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Effects of Hypercapnia on BP in Hypoalbuminemic and Nagase Analbuminemic Rats^*

Jose L. Gómez, MD; Kyle J. Gunnerson, MD; Mingchen Song, MD, PhD; Jinyou Li, PhD and John A. Kellum, MD, FCCP

^* From the MANTRA Laboratory, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA. Presently at Virginia Commonwealth University Reanimation Engineering and Shock Center Laboratory, Departments of Anesthesiology/Critical Care and Emergency Medicine, Virginia Commonwealth University Medical Center, Richmond, VA.

Correspondence to: John A. Kellum, MD, FCCP, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Scaife Hall, Room 608, 3550 Terrace St, Pittsburgh, PA 15261; e-mail: kellumja{at}ccm.upmc.edu

Abstract

Study objective: To determine if animals with abnormally low albumin levels are more susceptible to the effects of hypercapnia on BP compared to normal animals.

Design: Prospective, controlled laboratory experiment.

Setting: University research laboratory.

Animals: Eighteen male Sprague-Dawley rats: 6 rats 10 to 12 weeks old (young Sprague-Dawley [YSD]), 6 rats 6 to 9 months old (old Sprague-Dawley [OSD]), and 6 rats 10 to 12 weeks old (Nagase analbuminemic mutant Sprague-Dawley [NAR]).

Methods: Under general anesthesia and paralysis, we varied the PaCO₂ by changing the respiratory rate on mechanical ventilation. Mean arterial pressure (MAP) was monitored in a continuous fashion. We obtained arterial blood for blood gas and electrolyte analysis, and nitric oxide (NO) production.

Results: OSD rats had reduced serum albumin, while NAR rats were analbuminemic. Although NAR animals had a decreased buffer capacity compared to age-matched control animals (0.010 vs 0.013, p < 0.05), the MAP decreased in an identical fashion in all three groups. NO production increased with hypercapnia but was similar in all three groups. However, NAR rats had consistently higher plasma strong ion gap (2.8 to 4.1 mEq/L greater) compared to either YSD or OSD rats (p < 0.01), and baseline strong ion difference (mean ± SD) was significantly lower in NAR rats (28.7 ± 2.1 mEq/L) compared to either YSD rats (33.0 ± 5.1 mEq/L) or OSD rats (31.2 ± 5.1 mEq/L) [p < 0.05].

Conclusions: These findings suggest that analbuminemic or hypoalbuminemic rats are not more susceptible to hypercapnia-induced hemodynamic instability. Baseline values for apparent strong ion difference are lower in NA rats consistent with a reduced buffer base resulting from analbuminemia.

Key Words: acid-base balance • analbuminemia • BP • hypercapnia • hypoalbuminemia • pH

Hypoalbuminemia is common among critically ill patients, both adult and pediatric.¹²³ Among its many physiologic functions, albumin plays an important role in the maintenance of intravascular colloid osmotic pressure⁴ and, as a weak acid, regulation of blood pH.⁵⁶ Hypercapnia has known effects on the vasomotor tone of blood vessels, and it also affects cardiac performance, leading to hypotension. These effects are at least partially offset by an acidosis-induced increases in endogenous catecholamines. However, acidosis also increases nitric oxide (NO) release,⁷⁸ which further reduces arterial tone.

Hypoalbuminemia in critically ill patients is explained in part by pathophysiologic events in acute diseases such as decreased synthesis due to the effects of inflammatory cytokines on the liver, increased losses in burns, or decreased levels due to fluid shifts in the setting of sepsis. Poor nutritional status and a catabolic state seen with many critically ill patients further reduce protein synthesis. Loss of albumin invariably results in decreased plasma buffer capacity, and as such would be expected to result in poorer tolerance of hypercapnia.

Hypercapnia is frequently observed in the critically ill, either as a consequence of the underlying pulmonary or neurologic disease, or as a result of intentional reductions in minute ventilation to reduce airway pressure—so-called permissive hypercapnia. Increased PaCO₂ is expected to cause a decrease in BP.⁹¹⁰ Whether hypoalbuminemic (or analbuminemic) subjects are more susceptible to this effect is currently unknown. Thus, the current study was conducted to determine if hypoalbuminemic animals were at increased risk of hypercapnia-induced hypotension.

Materials and Methods

Animals
Following approval by the Animal Care and Use Committee of the University of Pittsburgh, standard Sprague-Dawley rats (Hilltop Farms; Pittsburgh, PA) and Nagase analbuminemic mutant Sprague-Dawley (NAR) rats (University of California at Davis; Davis, CA) were studied. We studied 18 animals: 6 rats 10 to 12 weeks old (young Sprague-Dawley [YSD]), 6 rats 6 to 9 months old (old Sprague-Dawley [OSD]), and 6 rats 10 to 12 weeks old (NAR).

Surgical Preparation
For anesthesia, we used pentobarbital sodium, 50 mg/kg intraperitoneally, for induction and then maintained anesthesia with 10 mg/kg intraperitoneally when needed. Each animal was intubated with a beveled 16-gauge angiocatheter and ventilated with room air using a rodent ventilator (Harvard; Holliston, MA) at a tidal volume of 6 mL/kg and a frequency sufficient to maintain the pH between 7.35 and 7.45. We isolated the right carotid artery by dissection and cannulated with 1.27-mm PE-90 tubing. This tubing was formed into a catheter by inserting a beveled 20-gauge needle. We placed a three-way stopcock to allow BP monitoring using a monitor (Hewlett Packard 78342A; Hewlett Packard; Andover, MA), blood sampling, drug administration, and fluid resuscitation. The whole system was flushed with 0.5 mL of heparinized (3,000 U/L) hetastarch in a buffered electrolyte solution (Hextend; Hospira; Lake Forest, IL).

Neuromuscular blockade was achieved by the use of pancuronium bromide (Elkins-Sinn; Cherry Hill, NJ). At time = 30 min, 0.1 mg/kg was administered; at time = 110 min, a second dose of 0.02 mg/Kg was administered. If there was spontaneous breathing or resistance to ventilation, another 0.02 mg/kg dose was administered. Pancuronium was selected based on its pharmacologic properties, nondepolarizing, long half-life (90 to 120 min), and low protein binding (94%).

Experimental Protocol
After the instrumentation, we drew 150 µL of blood into a heparinized syringe for arterial blood gas analysis and hemoglobin, lactate, and electrolyte concentrations (ABL-725; Radiometer; Copenhagen, Denmark). The animals were then maintained at a steady state as defined by stable BP for at least 10 min. After this period, 3 mL of whole blood were collected in a heparinized syringe over a 6-min period to avoid hypotension, and BP determinations were obtained at 0 min, 3 min, and 6 min. This sample was used for blood gas analysis and for measurement of electrolytes, albumin, total protein, magnesium, and phosphate. We administered 3 mL of heparinized Hextend as fluid replacement and allowed 10 min for stabilization.

In order to define the pH/PaCO₂ relationship across the entire physiologic range, we began by altering minute ventilation (E) from baseline determined by pH of 7.35 to 7.45, to 125%, 150%, 175%, and 200% of E in the hyperventilation arm. We next obtained a second baseline, and the hypoventilation arm of the study was performed by decreasing the E to 80%, 60%, 40%, and 30% of that baseline. These changes were made every 20 min. Blood samples were obtained at the end of each period, from time = 0 min to time = 200 min. A total of 11 samples of 125 µL were obtained corresponding to prebaseline, baseline E, 125% E, 150% E, 175% E, 200% E, second baseline, 80% E, 60% E, 40% E, and 30% E.

At time = 200 min, prior to killing the animals, blood was obtained for blood gas analysis and for albumin, total protein, electrolyte, magnesium, and phosphate determinations. For all six NAR rats, this sample was also used to measure total nitrite as a means of determining NO production. The NO results were then compared to pooled data from three OSD rats and three YSD rats.

NO Production Assay
Total nitrite was measured using cadmium-mediated reduction of NO₃^– to NO₂^– followed by the Griess reagent.¹¹ To reduce NO₃^– to NO₂^– in plasma, cadmium filings (0.4 to 0.7 g per tube) [Fluka Chemicals; Milwaukee, WI] were loaded into 1.5-mL microcentrifuge tubes. The filings were washed twice with 1.0 mL of deionized water, twice with 1.0 mL of 0.1 mol/L HCl, and twice with 0.1 mol/L NH₄OH. Ten microliters of 30% (weight/volume) ZnSO₄ were added to 200 µL of plasma, vortexed, incubated at room temperature for 15 min, and centrifuged at 14,000g for 5 min. The resulting supernatants were added to the cadmium-containing microcentrifuge tube and incubated at room temperature overnight with constant mixing. The samples were transferred to fresh microcentrifuge tubes and centrifuged again. The samples were subsequently measured for NO₂^– content by the Griess reagent.¹² The plates were read using a microplate reader (MRX; Dynex Technologies; Chantilly, VA) at 550 nm. NaNO₂ was used to generate a standard curve.

Calculations and Statistics
Standard base excess (SBE) was calculated as previously described.¹³ The apparent strong ion difference (SIDa) was calculated from arterial plasma as follows: SIDa = Na⁺ + K⁺ + Mg⁺⁺ + Ca⁺⁺ – Cl^– – lactate, all expressed in milliequivalents per liter.¹⁴¹⁵ The effective strong ion difference (SIDe) was determined as follows: SIDe = 2.46 x 10^–8 x PCO₂ (millimeters of mercury)/10^–pH + [albumin (grams per liter)] x (0.123 x pH – 0.631) + [PO₄] x (0.309 x pH – 0.469).¹⁵ Strong ion gap (SIG) was then calculated as the difference between SIDa and SIDe as previously described¹⁴: SIG = SIDa – SIDe. Finally, we calculated buffer capacity as the reciprocal of the slope of PCO₂/pH.¹⁶

Our primary analysis was between the three groups in terms of mean arterial pressure (MAP) over time. Secondary analyses included plasma nitrate/nitrite levels and acid-base variables. Mean differences between and within groups were analyzed by analysis of variance adjusted for multiple comparisons, and then pairwise comparisons were performed using the Student-Newman-Keuls test. Error values given in the text are SDs. Statistical analysis was performed using statistical software (MedCalc, v 4.2; Mariakerke, Belgium; and Stata, v 6.0; StataCorp; College Station, TX); p < 0.05 was considered statistically significant.

Results

Hypercapnia-Induced Changes in MAP Were Identical in All Three Groups
All animals completed the 200-min protocol. Compared to YSD rats, OSD rats had reduced serum albumin levels, while NAR rats were analbuminemic as expected. The MAP over time is shown in Figure 1 , which demonstrates an identical pattern in all three groups.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 1. MAP values in each group.

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Plasma nitrite concentration at baseline (open bars) and during hypercapnia (solid bars). Data from OSD and YSD animals are obtained from three animals, while NAR animals included all six in the hypercarbia condition and one representative animal for baseline measurement. Error bars represent SD. Nitrite concentrations under hypercapnic conditions were not different (p = NS), while the change from baseline to hypercapnia was significantly greater for OSD animals compared to YSD animals (p = 0.02).

Hypoalbuminemia is very common among the critically ill¹² and is associated with adverse outcomes.³¹⁷¹⁸ However, it is not known whether hypoalbuminemia is itself responsible for the adverse effect on outcome or whether albumin, which correlates inversely with nutritional status and age, is merely a marker of the baseline clinical condition. Hypoalbuminemia is known to effect colloid oncotic pressure,⁴ and therefore is likely to influence hemodynamics and extravascular lung water among other factors. Furthermore, albumin is the major buffer in blood plasma, and thus hypoalbuminemia causes a reduction in buffer capacity.⁵ Therefore, the complications of acidosis may be more severe in the presence of hypoalbuminemia.

One such complication of acidosis is the effect on systemic BP. For example, hypercapnia may lead to hypotension. The mechanisms involved in hypercapnia-induced hypotension are complex and are represented by a variety of major organ physiologic changes and mediated by multiple molecular cellular mechanisms. At the organ system level, it has been long recognized that although acute hypercapnia may induce tachycardia and hypertension, both bradycardia and hypotension may occur particularly when the subject is sedated.⁹ Hypercapnia may also decrease vascular capacitance¹⁰ with relative volume entrapment in the pulmonary circulation. At the cellular level, the interaction between plasma and the components of the vascular wall is less well understood. In the plasma, NO exists as an S-nitroso adduct of circulating albumin, and it is stabilized by the reaction with this carrier molecule.¹⁹ However, hypercapnia elicits the release of NO from the vascular endothelium by a direct effect²⁰ and an indirect effect on prostaglandin induction of endothelial NO synthase.²¹ The downstream effects of NO on the smooth-muscle cells are complex and in part related to the amount of cyclic guanosine monophosphate synthesized in response to it. Cyclic guanosine monophosphate has a permissive effect on the activity of adenosine triphosphate-sensitive potassium channels and potassium/calcium channels that lead to relaxation of the muscle and vasodilation.²² However, NO-independent factors are also present and are related to pH, as intracellular acidification activates adenosine triphosphate-sensitive potassium channels,²³²⁴ and other vasoactive molecules such as adenosine.

Thus, we might expect that NO would be decreased in NAR rats because of decreased stabilization. However, acidosis and hypercapnia result in an increase in NO release,²⁵ and it is possible that the decrease in buffer capacity seen during hypoalbuminemia results in a greater sensitivity. Indeed, our results appear to be consistent with this interpretation. Baseline plasma nitrite levels were generally less in our animals with less circulating albumin (OSD and NAR rats), while hypercapnia resulted in a greater increase in these animals compared to control animals (YSD rats). The net result was a similar level of plasma nitrite under conditions of hypercapnia and, interestingly, almost identical effects on MAP. A previous study²⁶ in a nonstimulated state of NO synthase activity, evaluating the role of albumin as a reservoir of NO, found that analbuminemic rats were not more sensitive to hypotension after injection of a NO donor. It appears that NO-dependent factors in vasodilation elicited by hypercapnia do not differ among groups of NAR and normoalbuminemic rats. Although extrapolation of our results to the clinical situation must be done with care, our study would suggest that hypoalbuminemia in humans is unlikely to result in greater sensitivity to hypercapnia. Similarly, albumin supplementation cannot be recommended on the basis of improving buffer capacity.

Previous observations²⁷ in analbuminemic animals have revealed that there are no major differences in NO synthase or plasma volume; in our study, standard acid-base parameters (pH, bicarbonate, base excess, and plasma lactate concentrations) were not significantly different among the three groups. However, prehypercapnia values for SIDa were lower in NAR rats, along with the reduced total weak acid concentration and resultant reduction in buffer base. Despite this fact, NAR rats did not reveal increased susceptibility to hypercapnia and acidosis-induced hypotension when compared to normoalbuminemic rats. Importantly, the presence of a lower SIDa in the NAR rats, despite a similar base excess, is consistent with a reduction in the "set point" for SIDa to maintain acid-base equilibrium in the face of a reduced weak acid content. While some authors²⁸ have suggested this combination represents a mixed acid-base disorder, our results suggest that it is a normal compensatory mechanism. A similar observation was made in critically ill patients, in whom an increased concentration of chloride was found in response to hypoalbuminemia, with an increase in SIDa.²⁹ Thus, we speculate that the normal physiologic response to hypoalbuminemia is to lower the SIDa, and as a result total buffer capacity is also reduced. Notably, NAR rats had significantly higher SIG, even at baseline, compared to YSD and OSD rats. This finding could represent anionic proteins produced in place of albumin, or it might represent a greater stress response in the NAR animals, potentially leading to a worse outcome.³⁰ The finding that SBE was virtually identical across all three groups favors the first explanation, as there was no evidence of increased acidosis in the NAR animals.

Our study has important limitations. First, hypoalbuminic and analbuminemic but otherwise healthy animals do not have the same clinical problems seen in the critically ill. Although peripheral edema may develop from reduced transcapillary oncotic pressure gradient, pulmonary edema does not develop unless there is a concurrent rise in left atrial and pulmonary capillary pressures. Another limitation to our model is that we only measured arterial BP, not hemodynamics. Given the amount of blood already obtained, we were reluctant to obtain additional blood tests (eg, central venous oxygen saturation). Finally, by examining only plasma acid-base balance, we have neglected the possible role of intracellular acidosis. Furthermore, in the permissive hypercapnia approach, it is suggested that hypercapnia be achieved in steps not exceeding 10 mm Hg every 3 h. Changing PCO₂ more rapidly may dissociate the intracellular and extracelluar acid-base status, complicating interpretation of acid-base effect on the hemodynamic parameters. However, since albumin is a plasma buffer and unlikely to influence the intracellular environment, it is unlikely that a slower hypercapnia would have resulted in significantly different results.

Conclusion

Analbuminemic and hypoalbuminemic rats are not more susceptible to hypercapnia-induced hemodynamic instability. The opposing effects of reduced NO stability and increased NO release with hypercapnia secondary to a decreased buffer capacity may have been offsetting.

Footnotes

Abbreviations: MAP = mean arterial pressure; NAR = Nagase analbuminemic mutant Sprague-Dawley; NO = nitric oxide; NS = not significant; OSD = old Sprague-Dawley; SBE = standard base excess; SIDa = apparent strong ion difference; SIDe = effective strong ion difference; SIG = strong ion gap; E = minute ventilation; YSD = young Sprague-Dawley

This work was funded by The Laerdal Foundation for Acute Medicine.

None of the authors have any relevant conflicts of interest to disclose.

Received for publication August 18, 2006. Accepted for publication December 15, 2006.

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Gómez, J. L. Articles by Kellum, J. A. Search for Related Content PubMed PubMed Citation Articles by Gómez, J. L. Articles by Kellum, J. A. Related Content Related Editorial