Evaluation of Metabolic Acid-base Abnormalities in Pre-eclamptic Women Applying the Stewart-Fencl Approach
Condition: Mild Pre-eclampsia; Severe Pre-eclampsia
MeSH terms: Eclampsia; Pre-Eclampsia
Study type: Observational

Summary: 
      Acid/base imbalances are not well understood in pre-eclamptics, and better tools are needed
      to allow a thorough and meaningful evaluation. Disorders of electrolytes and albumin are
      common findings [13, 14], and the impact of such disorders on acid-base homeostasis has
      increasingly been acknowledged [4, 15]. The purpose of this prospective case-control study is
      to evaluate acid-base status in 100 women with mild or severe pre-eclampsia and 25 healthy
      controls by applying the Stewart Fencl's physicochemical acid-base model. We hypothesize that
      several simultaneous, and possibly offsetting, metabolic acid-base disorders will be
      identified and quantified, and that these may be useful to guide clinicians in their medical
      management and indication for delivery. Intermediate and long-term goals are to evaluate the
      ability of the Stewart Fencl's physicochemical acid-base model to guide fluid management and
      predict maternal and neonatal outcomes.
    

Detailed description: 
      Studies evaluating acid/base imbalances are scarce in pre-eclamptics, and tools to thoroughly
      evaluate them are lacking. The detection of metabolic acidosis has been proposed as a
      diagnostic criterion for a severe disease state8, 11, however other studies entirely reject
      the presence of any metabolic acid-base disorder in pre-eclampsia10. One reason for this
      controversy may lie in the fact that no study performed a full comprehensive acid base
      analysis. Whereas some measured plasma pH, HCO3 and BE8, 11 others focused on AG1 or AG and
      HCO32, 10 only. Merely one study corrected the AG for low albumin1, and no study focused on
      independent variables. While some of the cited reports were based on retrospective chart
      review without differentiating mild and severe disease state1, 2, the few prospective studies
      available were of low sample size including a total number of 311 or 98women with severe
      pre-eclampsia. As indicated above, it is totally legitimate to use the traditional approach
      to describe changes in hydrogen ion concentration and HCO3. The Henderson-Hasselbach equation
      does differentiate well between respiratory and metabolic acid-base changes. However, it is
      unable to quantify metabolic causes15. SBE quantifies net change in metabolic acid-base
      status in vivo, but does not tell us about mechanisms16. The AG is insufficient to detect
      unmeasured anions17, 18, but when corrected for low albumin it does not detect all unmeasured
      cations16.

      Intravascular volume depletion and disorders of electrolytes and albumin are common findings
      in pre-eclampsia1, 2 and the impact of such disorders on acid-base homeostasis has been
      increasingly acknowledged in the last decade3, 19. Decreased serum albumin has an alkalizing
      effect on plasma, resulting in hypoalbuminemic alkalosis. Furthermore, derangements in
      volume, sodium and chloride homeostasis, as well as the accumulation of unmeasured anions,
      are common findings in pre-eclampsia7 and may result in multiple acid-base disorders. The
      presence of hyponatremia or hyperchloremia has an acidifying effect on blood pH, whereas
      hypernatremia or hypochloremia lead to alkalosis. The accumulation of unmeasured anions, such
      as lactate or uric acid, will lead to acidemia, if not otherwise compensated3, 20.

      We hypothesize that with comprehensive analysis, clinically significant and complex metabolic
      derangements might be discovered in pre-eclamptics that will potentially impact their care
      plan. To our knowledge, this will be the first time that the Stewart-Fencl methodology will
      be used to determine causes of acid-base status in pre-eclamptics, which takes into account
      the multiple, potentially opposing, electrochemical disturbances observed in this patient
      population.

      Specific Aims

      Aim 1: Prevalence

      The primary aim is a description of the prevalence of acid-base disorders in pregnant women
      with pre-eclampsia at three time points:

        1. at time of diagnosis with mild pre-eclampsia,

        2. at time of progression to severe pre-eclampsia, and

        3. at time of delivery. Pregnant women without pre-eclampsia will be used as a comparison
           group for (a) and (b) for testing whether the.prevalence of acid-base disorders is
           higher in pre-eclampsia than in pregnancy without pre-eclampsia.

      Aim 2: Changes over time in acid base status This aim is to describe and test change over
      three time points in the prevalence of acid-base disorders among those women who progress
      from mild to severe pre-eclampsia, and change from initial diagnosis to delivery among women
      whose pre-eclampsia remains mild.

      Aim 3: Acid-base as clinical predictor This aim will test whether acid-base variables at time
      of diagnosis with mild pre-eclampsia predict which women will progress to severe
      pre-eclampsia and/or need an urgent delivery.

      Significance (Note-include significance in relation to translational health science)

      Pre-eclampsia complicates 2-8% of pregnancies, and is a major contributor to fetal and
      maternal morbidity/mortality worldwide5, 21, 22.

      The only cure for pre-eclampsia is delivery. However, especially remote from term, the
      premise that delaying delivery to allow for the fetus to continue to grow and thrive in utero
      is a big part of what expectant management is trying to achieve. The challenge remains to
      this day to balance the benefits of a prompt delivery (undeniably benefiting the mother)
      versus allowing the fetus to remain in utero (although if placental insufficiency is severe
      and endothelial dysfunction critical, the baby may well be better off delivered).
      Unfortunately, there are no strict criteria (hemodynamic, metabolic or other) or any
      predictive model that may guide obstetricians in the decision to proceed with a prompt
      delivery or allow prudent expectant management. Therefore, management is mostly guided by
      expert opinion-based guidelines, which do not accurately predict adverse maternal events23,
      24. The fullPIERS-model, recently published results from a large clinical trial, considers
      gestational age, chest pain or dyspnea, oxygen saturation, platelet count, serum creatinine
      levels and aspartate transaminase concentration, to predict adverse maternal outcome with a
      sensitivity of 75% and a specificity of 87%25. However, for most of these predictors the
      worst values recorded during the first 48 hours of study were used to predict complications
      within the same 48 hour time frame 26. In practice, a model based exclusively on information
      available at admission is still needed. The data evaluated by the proposed Stewart-method
      would add to the physiologic understanding of the disease, would be easy to obtain at
      admission and possibly discover new predictors for adverse maternal and perinatal events.

      Research Approach

      In this prospective case-control study, previously normotensive women diagnosed with mild
      pre-eclampsia as defined by the American Association of Hypertension 27 will be enrolled.
      Blood samples from women with pre-eclampsia and healthy controls will be gathered, and plasma
      pH, HCO3- and BE will be measured. According to the Stewart-Fencl methodology these
      parameters are dependent variables of the following four factors 12, 28:

        -  The difference of strong cation and anion concentration, or 'strong ion difference'
           (SID)

        -  The pCO2

        -  The concentration of weak acids, which are mainly albumin and phosphate (Atot)

        -  The presence of other acids, so called unmeasured anions (UMA) or strong ion group (SIG)

      Based on that concept, BE can be defined by:

      (A) plasma dilution/concentration (=changes in Na+-concentration, (BENa+)) (B) changes in
      chloride concentration (BECl-) (C) changes in albumin concentration (BEAlb) (D) changes in
      lactate (BELac) (E) changes in unmeasured anions (BEUMA). BE = BENa+ + BECl- + BEAlb + BELac
      + BEUMA

      Each component will be identified and quantified as described by Gilfix et al.17. (A detailed
      explanation can be found in the Appendix of this application).

      Statistical Analysis Because of the descriptive and exploratory nature of this pilot study,
      no controls for multiple comparisons will be made. Any results from this study will be
      interpreted as hypothesis generating, to justify a larger further study.

      Aim 1: Prevalence The primary aim is a description of the prevalence of acid-base disorders
      in pregnant women with pre-eclampsia at three time points: (a) at time of diagnosis with mild
      pre-eclampsia, (b) at time of progression to severe pre-eclampsia, and (c) at time of
      delivery, in comparison to pregnant women without pre-eclampsia.

      For each of the BE measures, abnormal will be defined as differing from +/-2mEq/l or more. If
      any one of the BE measures is abnormal, the woman will be classified as having an acid-base
      disorder. Descriptive displays (tables and/or bar charts) will be used to describe the
      percent of women with an acid-disorder at each of (a) to (b) and in control women. In
      addition, we will describe how many of these cases have offsetting disorders so that the
      total BE is normal, i.e. they would not have been identified by the traditional approach.
      Further displays will describe the prevalence of abnormal values for each of the 5 components
      separately. In addition, we will explore the utility of displaying means and SDs of each of
      the 5 BE components.

      Logistic regression will be used to test for differences in prevalence of acid-base disorder
      in pre-eclampsia versus controls, at each of (a) and (b) time points, while controlling for
      gestational age as a covariate. Linear regression will be used to test for differences in the
      means of each of the BE components between pre-eclampsia and controls, controlling for
      gestational age.

      Aim 2: Changes over time in acid base status This aim is to describe and test change over
      three time points in the prevalence of acid-base disorders among those women who progress
      from mild to severe pre-eclampsia, and change from initial diagnosis to delivery among women
      whose pre-eclampsia remains mild.

      Mixed models for binary outcome data, using for example xtlogit in Stata, will be used to
      test for changes over time in prevalence. Further analyses will use mixed models for
      continuous outcomes to test for changes in means of the individual BE scores over time.

      Aim 3: Acid-base as clinical predictor This aim will test whether acid-base variables at time
      of diagnosis with mild pre-eclampsia predict which women will progress to severe
      pre-eclampsia and/or need an urgent delivery. A chi-square test can be used to test whether
      the fraction of women progressing to sever pre-eclampsia is different in those with abnormal
      versus normal acid-base at time of diagnosis of mild pre-eclampsia. Further analysis will use
      logistic regression analyses to test whether the 5 BE components predict probability of
      progression. Potential confounding variables such as medications (e.g furosemide) used to
      control symptoms or severity of the disease will also be evaluated to see whether controlling
      for these variables changes the association of acid-base variables with risk of progression.

      We will further explore a variety of neonatal and maternal outcome variables for a possible
      association with acid-base predictors. Please find those secondary outcome variables
      described in detail in the appendix of the revised application. Please find also clarified if
      variables are categorical or continuous.

      • Sample size

      Sample size is based on the observation in a pilot sample of 25 paired arterial and venous
      blood specimens in women with severe pre-eclampsia of mean venous BE(Alb) = + 4.4 (± 0.75)
      mEq/l. Considering a power of 1.0 and an alpha of 0.05, a sample size of 25 women in each
      group was needed to show a difference of 20% in BE(Alb) between cases and control groups.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients diagnosed with mild pre-eclampsia and admitted on the labor and delivery unit at
        the UWMC will be included consecutively and their clinical course will be followed, until
        25 cases have progressed to severe pre-eclampsia. At each state of the disease a blood gas
        will be drawn (mild disease, severe disease, beginning labor or with decision for cesarean
        delivery). However, some women will deliver before severe pre-eclampsia develops
        (continuing mild pre-eclampsia), because disease is either late or only slowly progressing
        (study flow chart).

        Analyzing the number of women treated for mild and severe pre-eclampsia in 2011 and 2012,
        we are expecting to see a 3x higher number of mild than severe cases of pre-eclampsia,
        which means we will need to enroll approximately 100 women with mild pre-eclampsia in order
        to have 25 who develop severe pre-eclamsia..
      
Biospecimen description: 
      VBGs