen saturation (PO2), resting heart rate, blood pressure, retinal findings, and the Lake Louise score for acclimatization grading., Results: IOP decreased significantly in the ascent phase (0.58 mmHg/100 m) and recovered (0.71 mmHg/100 m) during acclimatization and descent. A direct proportional correlation between decreases in PO2 and IOP was evaluated. Arterial blood pulse and pressure increased during acclimatization, while IOP decreased. No retinal hemorrhages were observed in well-acclimatized and incompletely acclimatized climbers., Conclusions: Every new active exposure to hypobaric hypoxia in the ascent phase induced a decrease in the IOP parallel to the PO2 decrease and to the level of acclimatization. The results from our study suggest that IOP changes are related to hypoxia-induced respiratory alkalosis and acclimatization stage, which could be used as a simple mobile screening test for acclimatization level to reveal acute mountain sickness and its severe consequences.

Acid-base disturbances, such as metabolic or respiratory alkalosis, are relatively common in critically ill patients. We examined the effects of alkalosis (hypocapnic or metabolic alkalosis) on alveolar fluid reabsorption in the isolated and continuously perfused rat lung model. We found that alveolar fluid reabsorption after 1 hour was impaired by low levels of CO2 partial pressure (PCO2; 10 and 20 mm Hg) independent of pH levels (7.7 or 7.4). In addition, PCO2 higher than 30 mm Hg or metabolic alkalosis did not have an effect on this process. The hypocapnia-mediated decrease of alveolar fluid reabsorption was associated with decreased Na,K-ATPase activity and protein abundance at the basolateral membranes of distal airspaces. The effect of low PCO2 on alveolar fluid reabsorption was reversible because clearance normalized after correcting the PCO2 back to normal levels. These data suggest that hypocapnic but not metabolic alkalosis impairs alveolar fluid reabsorption. Conceivably, correction of hypocapnic alkalosis in critically ill patients may contribute to the normalization of lung ability to clear edema.

Experimental studies suggest that both alkalinisation and sodium loading are effective in reducing cardiotoxicity independently. Species and experimental differences may explain why sodium bicarbonate appears to work by sodium loading in some studies and by a pH change in others. In the only case series, the administration of intravenous sodium bicarbonate to achieve a systemic pH of 7.5-7.55 reduced QRS prolongation, reversed hypotension (although colloid was also given) and improved mental status in patients with moderate to severe tricyclic antidepressant poisoning. This clinical study supports the use of sodium bicarbonate in the management of the cardiovascular complications of tricyclic antidepressant poisoning. However, the clinical indications and dosing recommendations remain to be clarified. Hypotension should be managed initially by administration of colloid or crystalloid solutions, guided by central venous pressure monitoring. Based on experimental and clinical studies, sodium bicarbonate should then be administered. If hypotension persists despite adequate filling pressure and sodium bicarbonate administration, inotropic support should be initiated. In a non-randomised controlled trial in rats, epinephrine resulted in a higher survival rate and was superior to norepinephrine both when the drugs were used alone or when epinephrine was used in combination with sodium bicarbonate. Sodium bicarbonate alone resulted in a modest increase in survival rate but this increased markedly when sodium bicarbonate was used with epinephrine or norepinephrine. Clinical studies suggest benefit from norepinephrine and dopamine; in an uncontrolled study the former appeared more effective. Glucagon has also been of benefit. Experimental studies suggest extracorporeal circulation membrane oxygenation is also of potential value. The immediate treatment of arrhythmias involves correcting hypoxia, electrolyte abnormalities, hypotension and acidosis. Administration of sodium bicarbonate may resolve arrhythmias even in the absence of acidosis and, only if this therapy fails, should conventional antiarrhythmic drugs be used. The class 1b agent phenytoin may reverse conduction defects and may be used for resistant ventricular tachycardia. There is also limited evidence for benefit from magnesium infusion. However, class 1a and 1c antiarrhythmic drugs should be avoided since they worsen sodium channel blockade, further slow conduction velocity and depress contractility. Class II agents (beta-blockers) may also precipitate hypotension and cardiac arrest.

Background: Contrast-enhanced echocardiography (CEE) using agitated saline can detect intrapulmonary vasodilatation (IPVD) in patients with hepatopulmonary syndrome (HPS). We estimated the pulmonary transit time of erythrocytes (PTT) by CEE, using microbubbles, and studied its relationship to arterial oxygenation in chronic liver disease., Methods: Sixteen patients with chronic liver disease and seven healthy subjects were studied. PTT was defined as the time between opacification of the right atrium and left atrium on CEE, using human serum albumin-air microbubble complexes with a mean diameter of 4 microm (Albunex). IPVD was detected by CEE with agitated saline. Arterial blood gases were analyzed with patients in the supine position, and while they were seated. Cardiac output (CO) was determined by Doppler echocardiography., Results: The mean PTT value for all of the patients was 4.0 +/- 1.4 s. One of the 3 patients who showed IPVD was normoxemic. Mild orthodeoxia was observed in the patients with abnormal alveolar-arterial oxygen difference (A-aDO2) values (>15 mmHg), but not in those with normal A-aDO2 values, or in the healthy subjects. PTT was correlated with PaO2 (r = 0.52; P < 0.05; n = 16) and A-aDO2 (r = -0.54; P < 0.05; n = 16) in the seated position. CO was significantly correlated with PTT (r = -0.62; P < 0.05; n = 15), but not with PaO2 and A-aDO2, in both positions., Conclusions: PTT may be a useful parameter for evaluating arterial oxygenation in patients with chronic liver disease with early HPS.

Previous reports suggest that an important characteristic of chemosensitive neurones is an unusually large change of steady-state intracellular pH in response to a change in extracellular pH (DeltapH(i)/DeltapH(o)). To determine whether such a correlation exists between neurones from the medullary raphe (a chemosensitive brain region) and hippocampus (a non-chemosensitive region), we used BCECF to monitor pH(i) in cultured neurones subjected to extracellular acid-base disturbances. In medullary raphe neurones, respiratory acidosis (5%--> 9% CO(2)) caused a rapid fall in pH(i) (DeltapH(i) approximately 0.2) with no recovery and a large DeltapH(i)/DeltapH(o) of 0.71. Hippocampal neurones had a similar response, but with a slightly lower DeltapH(i)/DeltapH(o) (0.59). We further investigated a possible link between pH(i) regulation and chemosensitivity by following the pH(i) measurements on medullary raphe neurones with an immunocytochemistry for tryptophan hydroxylase (a marker of serotonergic neurones). We found that the DeltapH(i)/DeltapH(o) of 0.69 for serotonergic neurones (which are stimulated by acidosis) was not different from either the DeltapH(i)/DeltapH(o) of 0.75 for non-serotonergic neurones (most of which are not chemosensitive), or from the DeltapH(i)/DeltapH(o) of hippocampal neurones. For both respiratory alkalosis (5%--> 3% CO(2)) and metabolic alkalosis (22 mm--> 35 mm HCO(3)(-)), DeltapH(i)/DeltapH(o) was 0.42-0.53 for all groups of neurones studied. The only notable difference between medullary raphe and hippocampal neurones was in response to metabolic acidosis (22 mm--> 14 mm HCO(3)(-)), which caused a large pH(i) decrease in approximately 80% of medullary raphe neurones (DeltapH(i)/DeltapH(o)= 0.71), but relatively little pH(i) decrease in 70% of the hippocampal neurones (DeltapH(i)/DeltapH(o)= 0.09). Our comparison of medullary raphe and hippocampal neurones indicates that, except in response to metabolic acidosis, the neurones from the chemosensitive region do not have a uniquely high DeltapH(i)/DeltapH(o). Moreover, regardless of whether neurones were cultured from the chemosensitive or the non-chemosensitive region, pH(i) did not recover during any of the acid-base stresses.

We present an 84-year-old man with a history of chronic obstructive pulmonary disease, type 2 diabetes, hypertension, glaucoma, and bladder cancer who presented to the emergency department after the police found him disoriented and confused. Metformin therapy began 3 days before, and he denied any overdose or suicidal ideation. Other daily medications included glipizide, fluticasone, prednisone, aspirin, furosemide, insulin, and potassium supplements. In the emergency department, his vital signs were significant for hypertension (168/90), tachycardia (120 bpm), and Kussmaul respirations at 24 breaths per minute. Oxygen saturation was 99% on room air, and a fingerstick glucose was 307 mg/dL. He was disoriented to time and answered questions slowly. Metformin was discontinued, and by day 3, the patient's vital signs and laboratory test results normalized. He has been asymptomatic at subsequent follow-up visits. Metformin-associated lactic acidosis is a well-known phenomenon. Respiratory alkalosis may be an early adverse event induced by metformin prior to the development of lactic acidosis.

Central neurogenic hyperventilation refers to progressive tachypnea leading to hypocarbia and respiratory alkalosis caused by cortical disorders, initially reported in comatose patients with mainly pontine infarction. Central neurogenic hyperventilation in conscious patients is even rarer, numbering around 30 reported cases including seven children, mainly associated with infiltrative gliomas and lymphomas of the brainstem and pons. We report the evolution of central neurogenic hyperventilation in a conscious child associated with an infiltrative glioblastoma multiforme diagnosed 1 year before admission. He presented with progressive tachypnea and dyspnea of 1 week duration. On examination he was fully alert and aware of his respiratory disorder. Respiratory rate was 56 breaths per minute using accessory respiratory muscles. Hyperventilation was unchanged during sleep. Arterial blood gases disclosed marked hypocarbia: Pco(2) of 8 mm Hg resulting in severe respiratory alkalosis at pH of 7.8. Central neurogenic hyperventilation was therefore suggested after exclusion of other respiratory or cardiac disorders. The exaggerated tachypnea persisted along with respiratory alkalosis. Over a period of 2 months his overall state markedly deteriorated; he lapsed into coma, and finally succumbed after involvement of medullary cardiovascular centers. Although extremely rare in the pediatric age group, central neurogenic hyperventilation should be suspected in any alert child presenting with unexplained increasing tachypnea and hypocarbia leading to respiratory alkalosis. The evolution of such a disorder may be an alarming sign of ensuing deterioration in patients with tumors of the brainstem and medulla before cardiovascular derangement.

One hundred and fifty-seven men with alcohol withdrawal syndrome, including 127 with delirium of different severity, have been studied. During delirium, sequestration of erythrocytes in the vessels and exudation of the fluid into the cellular space developed. There were marked capillary blood flow disturbances with erythrocyte aggregation, metabolic acidosis, compensated with respiratory alkalosis, total lactate dehydrogenase activity elevation, Na+ and K+ decrease in blood plasma and K+ reduction in erythrocytes in a severe form of alcohol delirium. The authors suggest that the complex of disorders observed is similar to shock process, and hemodynamic disturbances may be involved in the development of consciousness disorders.

Unlabelled: Acute alkalosis may directly affect PTH secretion. The effect of acute metabolic and respiratory alkalosis was studied in 20 dogs. PTH values were lower in the metabolic (5.6 +/- 0.8 pg/ml) and respiratory (1.8 +/- 0.6 pg/ml) alkalosis groups than in the control group (27 +/- 5 pg/ml). Acute alkalosis is an independent factor that decreases PTH values during normocalcemia and delays the PTH response to hypocalcemia., Introduction: We recently showed that acute metabolic and respiratory acidosis stimulated PTH secretion. This study was designed to evaluate whether acute metabolic and respiratory alkalosis suppressed parathyroid hormone (PTH) secretion., Materials and Methods: Three groups of 10 dogs were studied: control, acute metabolic alkalosis, and acute respiratory alkalosis. Metabolic alkalosis was induced with an infusion of sodium bicarbonate and respiratory alkalosis by hyperventilation. Calcium chloride was infused to prevent alkalosis-induced hypocalcemia during the first 60 minutes. During the next 30 minutes, disodium EDTA was infused to induce hypocalcemia and to evaluate the PTH response to hypocalcemia. Because the infusion of sodium bicarbonate resulted in hypernatremia, the effect of hypernatremia was studied in an additional group that received hypertonic saline., Results: After 60 minutes of a normocalcemic clamp, PTH values were less (p < 0.05) in the metabolic (5.6 +/- 0.8 pg/ml) and respiratory (1.8 +/- 0.6 pg/ml) alkalosis groups than in the control group (27 +/- 5 pg/ml); the respective blood pH values were 7.61 +/- 0.01, 7.59 +/- 0.02, and 7.39 +/- 0.02. The maximal PTH response to hypocalcemia was similar among the three groups. However, the maximal PTH response was observed after a decrease in ionized calcium of 0.20 mM in the control group but not until a decrease of 0.40 mM in the metabolic and respiratory alkalosis groups. In contrast to the metabolic alkalosis group, hypernatremia (157 +/- 2 mEq/liter) in the hypertonic saline group was associated with an increased PTH value (46 +/- 4 pg/ml). Finally, the half-life of intact PTH was not different among the control and two alkalosis groups., Conclusions: Acute metabolic and respiratory alkalosis markedly decreased PTH values during normocalcemia and delayed the PTH response to hypocalcemia. Whether acute metabolic and respiratory alkalosis affect PTH and calcium metabolism in such settings as the postprandial alkaline tide (metabolic alkalosis) and acute sepsis (respiratory alkalosis) deserves to be evaluated in future studies.

We determined the effects of changing ventilatory stimuli on the hypocapnia-induced apneic and hypopneic thresholds in sleeping dogs. End-tidal carbon dioxide pressure (PET(CO2)) was gradually reduced during non-rapid eye movement sleep by increasing tidal volume with pressure support mechanical ventilation, causing a reduction in diaphragm electromyogram amplitude until apnea/periodic breathing occurred. We used the reduction in PET(CO2) below spontaneous breathing required to produce apnea (DeltaPET(CO2)) as an index of the susceptibility to apnea. DeltaPET(CO2) was -5 mm Hg in control animals and changed in proportion to background ventilatory drive, increasing with metabolic acidosis (-6.7 mm Hg) and nonhypoxic peripheral chemoreceptor stimulation (almitrine; -5.9 mm Hg) and decreasing with metabolic alkalosis (-3.7 mm Hg). Hypoxia was the exception; DeltaPET(CO2) narrowed (-4.1 mm Hg) despite the accompanying hyperventilation. Thus, hyperventilation and hypocapnia, per se, widened the DeltaPET(CO2) thereby protecting against apnea and hypopnea, whereas reduced ventilatory drive and hypoventilation narrowed the DeltaPET(CO2) and increased the susceptibility to apnea. Hypoxia sensitized the ventilatory responsiveness to CO2 below eupnea and narrowed the DeltaPET(CO2); this effect of hypoxia was not attributable to an imbalance between peripheral and central chemoreceptor stimulation, per se. We conclude that the DeltaPET(CO2) and the ventilatory sensitivity to CO2 between eupnea and the apneic threshold are changeable in the face of variations in the magnitude, direction, and/or type of ventilatory stimulus, thereby altering the susceptibility for apnea, hypopnea, and periodic breathing in sleep.

Study Design: A pilot case control study of the acid-base and electrolyte status in 30 long-term ventilator-dependent (LTVD) and 30 self ventilating persons with tetraplegia., Objectives: To assess the extent of respiratory alkalosis and screen for associated hypokalaemia, hypomagnesaemia and/or hypophosphataemia., Setting: Medically stable persons with tetraplegia under the long-term care of the Southport Spinal Injuries Centre, England., Methods: Blood gases and electrolytes were sampled from 30 control patients with tetraplegia and from 30 patients having been LTVD for more than 12 months., Results: All the blood gas measurements in the LTVD group lay outside both the reference range and the 95% confidence intervals (CI) of the control group: pH 7.46 (0.06); PCO(2) 3.46 (1.1) kPa; bicarbonate 18.3 (3.8) and base excess -3.2 (2.8) mmol/l; PO(2) 13.8 (2.8) kPa (means and standard deviations). The serum potassium, magnesium, phosphate, and sodium means lay within the reference ranges but the potassium, phosphate and calcium were at or below the 95% CI of the control values. One patient on part-time ventilatory support having less bicarbonate compensation had low serum electrolytes during ventilation., Conclusion: There was no evidence of biochemical jeopardy from long-term mechanical hyperventilation although acutely administered hyperventilation has the potential to cause falls in serum potassium, magnesium and phosphate and so caution should be exercised in part-time ventilated persons. The full range of electrolytes should be assayed during stabilisation in LTVD and periodically thereafter. Hyperventilation helps to maintain good oxygenation in LTVD persons with paralysis and normal lungs., Sponsorship: None.

The decrease in brain CO(2) partial pressure (pCO(2)) that takes place both during voluntary and during pathological hyperventilation is known to induce gross alterations in cortical functions that lead to subjective sensations and altered states of consciousness. The mechanisms that mediate the effects of the decrease in pCO(2) at the neuronal network level are largely unexplored. In the present work, the modulation of gamma oscillations by hypocapnia was studied in rat hippocampal slices. Field potential oscillations were induced by the cholinergic agonist carbachol under an N-methyl-D-aspartate (NMDA)-receptor blockade and were recorded in the dendritic layer of the CA3 region with parallel measurements of changes in interstitial and intraneuronal pH (pH(o) and pH(i), respectively). Hypocapnia from 5 to 1% CO(2) led to a stable monophasic increase of 0.5 and 0.2 units in pH(o) and pH(i), respectively. The mean oscillation frequency increased slightly but significantly from 32 to 34 Hz and the mean gamma-band amplitude (20 to 80 Hz) decreased by 20%. Hypocapnia induced a dramatic enhancement of the temporal stability of the oscillations, as was indicated by a two-fold increase in the exponential decay time constant fitted to the autocorrelogram. A rise in pH(i) evoked by the weak base trimethylamine (TriMA) was associated with a slight increase in oscillation frequency (37 to 39 Hz) and a decrease in amplitude (30%). Temporal stability, on the other hand, was decreased by TriMA, which suggests that its enhancement in 1% CO(2) was related to the rise in pH(o). In 1% CO(2), the decay-time constant of the evoked monosynaptic pyramidal inhibitory postsynaptic current (IPSC) was unaltered but its amplitude was enhanced. This increase in IPSC amplitude seems to significantly contribute to the enhancement of temporal stability because the enhancement was almost fully reversed by a low concentration of bicuculline. These results suggest that changes in brain pCO(2) can have a strong influence on the temporal modulation of gamma rhythms.

Respiratory alkalosis is an extremely common and complicated problem affecting virtually every organ system in the body. This article reviews the various facets of this interesting problem. Respiratory alkalosis produces multiple metabolic abnormalities, from changes in potassium, phosphate, and calcium, to the development of a mild lactic acidosis. Renal handling of the above ions is also affected. The etiologies may be related to pulmonary or extrapulmonary disorders. Hyperventilation syndrome is a common etiology of respiratory alkalosis in the emergency department setting and is a diagnosis by exclusion. There are many cardiac effects of respiratory alkalosis, such as tachycardia, ventricular and atrial arrhythmias, and ischemic and nonischemic chest pain. In the lungs, vasodilation occurs, and in the gastrointestinal system there are changes in perfusion, motility, and electrolyte handling. Therapeutically, respiratory alkalosis is used for treatment of elevated intracranial pressure. Correction of a respiratory alkalosis is best performed by correcting the underlying etiology.

Objective: To test the hypothesis that prolonged alkalosis decreases cardiac output and, furthermore, exacerbates hypoxic pulmonary vasoconstriction, as respiratory alkalosis is frequently induced as a therapy for persistent pulmonary hypertension of the newborn despite a lack of controlled evidence of improved outcomes. Potential adverse effects of prolonged alkalosis have been demonstrated., Method: Two groups (control, n = 6, and hypocapnic alkalosis, n = 6) of 1-3 day old fentanyl-anesthetized, vecuronium-paralyzed piglets were instrumented to measure cardiac index (CI) and mean systemic (MAP) and pulmonary (PAP) arterial pressures. Baseline values were recorded. Alveolar hypoxia was then induced to achieve an arterial oxygen saturation of between 50 and 60% for 15 min. Respiratory alkalosis was then induced, by increasing ventilation to achieve a pH between 7.55-7.60, and was continued for 240 min. Inspired carbon dioxide was used with hyperventilation in the control group to maintain pressure of arterial carbon dioxide (PaCO2) at 35-45 mmHg and pH of 7.35-7.45. Hypoxia was induced again at 15 and 240 min. Pulmonary and systemic vascular resistances (PVR and SVR) were calculated., Results: Prolonged alkalosis led to a significant and progressive fall in mean MAP from 61 (SD 7) mmHg at the start of the study falling to 50 (SD 6.9, p = 0.043), with no effect on CI. Calculated SVR decreased (0.45 SD 0.03 vs 0.36 SD 0.05). There were no statistically significant changes in any of the variables in the control group. Neither acute nor prolonged respiratory alkalosis had a significant effect on hypoxic pulmonary vasoconstriction., Conclusions: Prolonged hyperventilation leads to systemic hypotension, however it does not exacerbate hypoxic pulmonary vasoconstriction.