Causes of metabolic acidosis in canine hemorrhagic shock: role of unmeasured ions
© Bruegger et al.; licensee BioMed Central Ltd. 2007
Received: 14 August 2007
Accepted: 14 December 2007
Published: 14 December 2007
Metabolic acidosis during hemorrhagic shock is common and conventionally considered to be due to hyperlactatemia. There is increasing awareness, however, that other nonlactate, unmeasured anions contribute to this type of acidosis.
Eleven anesthetized dogs were hemorrhaged to a mean arterial pressure of 45 mm Hg and were kept at this level until a metabolic oxygen debt of 120 mLO2/kg body weight had evolved. Blood pH, partial pressure of carbon dioxide, and concentrations of sodium, potassium, magnesium, calcium, chloride, lactate, albumin, and phosphate were measured at baseline, in shock, and during 3 hours post-therapy. Strong ion difference and the amount of weak plasma acid were calculated. To detect the presence of unmeasured anions, anion gap and strong ion gap were determined. Capillary electrophoresis was used to identify potential contributors to unmeasured anions.
During induction of shock, pH decreased significantly from 7.41 to 7.19. The transient increase in lactate concentration from 1.5 to 5.5 mEq/L during shock was not sufficient to explain the transient increases in anion gap (+11.0 mEq/L) and strong ion gap (+7.1 mEq/L), suggesting that substantial amounts of unmeasured anions must have been generated. Capillary electrophoresis revealed increases in serum concentration of acetate (2.2 mEq/L), citrate (2.2 mEq/L), α-ketoglutarate (35.3 μEq/L), fumarate (6.2 μEq/L), sulfate (0.1 mEq/L), and urate (55.9 μEq/L) after shock induction.
Large amounts of unmeasured anions were generated after hemorrhage in this highly standardized model of hemorrhagic shock. Capillary electrophoresis suggested that the hitherto unmeasured anions citrate and acetate, but not sulfate, contributed significantly to the changes in strong ion gap associated with induction of shock.
During hemorrhagic shock, metabolic acidosis is common and conventionally considered to be due essentially to hyperlactatemia. The increase in blood lactate generally originates from both increased lactate production and reduced lactate metabolism. However, there is an increasing awareness that hyperlactatemia alone fails to explain the full extent of metabolic acidosis [1, 2]. The presence of nonlactate, unmeasured anions has been suggested as an alternative marker of tissue hypoxia .
Traditionally, an elevated anion gap (AG) was thought to represent the presence of unmeasured anions. However, the AG can be confounded by lactate, electrolyte, and protein abnormalities [4, 5]. Abnormalities of these plasma components are accounted for in the physicochemical approach to acid-base balance . In this approach, the plasma weak acid concentrations (albumin and phosphate), the partial pressure of carbon dioxide (pCO2), and the strong ion difference (SID) (that is, the net charge difference between strong cations and strong anions) are identified as variables with independent effects on pH . This technique will identify the presence of unmeasured cations or anions in plasma by calculating the strong ion gap (SIG) . Moreover, the SIG has recently been identified as a powerful independent clinical predictor of mortality when it was the major source of metabolic acidosis .
The aims of this study, therefore, were twofold: (a) to determine the temporal profile of unmeasured anions in relation to other acid-base parameters on the basis of quantitative analysis in a highly standardized canine model of hemorrhagic shock and (b) to identify potential contributors to unmeasured anions. Capillary electrophoresis allows for both qualitative identification and then quantitative analysis of charged species in plasma. Candidates could be inorganic anions, such as sulfate derived from degradation of organic sulfates in tissue, and small organic anion intermediates of mitochondrial and cytosolic metabolism released into the extracellular space. Moreover, a healthy vascular endothelium is coated by an endothelial glycocalyx and this structure consists of large amounts of bound polyanionic heparan sulfates. During hemorrhagic shock, degradation of the endothelial glycocalyx might be associated with increased levels of circulating heparan sulfate and hence be an additional potential source of negatively charged species.
Materials and methods
The results presented in this report originate from a comprehensive experimental study investigating the effects of a perfluorocarbon-based artificial oxygen carrier given to anesthetized dogs during resuscitation from hemorrhagic shock . However, the aforementioned study does not contain data on acid-base balance, nor have these data been analyzed before. The investigation conforms to the Guide for the Care and Use of Laboratory Animals . Licensure and approval of the investigation were obtained from the government of Upper Bavaria.
The study was performed in 11 beagle dogs of either gender (weight 15.7 ± 1.1 kg). All animals were splenectomized at least 8 weeks prior to the experiment to exclude changes in red cell mass induced by splenic contraction during hemorrhage and acute anemia. Anesthetic management, surgical preparation, and insertions of different catheters have been described in detail elsewhere . Briefly, after induction of anesthesia, mechanical ventilation was performed on room air to maintain normocapnia. Because of the large surgical wound area and because of a lack of heating in the ventilatory circuit, fluid losses required intravenous fluid replacement by an electrolyte solution containing 154 mmol/L Na+ and 154 mmol/L Cl- (15 mL/kg per hour), supplemented by 20 to 40 mmol potassium chloride. Core body temperature was kept at approximately 36°C with a warming pad and a warming lamp. After completion of surgical preparation, a 30-minute stabilization period was allowed to elapse before baseline control values were collected (time point: baseline, B). O2 consumption was measured noninvasively at 1-minute intervals using a Deltatrac metabolic monitor (Deltatrac II MBM-200; Datex-Ohmeda, part of GE Healthcare, Little Chalfont, Buckinghamshire, UK) connected to the respirator. Subsequently, all animals were hemorrhaged to a mean arterial pressure of 45 mm Hg. At all times during hemorrhage, the actual O2 consumption value was subtracted from the baseline value, and by use of a computer program, the actual integrated O2 debt was determined as a function of body weight . Mean arterial pressure was kept at 45 mm Hg by stepwise withdrawing and reinfusing whole blood until a standard O2 debt of 120 mL/kg had been achieved. The induction of a standardized metabolic insult with an accumulated O2 debt of 120 mL/kg results in reproducible tissue hypoxia and a predictable mortality of 50%, which comes very close to clinical practice [11, 12]. The blood was reserved for reinfusion and was stored with a CPDA (citrate, phosphate, dextrose, and adenine) additive (Compoflex; Biotrans GmbH, Dreieich, Germany) at 10% vol/vol.
After the standardized induction of shock, a second set of measurements was obtained (time point: shock, Sh) and the fractional inspiratory O2 concentration was increased to 1.0. Thereafter, for restoration of tissue perfusion, a 6% pentastarch solution (6% hydroxyethyl starch, 200/0.5; Fresenius SE, Bad Homburg, Germany) containing 154 mmol/L of sodium and 154 mmol/L of chloride was given at a dose equal to the volume of shed blood. A third measurement was performed after completion of resuscitation (time point: post-treatment, pT). Additional measurements were performed 30, 60, and 180 minutes post-therapy (time points: 30', 60', and 180', respectively). The animals did not receive any acetate-containing solutions.
Blood sampling and analysis
Arterial blood samples were collected in blood gas syringes containing lithium heparin (Rapidlyte; Bayer Diagnostics, Fernwald, Germany) at B, Sh, pT, 30', 60', and 180'. These were immediately analyzed for pH, pCO2 (standard electrodes), and the plasma concentrations of sodium (Na+), potassium (K+), calcium (Ca2+), magnesium (Mg2+), chloride (Cl-) (ion-selective electrodes), and lactate (Lac-) (enzymatic method, quantification of H2O2), all integrated in a blood gas and electrolyte analyzer (Rapidlab 860; Bayer Diagnostics) and measured at 37°C. Additionally, serum phosphate (Phos) (UV photometry of a phosphomolybdate complex) and albumin concentration (Alb) (colorimetry of bromocresol complex) were measured using the same blood samples. Values for standard base excess and bicarbonate (Bic-) were derived by the blood gas analyzer.
Additional arterial blood samples were drawn into serum monovette tubes at the above-mentioned time points for capillary electrophoresis and determination of heparan sulfate concentrations. Serum was rapidly separated by centrifugation at 2,000 g for 10 minutes and was stored at -80°C until assayed.
For each sample, an apparent strong ion difference (SIDa) was calculated:
SIDa = (Na+ + K+ + Ca2+ + Mg2+) - (Cl- + Lac-).
The amount of weak plasma acid (A-) was calculated :
A- = [Alb] × (0.123 × pH - 0.631) + [Phos] × (0.309 × pH - 0.469).
The effective strong ion difference (SIDe) was calculated :
SIDe = 1,000 × 2.46 × 10-11 × (pCO2/10-pH) + A-.
To quantify unmeasured charges, an SIG was calculated :
SIG = SIDa - SIDe.
The traditional AG was also calculated:
AG = (Na+ + K+) - (Cl- + Bic-).
The AG corrected for albumin and lactate (AGcorr) was calculated :
AGcorr = AG + 2.5 × (4 - [Alb]) - Lac-.
A capillary electrophoresis system (Waters Chromatography, Division of Milipore, Milford, MA, USA) was used with UV detection of solutes at 214 nm. Separations were obtained on a fused-silica capillary (length, 60 cm; internal diameter, 75 μm) (Waters) or on a polyvinyl alcohol (PVA)-coated capillary (length, 60 cm; internal diameter, 50 μm) (Agilent Technologies, Böblingen, Germany). To prepare the samples for assay, 10 μL of serum was mixed with 990 μL of distilled water (dilution 1:100). In the case of the first type of capillary, an inorganic anion buffer for capillary electrophoresis (pH 7.7) (Agilent Technologies) was used. Samples were loaded hydrostatically for 30 seconds. Separations were conducted at a constant voltage of 20 kV. Under these conditions, a current of 15 μA was encountered while samples were running. All data were recorded on a computer with Millenium software (Waters Chromatography, Division of Milipore, Milford, MA, USA).
Measurement of heparan sulfate concentration and alkaline hydrolysis
Heparan sulfate concentrations were measured after pretreatment of serum with Actinase E (Sigma-Aldrich, St. Louis, USA) by using an enzyme-linked immunosorbent assay (Seikagaku Corporation, Tokyo, Japan). Additionally, serum samples were boiled with 1.0 M NaOH for 2 hours and serum sulfate concentrations were subsequently analyzed using capillary electrophoresis (see above).
All data are presented as mean ± standard error of the mean. For normally distributed data (tested by Kolmogorov-Smirnov test), comparisons were made using analysis of variance for repeated measurements. For data that were not normally distributed, comparisons were made using analysis of variance on ranks. Post hoc testing was performed using the Student-Newman-Keuls method for multiple comparisons. Correlation between variables was evaluated using Pearson's product moment correlation. Differences were considered significant at a p value of less than 0.05.
Measured and calculated values of the acid-base status
Time point of measurement
Immediately after therapy
30 minutes after therapy
60 minutes after therapy
180 minutes after therapy
7.41 ± 0.01
7.19 ± 0.02a
7.13 ± 0.02a
7.23 ± 0.01a
7.27 ± 0.01a
7.26 ± 0.01a
33.4 ± 1.4
32.5 ± 2.6
43.8 ± 2.6a
39.4 ± 1.5a
36.4 ± 2.1
33.8 ± 1.0
-3.2 ± 0.5
-15.0 ± 1.0a
-14.7 ± 0.6a
-10.8 ± 0.7a
-9.5 ± 0.6a
-11.2 ± 0.4a
149 ± 0.9
150 ± 0.9
150 ± 0.9
150 ± 1.2
151 ± 1.2
152 ± 1.9
3.8 ± 0.3
3.7 ± 0.3
3.9 ± 0.3
4.4 ± 0.3
4.5 ± 0.3
4.5 ± 0.3
3.7 ± 0.1
3.3 ± 0.2
3.3 ± 0.1a
3.2 ± 0.1a
3.3 ± 0.1a
3.4 ± 0.1
1.2 ± 0.1
1.5 ± 0.1
1.3 ± 0.1
1.3 ± 0.1
1.3 ± 0.1
1.2 ± 0.1
130 ± 1.7
130 ± 1.9
134 ± 2.1
136 ± 1.1
139 ± 1.5a
145 ± 1.8a
1.5 ± 0.2
5.5 ± 0.9a
5.6 ± 0.7a
3.7 ± 0.5a
2.3 ± 0.4
2.5 ± 0.5
26.1 ± 1.0
24.3 ± 1.5
19.9 ± 2.0a
19.0 ± 0.5a
19.3 ± 1.6a
15.6 ± 1.2a
2.5 ± 0.2
3.0 ± 0.2
3.2 ± 0.2
3.4 ± 0.3
3.2 ± 0.4
2.6 ± 0.2
1.5 ± 0.2
1.1 ± 0.1a
0.7 ± 0.1a
0.7 ± 0.1a
0.7 ± 0.1a
0.5 ± 0.1a
27.8 ± 0.9
19.2 ± 0.7a
19.3 ± 0.4a
21.6 ± 1.0a
21.6 ± 1.0a
19.6 ± 0.4a
-2.0 ± 1.5
5.1 ± 2.2a
0.6 ± 2.0
-2.6 ± 1.3
-2.2 ± 1.4
-2.9 ± 1.5
3.1 ± 1.2
14.1 ± 3.3a
5.8 ± 1.6
2.1 ± 1.2
0.0 ± 1.0
-0.2 ± 1.3
7.8 ± 1.6
18.6 ± 2.9a
8.8 ± 1.8
6.9 ± 1.0
6.6 ± 1.0
5.5 ± 1.2
Analysis of anions by means of capillary electrophoresis
Time point of measurement
Immediately after therapy
30 minutes after therapy
60 minutes after therapy
180 minutes after therapy
2.4 ± 0.5
4.4 ± 0.9
5.8 ± 0.4a
4.8 ± 0.5
3.9 ± 1.0
2.3 ± 0.5
1.7 ± 0.7
2.0 ± 0.3
1.7 ± 0.2
2.6 ± 1.2
2.9 ± 1.3
2.6 ± 0.9
1.4 ± 0.1
1.5 ± 0.1
1.4 ± 0.1
1.4 ± 0.1
1.3 ± 0.1
1.3 ± 0.1
0.5 ± 0.1
2.4 ± 0.7a
1.2 ± 0.2
1.3 ± 0.3
1.2 ± 0.2
1.5 ± 0.4
6.2 ± 1.3
6.7 ± 2.2
4.1 ± 1.3
3.7 ± 1.5
5.0 ± 1.3
35.3 ± 10.4
25.3 ± 7.9
28.8 ± 4.5
27.8 ± 4.1
20.8 ± 8.5
15.1 ± 1.1
55.9 ± 14.4a
32.7 ± 4.1a
26.5 ± 8.5
18.3 ± 2.9
It has been known for many years that hemorrhagic shock causes metabolic acidosis. In the present model, a prolonged metabolic acidosis associated with a transient increase in AG after shock induction was observed but was not adequately accounted for by the concomitant hyperlactatemia. In addition, the SIG increased significantly after induction of shock.
The physicochemical approach to acid-base balance originally described by Stewart  and subsequently modified by Watson , Fencl and Rossing , and Figge and colleagues [13, 17] has become common in the last decade [18–26]. According to this approach, the dissociation equilibrium is supplemented with equations incorporating the necessity for electrical neutrality and the principles of conservation of mass. Weak acid concentrations (albumin and phosphate), the pCO2, and the SID have been identified as variables with independent effects on pH . Two different methods of calculating the SID exist. The first, leading to the apparent SID (SIDa), relies on simply measuring as many strong cations and anions as possible and then summing their charges. The second, yielding the effective SID (SIDe), estimates the SID from the pCO2 and the concentrations of the weak acids . The difference between SIDa and SIDe has been termed SIG and attains a positive value when unmeasured anions are present in excess of unmeasured cations and attains a negative value when unmeasured cations exceed unmeasured anions .
In the present study, a negative SIG obtained at baseline indicates an excess of unmeasured cations. However, it should be noted that the baseline values were established after surgical preparation and infusion of large amounts of a crystalloid solution, resulting in electrolyte concentrations with particularly high serum chloride levels. Therefore, for graphical depiction, we used relative values representing increments and decrements in SIG and AG.
The data from the present study strongly suggest that large amounts of unmeasured anions, expressed either as the AG or as the SIG, are likely to be generated during states of global tissue hypoxia. This finding is in line with results of Kaplan and Kellum , who reported increases in SIG in patients with major vascular injury, a condition generally associated with global tissue hypoperfusion. Also, in a study investigating the cause of the metabolic acidosis after cardiac arrest, Makino and colleagues  showed that increases in SIG contributed approximately 33% to the metabolic acidosis.
With regard to the source of unmeasured anions, one can only speculate. An increased SIG appears to occur in patients with renal  and hepatic  impairment, and unexplained anions have been shown experimentally to arise from the liver in animals challenged with bolus intravenous endotoxin . In our canine model of hemorrhagic shock, serum concentrations of citrate were significantly increased after shock induction. This is in accordance with a recent finding of Forni and colleagues , who found elevated levels of anions usually associated with the Krebs cycle in patients with large AG acidosis. Citric acid, a tribasic acid, is reported to be 97% ionized at a pH of 7.0 . Thus, each molecule of citric acid adds three protons to a solution upon ionization, and the contribution of citrate to the generation of unmeasured anions is of much greater significance than is apparent from its molarity.
pK values of Krebs cycle intermediates
Another potential source of citrate might have been the stepwise reinfusion of whole blood during the standardized induction of shock given that the blood was stored with a CPDA solution. This blood contained approximately 12 mmol citrate per liter, and amounts ranging from 0 to 360 mL were given. However, there was absolutely no correlation between the individually reinfused volume of blood and the level of citrate found afterward in blood samples taken following induction of shock (results not shown). Since citrate changes in serum are a balance between endogenous production, exogenous load, and liver metabolism, a contribution of exogenous citrate to the changes in SIG cannot be ruled out totally.
The rise of acetate during induction of shock is not really surprising. Irrespective of the type of energy-yielding substrate (sugars, amino acids, and fats), oxidative utilization always passes via degradation to acetate, which is then coupled to coenzyme A. Hydrolytic cleavage of acetyl-coenzyme A back to acetate will occur when there is a block in mitochondrial consumption of this thiol-ester. Thus, increased acetate also supports the assumption that mitochondrial dysfunction was caused by the hemorrhagic shock.
Serum concentration of urate also increased significantly after shock induction. This is in excellent agreement with induction of a state of catabolism of high-energy adenine and guanine nucleotides during shock. The rise in urate supports the presumed damage to hepatic metabolism because urate is normally degraded to allantoin in the dog liver. However, the concentrations of this metabolite in dog serum, as befits a non-primate species, were much too low to account for the changes in SIG.
The healthy vascular endothelium is coated by a large variety of extracellular domains of membrane-bound molecules, which together constitute the glycocalyx. Heparan sulfate is a polysulfated polysaccharide that is linked to core molecules of the endothelial glycocalyx. Shedding of these polyanionic heparan sulfates might be another potential source of unmeasured anions, and, indeed, our group has recently demonstrated acute destruction of the endothelial glycocalyx in humans experiencing ischemia and reperfusion injury . The present study also indicates shedding of heparan sulfate after hemorrhagic shock. However, this did not parallel the changes in SIG (Figures 3 and 5). After alkaline hydrolysis of serum, sulfate anions, already present in canine serum at levels of approximately 0.7 mM, did not change enough to account for much of the changes in SIG.
Outcome prediction based on the quantitative approach remains controversial. Some investigators have found that the pH and the standard base excess are better outcome predictors than the SIG . However, other investigators have found that the SIG is a powerful predictor of outcome in acutely ill or injured patients. In critically ill patients, SIG was a strong independent predictor of mortality when it was the major source of acidosis . Also, in patients with major vascular injury  and in children following cardiopulmonary bypass surgery [27, 37], an elevated SIG appeared to be superior to other conventional mortality predictors.
Growing evidence suggests that extracellular acidosis itself has profound effects on the host, particularly in the area of immune function. It is now becoming apparent that different forms of acidosis and even different types of metabolic acidosis produce different effects , and SIG generation may be one feature.
Fluid resuscitation might have affected the SIG in the present model of hemorrhagic shock, although only hydroxyethyl starch solutions were given. The colloid molecule itself may be a weak acid. Albumin and gelatin preparations contain a weak acid activity [20, 39]. Gelatins have been shown to increase both AG and SIG, most likely due to their negative charge and relatively long circulating half-life .
There are several limitations in this study. First, we were not able to find a strict correlation between SIG and the serum concentrations of citrate and/or acetate. This is not entirely unexpected since the generation of the SIG is most probably multifactorial. Second, we have used capillary electrophoresis for identification of potential candidates, and concentrations of still-unknown metabolites may be below the level of detection of this method. Third, using Stewart's approach to acid-base balance has some limitations. A major criticism is a possible inaccuracy of determinations of plasma electrolyte concentrations. Such inaccuracy means that the calculation of the SIDa, AG, and SIG can be erroneous [41, 42]. If, as in our study, mean values of larger collectives are used, always with utilization of the same measurement techniques for determinations of electrolytes, these limitations should be insignificant.
We demonstrated that large amounts of unmeasured anions were generated after hemorrhage in this highly standardized canine model of shock. Using Stewart's quantitative approach to acid-base balance, we found that the strongest determinant of this acidosis was the SIG. Capillary electrophoresis identified acetate as an important contributor to the SIG. Moreover, we have shown that the serum concentrations of citrate, fumarate, and α-ketoglutarate, all three intermediates of mitochondrial metabolism, were elevated after induction of shock. Sulfate and β-hydroxybutyrate, on the other hand, though present in relevant amounts in serum, did not contribute to the change in SIG associated with hemorrhagic shock. Our study did not assay for a number of other metabolites with potential relevance for acid-base balance as single individual contributors to the unmeasured anions in hemorrhagic shock. These include nitrite, nitrate, oxalate, malonate, oxalacetate, malate, succinate, oxoglutarate, and glucuronate. The amount of sulfate equivalents liberated into plasma as a result of shedding of the endothelial glycocalyx after hemorrhagic shock seems too small to be of quantitative significance. However, taken together, the expected elevations of all these anions in plasma in association with states of hypoxia and shock are undoubtedly significant.
The present canine model of standardized hemorrhagic shock shows a prolonged metabolic acidosis associated with a transient increase in unmeasured anions after shock induction.
Capillary electrophoresis suggests that this increase in unmeasured anions is largely attributable to acetate and to anions associated with the Krebs cycle.
30 minutes post-therapy
60 minutes post-therapy
180 minutes post-therapy
amount of weak plasma acid
serum concentration of albumin
serum equivalents of calcium
serum concentration of chloride
citrate, phosphate, dextrose, and adenine
serum concentration of potassium
serum concentration of lactate
serum equivalents of magnesium
serum concentration of sodium
partial pressure of carbon dioxide
serum concentration of phosphate
strong ion difference
apparent strong ion difference
effective strong ion difference
strong ion gap.
The authors thank Dora Kiesl and Alke Schropp for excellent technical assistance and Brigitte Blount for animal care. The work was performed using departmental research funding provided by the government of Bavaria (Bavarian State Ministry of Science, Research, and the Arts, Munich, Germany) and a grant provided by the Friedrich-Baur-Foundation (Munich). The original study was supported by Alliance Pharmaceutical Corp. (San Diego, CA, USA) and the Clinic of Anesthesiology, Ludwig-Maximilians-University (Munich).
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