Several studies show that changes in osmolality influence ventilation in animals and humans.1 Increased osmolality inhibited panting in dogs2 and opposed sweating and ventilatory response to hyperthermia in humans.3,4 However, animal studies also indicate that decreased osmolality stimulates ventilation.5 Most human observations in this field have been made during pregnancy because pregnant women experience a decrease in osmolality of approximately 10 mOsm/kg, mostly caused by a reduction in plasma sodium of 3 to 5 mmol/L.6 The resulting decrease in strong ion difference (SID) indicates metabolic acidosis, according to Stewart’s physicochemical approach.7,8 Concomitantly, there is a decrease in arterial PCO2 (PaCO2) of approximately 6 mm Hg.9 Similar but smaller changes are also present in the luteal phase of menstruation.10 Studies of pregnant and nonpregnant women have shown that PaCO2 can be predicted by changes in osmolality and SID.6,9 Because these studies also correlate progesterone levels to changes in PaCO2, the results have not been applied to men.
We investigated the hypothesis that osmolality would influence ventilation, so that increased osmolality will decrease ventilation and decreased osmolality will also cause respiratory alkalosis in men.
IV of hypertonic saline 3% for 2 hours was used to create hyperosmolality. Drinking tap water for 2 hours caused hypoosmolality. Arterial blood samples for analysis of blood gases, electrolytes, and osmolality were collected throughout the fluid-loading procedures. Sensitivity to CO2 was determined by rebreathing tests performed before and after fluid-loading procedures.
The study was approved by the Regional Ethical Review Board, Linköping University, Linköping, Sweden, and registered in the public registry ClinicalTrials.gov (NCT 01008644 ID M-126-09) on November 5, 2009, by the principal investigator, Vibeke Moen. After giving written informed consent, 10 men (mean 28 years; range 20–40) and 9 women (mean 33 years; range 22–43) were included and completed the study. All women participated in both the follicular and luteal phase of the menstrual cycle. Ovulation was predicted with the aid of ovulation prediction kits (Clear Blue, SPD, Swiss Precision Diagnostics GmbH, Geneva, Switzerland), and ovulation was confirmed with determination of plasma progesterone levels. Every woman participated on 4 separate occasions, whereas the men participated twice. In addition, 1 man and 5 women were excluded because they did not participate on all planned occasions. These subjects were replaced, and data from their study occasions are not included in our results.
The study was performed in a temperature-controlled room in the Kalmar County Hospital between November 2009 and November 2010. All study participants were healthy, ASA physical status I and in good physical condition but not trained athletes. Exclusion criteria were body mass index (BMI) <19 or >26, smoking or use of chewing tobacco, diabetes, kidney disease, oral steroid therapy, or any hormone replacement therapy.
Participants were asked to refrain from drinking alcohol or heavy exercise for 24 hours before each test. The subjects fasted from midnight, had a light breakfast at home, and arrived in the laboratory at 0800 in the morning. On arrival, the subjects were weighed, and their BMI was calculated. After infiltration anesthesia, a 20-G arterial line was placed in the radial artery, and when required, an 18-G venous line was placed for infusion of hypertonic saline. Hypernatremia was obtained by IV infusion of hypertonic saline 3% and hyponatremia by drinking tap water. Test assignment was random crossover, and at least 1 week passed between occasions of study participation. After 30 minutes of rest, baseline samples were collected for determination of hemoglobin and hematocrit (Hct), blood gases, and plasma sodium, potassium, and chloride, and calculated values for plasma osmolality were all analyzed with Radiometer ABL 800 Flex (Acid Base Laboratory, Radiometer Medical AS, Copenhagen, Denmark). Radiometer ABL 800 Flex calculates plasma osmolality by an abbreviated formula:
SID was calculated by the formula:
Blood samples for determination of electrolytes and blood gases were also collected every 20 minutes during the fluid-loading procedures, ending 1 hour after termination. On each occasion, a 1-mL blood sample was sufficient to perform all analyses, and the samples were immediately analyzed.
In addition, blood samples collected at baseline and after termination of fluid-loading procedures were sent to the central laboratory of the hospital for analysis of plasma urea, albumin, and serum osmolality, determined by the cryoscopy method (Advanced Osmometer Model 3D3, Molek AB, Enskede, Sweden).
In our statistics, we used the calculated values of plasma osmolality, obtained at all sample occasions. To investigate data reliability we used a BlandAltman plot to compare these calculated values of plasma osmolality with serum osmolality determined by the cryoscopy method, measured at baseline and immediately after termination of the fluid-loading procedures. The Bland-Altman plot showed that the calculated values for plasma osmolality were consistently 12 units lower (4%) compared with the measured values for serum osmolality but showed no coupling to osmolality levels. Changes are therefore independent of method (Fig. 1).
Blood gas analyses were performed to monitor the effect on PaCO2 of varying plasma electrolytes and osmolality during the fluid-loading procedures. A rebreathing test was performed immediately before and after the fluid-loading procedures to investigate whether the changes in PaCO2, if any, were caused by altered sensitivity to CO2. Heart rate, invasive arterial blood pressure, and pulse oximetry were monitored continuously throughout the study (Datex monitor S/5 MCVOX, GE Healthcare, Stockholm, Sweden).
The study subjects were invited to urinate on arrival and during the study period. Spontaneously voided urine was collected, and volumes were recorded.
Water loading by drinking 20 mL · (kg body wt)−1 · h−1 for 2 hours can decrease plasma osmolality by 5 mOsm/kg.10,11 Hypertonic saline 3% infused IV at the rate of 0.1 mL · (kg body wt)−1 · min−1 for 120 minutes can be expected to increase plasma osmolality by at least 10 mOsm/kg.10,12 In either case, plasma osmolality is predictably altered, and the effect on PaCO2, if any, should be present. With 10 paired comparisons, and a 3% coefficient of variation of plasma osmolality, plasma sodium, and PaCO2, 10 persons in each group would be sufficient to detect 5% changes of PaCO2 with a power of >90%.
During water loading the participants drank tap water 20 mL · (kg body wt)−1 · h−1 for 2 hours. This was administered as an initial volume of 400 mL of water, followed by 150 to 200 mL every 10 minutes for 2 hours, up to a total of approximately 2.5 L.10 Hypertonic saline 3% was infused intravenously at the rate of 0.1 mL · (kg body wt)−1 · min−1 for 120 minutes,12 up to a total of approximately 1 L. The hypertonic saline was prepared by APL (Apotek Produktion & Laboratorier AB, Kungens Kurva, Sweden).
The subjects were placed in a semirecumbent position during the procedures, with the head supported by a pillow. We used a slightly modified version of a recently described rebreathing system.13 A nose-clip was applied, and after breathing room air for 30 seconds through a mouthpiece with a heat-moisture exchanger and a capnograph, a modified Bain system without CO2 absorber was attached. This consisted of a 900-cm- long, 30-mm-wide open-ended tube with an internal volume of 6.4 L and a tube for fresh gas inflow, calculated as 75 mL · (kg body wt)−1 · min−1 air with 30% O2. The rebreathing test continued for 10 minutes when steady state was assumed to be reached, and close observation of the capnograph traces ensured that no breathing of CO2-free room air occurred. Our modification of the recently described system consisted of an elongation of the open-ended tube, from 490 to 900 cm, to prevent the subjects from breathing room air. The methodologic intraindividual error of the rebreathing test was calculated using the S-method first proposed by Dahlberg:
where di is the difference between the ith paired measurement and n is the number of differences.14 The methodologic intraindividual error of our rebreathing test after modification was 10% for all groups. Respiratory rates, inspired O2, and end-tidal PCO2 were recorded using the software Collect 1.0 (Datex, Helsinki, Finland).
Calculations of Changes in Blood Volume
Relative change in blood volume (ΔBV/BV) during loading procedures was calculated from Hct values before fluid loading (sampling occasion 3; Hct3) and for each sampling occasion (i) thereafter during fluid loading (Hcti; i = 4–9). Since Hct = ERV/BV or ERV = Hct · BV, where ERV (erythrocyte volume) is considered constant during the procedure, it follows that Hct3 · BV3 = Hcti · BVi, and hence
Denoting the relative change in BV at occasion i compared with the starting point (3) by (ΔBV/BV)i, where (ΔBV/BV)i= (BVi − BV3)/BV3 or BVi/BV3 − 1, Equation (1) can be rewritten as:
Data Analyses and Statistics
Variables sampled during the loading procedures were analyzed using repeated measures ANOVA with the various subject groups as categorical predictors either using all sampling occasions, sampling occasions at the end of the rebreathing tests, or sampling occasions during the loading procedures. Only in case of significant overall effect were these analyses then followed by Duncan’s post hoc test.
Decreased SID indicates metabolic acidosis according to Stewart’s model. We therefore assessed base excess (BE), pH, and PaCO2 at the time when SID reached its lowest level in each individual during the fluid-loading procedures, and differences from baseline were calculated for these variables. To investigate interrelationships between PaCO2 and SID, linear regressions were made individually for each subject using values recorded during fluid loading. In both cases, ANOVA was used to assess differences from baseline with groups as a categorical predictor for group differences.
Arterial blood pressure trends during the salt-loading procedure were also calculated for each individual, using linear regression at the sample occasions during fluid loading. The regression coefficients were then compared using repeated ANOVA to test for differences from zero with male and female as categorical predictors.
Graphs are basically descriptive with mean values and 95% confidence limits. Differences among the different groups at baseline were analyzed by t test (Table 1, column 1) and paired t test for paired measurements (Table 1, columns 2 and 3) and are shown only for descriptive, not inferential, reasons. P values <0.05 were considered statistically significant, and P < 0.001 is the lowest level used. The data were analyzed in Statistica version 10 (Statistica; StatSoft, Tulsa, OK).
Twenty-five subjects enrolled, but only the data from the 10 men and 9 women who participated on all planned occasions are included in the results. Characteristics of these study participants and baseline values with descriptive differences among the various groups are listed in Table 1. There were no differences in BMI between men and women, but men had significantly higher systemic blood pressure (P = 0.005). The significantly lower PaCO2 and SID in women compared with men was caused by the lower values of PaCO2 (P = 0.002) and SID (P = 0.01) in women in the luteal phase compared with men. For women in the follicular phase, the differences were not significant (P = 0.1, P = 0.5, respectively). SID, BE, and bicarbonate were significantly lower in women during the luteal phase compared with the follicular phase, and PaCO2 was probably also significantly lower during the luteal phase (P = 0.04)
The women drank on average (SD; range) 2758 (254; 2444–3160) mL water, and the men drank 3170 (245; 2640–3480) mL water. Water loading caused a decrease of plasma sodium and osmolality parallel with a decrease of SID and BE in all individuals (Fig. 2, A, B, E, and F). Mean (SD) plasma chloride decreased to 103.0 (2.0) mmol/L. Decreases in SID and BE reached nadir 80 minutes after the start of water loading (Fig. 2, E and F). A decrease of PaCO2 was significant in men and women during the luteal phase (Table 2), but the regression coefficients of PaCO2 on SID were significant in all groups (Fig. 3). Figure 4 shows PaCO2, BE, and pH at time for lowest SID in men and women. Pooled results show that PaCO2 decreased from 38.2 (3.3) mm Hg at baseline to 35.7 (2.8) mm Hg after 80 minutes of drinking water, P = 0.002, and mean pH (SD) remained unaltered: pH 7.43 (0.02) at baseline to pH 7.42 (0.02) at 80 minutes, P = 0.14, mean difference (confidence interval [CI]) = pH −0.07 (−0.017 to 0.003) (Fig. 2C). There was no difference in the increase in PaCO2 during the rebreathing test after water loading compared with the increase in PaCO2 during the rebreathing test at baseline, P = 0.25, or compared with the rebreathing test after salt loading, P = 0.12, mean difference (CI) = 1.26 mm Hg (−0.36 to 2.88) (Fig. 2D). Blood volume remained unchanged (Fig. 5A).
Arterial blood pressures are not shown because the study subjects were not at rest (being occupied with drinking and frequent visits to the toilet).
The women received on average (SD; range) 828 (76; 733–948) mL saline 3%, and the men received 951 (74; 792–1044) mL saline 3%. Salt loading increased plasma sodium and osmolality in all individuals, and SID and BE were reduced (Fig. 2, A, B, E, and F). Mean (SD) plasma chloride increased to 120.1 (2.0) mmol/L. Analysis of pooled data shows absence of respiratory compensation (Fig. 2D). Baseline arterial PCO2 (PaCO2) mean (SD) 37.8 (2.9) mm Hg remained unaltered, with lowest PaCO2 37.8 (2.9) mm Hg after 100 minutes, P = 0.70. Mean pH (SD) decreased from 7.42 (0.02) at baseline to 7.38 (0.02), P < 0.001. Figure 4 shows PaCO2, BE, and pH at time for lowest SID in men and women.
There was no difference in the increase in PaCO2 during the rebreathing test after salt loading compared with the increase in PaCO2 during the rebreathing test at baseline, P = 0.11, mean difference (CI) = −1.29 mm Hg (−2.91 to 0.34), or compared with the rebreathing test after water loading, P = 0.12, mean difference (CI) = 1.26 mm Hg (−0.36 to 2.88) (Fig. 2D). In women, Hct (SE) decreased from 0.37 (0.003) to 0.35 (0.004), P < 0.001, and in men, Hct decreased from 0.43 (0.007) to 0.40 (0.006), P < 0.001. The decrease in Hct was consistent with significant hypervolemia, P < 0.001 (Fig. 5A), and systolic blood pressure increased significantly in all groups (Fig. 5B).
The study participants produced only small urine volumes during salt loading (Fig. 6).
The major result of our study is that respiratory compensation for metabolic acidosis was suppressed after infusion of hypertonic saline, compared with an adequate response during water loading (Fig. 2, D, E, and F, and Fig. 4). The ventilatory response to metabolic acidosis is usually predictable and immediate,15 and we therefore interpret the absence of this response as depression of ventilatory drive. The rebreathing test after salt loading did not show decreased sensitivity to CO2, indicating that the ventilatory drive was suppressed by a different mechanism. We propose that increased osmolality, directly or indirectly, suppressed ventilation during the salt-loading procedure.
Maintenance of body fluid osmolality within species-specific limits is of utmost importance for all mammals, and the control of body fluid volume and composition is closely linked to osmoregulation.1 Water-dependent thermoregulatory responses, such as panting and sweating, may be suppressed in dehydrated animals because the maintenance of body fluid volume and composition takes preference even at the cost of increased core temperature.1–4
The neural pathways for these relationships are largely unknown16 but also involve the hormones that regulate osmolality and body fluid volume, arginine vasopressin (AVP), and angiotensin II (ANG II).8 Animal studies describe the less well-known respiratory effects of ANG II: IV infusion of ANG II stimulates ventilation,17 while ANG receptor blockers blunt the ventilatory response to hypotension.18 ANG II also stimulates thirst and AVP release,19 and AVP in turn antagonizes the ventilatory stimulation by ANG II.20
Healthy volunteers involved in a salt-loading study identical to ours showed progressive reduction in plasma renin activity and increase in plasma AVP concentration,12 and we repeated the water-loading procedures from another study that showed a decrease in AVP after water loading.10 It is therefore reasonable to assume that hormonal changes of similar magnitude occurred in our study participants. Concomitant opposite changes in plasma levels of ANG II (suppression) and AVP (increase) could also act as mediators, and increased blood volume and arterial blood pressure (Fig. 5) may also have suppressed renin activity.
Changes in electrolyte concentrations in plasma may influence acid-base balance, and the concept of SID, determined by the difference between the strong cations and anions, was presented by Stewart in his physicochemical approach to explain this correlation.7 In Stewart’s model, pH and bicarbonate are dependent variables determined by the 3 independent variables: pCO2 SID, and the nonvolatile weak acid buffer. A decrease in SID is associated with a decrease in buffer base causing metabolic acidosis, and in Stewart’s model, bicarbonate is a dependent variable. Several studies also show that SID is involved in chemical control of breathing and may replace hydrogen ion concentration, or pH, traditionally considered the chemical stimulus to respiration.8,9
Both fluid-loading procedures caused a decrease in SID and BE, thus causing metabolic acidosis both according to Stewart and the traditional acid-base model. The decrease in SID was even larger during salt loading when compared with water loading, but as PaCO2 remained unchanged, the decrease in pH was significant (Figs. 2D and 4D). During water loading, the expected respiratory compensation for metabolic acidosis was not opposed, and the rebreathing test did not reveal altered sensitivity to CO2.
The reduction in SID and BE alone would be expected to stimulate ventilation; therefore, the causative role of the decreased osmolality is not evident. Our results could indicate that the influence of osmolality on ventilation consists of depression of respiration in conditions of hyperosmolality, whereas this inhibitory effect on ventilation is absent in conditions of decreased osmolality, leaving the respiratory compensation unopposed.
The small urine volumes produced during salt loading confirm the earlier described inhibitory effect of hypernatremia on urine production.21 Hyperchloremia could, however, be the real mediator of this effect because hyperchloremia has also been shown to reduce renal blood flow in humans.22
Baseline values for women during the luteal phase of menstruation showed lower plasma sodium, SID, BE, and PaCO2 compared with men and women in the follicular phase of menstruation (Table 1), in accordance with previous studies.6,9,10
Water loading caused a decrease in plasma sodium and osmolality as well as a decrease in SID and BE in all individuals (Fig. 2, A, B, E, and F). The expected compensatory reduction in PaCO2 was small (Fig. 2D), but larger changes could not be expected because the metabolic acidosis was modest. The decrease in PaCO2 was significant in men, but only during the luteal phase in women. However, the regression coefficient of PaCO2 on SID was also significant in women during the follicular phase (Fig. 3).
Our study thus indicates that hypoosmolality with reduced SID will also stimulate ventilation in men and is therefore independent of progesterone levels.
Strengths and Limitations
In the most recent study of the influence of hyperosmolality on ventilation in humans, published in 1969, Senay4 described respiratory depression caused by hyperosmolality in dehydrated men, but PaCO2 was not measured. Our study correlates PaCO2 with osmolality, SID, and BE in humans of both sexes. The participation of women, and their dual participation in both phases of the menstrual cycle, enabled us to study the possible influence of female sex hormones.
Although results from only 9 women are included, our results reached significance. Scheingraber et al. described hyperchloremic acidosis after infusion of saline during gynecologic surgery using general anesthesia.23 Ventilation was controlled to maintain normocapnia; therefore, no respiratory compensation of the metabolic acidosis could be expected. We describe the absence of ventilatory response to hyperchloremic metabolic acidosis in spontaneously breathing healthy volunteers.
Our rebreathing test effectively caused PaCO2 to increase; however, our rebreathing test could have lacked the resolution to detect a small change in sensitivity to CO2, and we did not register spirometric breathing patterns. A more physiologic increase in osmolality could have been achieved by fluid restriction for 28 hours before the study.24 We refrained from adopting this model because we presumed that this protocol would be difficult for the subjects to adhere to, as well as being paired with a high risk of plasma osmolality not increasing significantly.12
Clinical Implications and Areas of Further Studies
Inhibition of respiratory compensation for metabolic acidosis after infusion of saline could be of clinical significance. In recent years, the widespread use of saline in fluid therapy has been questioned, and the resulting hyperchloremic metabolic acidosis is often considered in accordance with Stewart’s approach, although the clinical consequences of hyperchloremic metabolic acidosis remain unclear.25 However, for patients with increased plasma levels of sodium and chloride, often exceeding the levels observed in our study participants, a hitherto unrecognized cause for respiratory depression could be clinically significant. In palliative medicine, fluid restriction and dehydration are common, and hypoxemia often occurs. Future studies could address the influence of hyperosmolality on hypoxic ventilatory stimulation.
Our study cannot define the effects of a further increase in plasma osmolality or the degree of metabolic acidosis that will remain without respiratory compensation in conditions of increased osmolality. Further studies could address this issue.
Hyponatremia, on the other hand, is not uncommon during labor, and the ensuing maternal metabolic acidosis will also affect the fetus.26 Depressed respiratory compensation of metabolic acidosis in a hypernatremic mother could seriously affect fetal health.
Our results show that respiratory compensation to hyperchloremic metabolic acidosis was suppressed during hyperosmolality, analogous to the suppression of water-dependent thermoregulation previously described in hypernatremic animals and humans.
Water loading caused a decrease in osmolality and metabolic acidosis. Although the decrease in SID was smaller compared with salt loading, the expected respiratory compensation was observed. Ventilation was also stimulated in men, therefore independently of progesterone levels. We propose that the influence of osmolality on ventilation is mainly depression in conditions of hyperosmolality and that this depression is absent during hypoosmolality.
Name: Vibeke Moen, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Vibeke Moen has seen the original study data, reviewed the analysis of the data, and approved the final manuscript and is the author responsible for archiving the study files.
Name: Lars Brudin, MD, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Lars Brudin has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Mats Rundgren, MD, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Mats Rundgren has approved the final manuscript.
Name: Lars Irestedt, MD, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Lars Irestedt has approved the final manuscript.
This manuscript was handled by: Steven L. Shafer, MD.
The authors thank the subjects for participation in the study.
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