Buying time in situations of extreme hemodynamic instability by partially reversing acidemia with a controlled strategy involving bicarbonate, calcium and hyperventilation. Minimizing CO2 buildup as well as resulting hypocalcemia after alkalinization improves hemodynamics in a rat-derived french study.

1. pH DEPENDENT INOTROPIC
ENHANCEMENT
experimental observations from a rat study
ANESTHESIOLOGY, 2014

2. A plea for rat-derived studies
beginning of RAAS modulation era in clinical practice

3. A plea for rat-derived studies
 A bold NEJM editor – Dr Arnold
Relman
 A handful of experimental studies
believers
 A rat study – Brenner et al,
Mechanism of AgII – induced
proteinuria in rats, Am J Physiol
1977; 233:F13:21
Relman’s reply to the “new medical-industrial complex”

4. Assigning a context
 Is there any pH-dependent modulation of cardiovascular hemodynamics?
 Is there any pH-modulation of something other than cardiovascular hemodynamics that
might be of clinical significance?
 Is there any evidence at all for administering bicarbonate therapy to critically ill patients?
 Is there any role at all for bicarbonate therapy ?
 Is there any rationale for a holistic approach involving bicarbonate - SID - chloride – related
effects on any outcome?
 Is there any evidence for SID-dependent modulation of any outcome ?
 Beyond evidence-based medicine, what is the actual practice regarding bicarbonate/SID –
related therapeutics?

5. Assigning a context
-effects of bicarbonate on hemodynamics-

6. Assigning a context
-effects of bicarbonate on hemodynamics-

7. Assigning a context
-effects of bicarbonate on hemodynamics-

8. Assigning a context
-effects of bicarbonate on hemodynamics-

9.  pH modulates the delivery of Ca2+ as well as the myofilament sensibility to Ca2+
(JLiou and Chang, J Biochem. 136, 683–692;2004)
 A low pH is associated with depression of SERCA(SR-Ca2+ ATP-ase), the
ryanodine receptor and Na+/Ca2+ exchanger (Choi HS, J Physiol 2000, 529(Pt
3):661-668; Doering AE, J Physiol 1993, 466:481-499)
 A low pH has been shown to be associated with low Ca2+ transient amplitude
(Allen DG, Orchard CH, J Physiol 1983,335:555-567)
 Low pH induced KATP mediated vessel hyporeactivity (B. Levy, Intensive Care
Med (2010) 36:2019–2029)
 increased vulnerability to CO2-induced cardiac depression in patients receiving a
β-adrenergic receptor antagonist or with otherwise compromised inotropic
reserve (G.J.Crystal, Anesth Analg 2015;121:610–23)
Assigning a context
-acidosis induced myocardial dysfunction-

10. Assigning a context
-expanding the conundrum-
 Eight end-stage human failing hearts were obtained from patients undergoing transplantation
 Inclusion criteria were diagnosed terminal heart failure, listing for transplantation
(Eurotransplant criteria ) due to dilated or ischaemic cardiomyopathy.
 Intact isometrically twitching trabeculae were exposed to mild metabolic acidosis(pH 7.20);
they were stiumulated at increasing frequencies and finally exposed to increasing
concentrations of isoproterenol
 A mild metabolic acidosis caused a depression in twitch-force amplitude of 26% as compared
with pH7.40.
 At the maximal isoproterenol conc., the force amplitude was comparable but EC50 had a
fivefold increase in the acidosis group, reflecting impaired β-adrenergic response

11. Assigning a context
- getting a spur -

12. Assigning a context
- Beyond hemodynamics -
 87 unselected patients admitted to the ICU during a 2-year period were included
 Measurement of multiple inflammatory mediators in plasma using multiplex assays
 Evaluation the association between mediator concentrations and acid–base variables using a variety of
statistical modeling approaches, including generalized linear models, multiadaptive regression splines
and principal component analysis
 A principal component analysis including SAPS 3 indicated that the association between acid–base
components and inflammatory status was largely independent of illness severity, with both increased
SIG and decreased SIDa (both drivers of acidosis) associated with increased inflammation

13.  There is a strong interplay between acid-base variables and
immunological activation.
 Albumin may modulate circulating concentrations of
several cytokines in a complex interplay with other
components of acid-base status, such as SIG or SIDa.
 Higher SIG values appear to be associated with increasing
inflammation.
 The association between acid-base components and
inflammation cannot be explained only by illness severity
ALBIOS ?

14. Assigning a context
- targeting normochloremia ( Gilfix approach)-
 Association between intravenous chloride load during resuscitation and in-hospital mortality
among patients with SIRS, Shaw et al, Intensive Care Med (2014) 40:1897–1905
 Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid
Administration Strategy and Kidney Injury in Critically Ill Adults, Bellomo, Story et al, JAMA,
October 17, 2012—Vol 308, No. 15
 Lactated Ringer’s Solution Reduces Systemic Inflammation Compared with Saline in Patients
With Acute Pancreatitis, Wu et al, CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
2011;9:710–717
 Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis, Bellomo,
Venkatesh et al, Journal of Critical Care (2012) 27, 138–145
 Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis
in patients with diabetic ketoacidosis, Mahler et al, American Journal of Emergency Medicine
(2011) 29, 670–674
Na-Cl effect=0.3(Naobsv-140) + 102-Clobsv•140/Naobsv

15. Assigning a context
- Awaiting for the SPLIT trial -
Saline vs. Plasma-Lyte 148® for Intensive care fluid Therapy (SPLIT) study
 aim : to provide preliminary data on the comparative effectiveness of 0.9% saline vs. Plasma-
Lyte 148® as the routine IV fluid therapy in ICU patients
 type: prospective, multicentre, randomised, double-blind, cluster, double crossover feasibility
study conducted over 28 weeks in four New Zealand ICUs
 primary outcome : patients with either acute kidney injury (AKI) or renal failure according
(RIFLE) criteria definitions based on serum creatinine levels
 Secondary outcomes : the delta creatinine (difference between the serum creatinine
measured immediately prior to study enrolment and peak creatinine in ICU), the cumulative
incidence of acute AKI by category based on the RIFLE classification, the cumulative incidence
of acute AKI by KDIGO criteria, the need for RRT during ICU and after hospital discharge, the
proportion of patients requiring mechanical ventilation and duration of mechanical
ventilation, the proportion of patients who require ICU readmission during their hospital
admission, ICU and hospital length of stay, and ICU and in-hospital mortality

16. Assigning a context
- a 2006 context-

17. Background. Acute severe metabolic acidosis associated with lactic acidosis
or ketoacidosis can have severe detrimental effects on organ function, and
might contribute to mortality. A general consensus exists that elimination of
the cause of the acidosis is essential for treatment, but there is controversy
concerning the use of base for the treatment of these disorders. Some
physicians advocate administration of base when the acidosis is severe to
prevent a decrease in cardiac output, whereas others oppose administration
of base even when the acidosis is severe given the potential compromise of
cardiac function. Nephrologists and critical care specialists are often the
physicians developing recommendations for the treatment of severe acid-
base disorders
Kurtz et al,Clin Exp Nephrol (2006) 10:111–117

18. • 1. Do you administer base to patients with acute metabolic acidosis?
• 2. Does the type of metabolic acidosis present, i.e. high vs normal (hyperchloremic) anion gap acidosis, affect
your decision to give base?
• 3. Do you ever administer base to patients with ketoacidosis?
• 4. Do you ever administer base to patients with lactic acidosis?
• 5. Does the cardiac status of the patient with metabolic acidosis modify your decision as to whether to
administer base therapy?
• 6. If your answer to question 5 is yes, do you administer base therapy only when the cardiac function appears to
be reduced or only when it appears to be normal?
Only when it is reduced Only when it is normal Either when it is reduced or normal
• 7. Do you use blood pH or blood bicarbonate concentration to decide when to give base?
Blood pH Blood bicarbonate Other, please specify
• 8. If you use blood bicarbonate, what value do you choose to begin base administration?
<20 mEq/l <15 mEq/l <10 mEq/l <5 mEq/l
• 9. Does the level of PaCO2 affect your decision about giving base?
• 10. What level of bicarbonate do you aim to achieve?
>20 mEq/l >15 mEq/l >10 mEq/l >5 mEq/l Other

19. • 11. If you use blood pH, what blood pH do you choose to begin therapy?
<7.3 <7.2 <7.1 <7.0 Other, please specify.
• 12. What blood pH do you try to achieve with base administration?
pH 7.4 or greater pH 7.3 or greater pH 7.2 or greater pH 7.1 or greater pH 7.0 or greater Other
• 13. How rapidly do you try to achieve your target blood pH or bicarbonate concentration?
<2 hours 2–4 hours 4–8 hours 8–12 hours 12–24 hours Other, please specify.
• 14. Do you give base in the form of bicarbonate?
• 15. If you administer base as bicarbonate, how do you give it?
Bolus Infusion Other, please specify
• 16. Do you give forms of base other than bicarbonate? If the answer is yes, specify what are they are
• 17. Do you calculate the amount of base to be administered and if so what volume of distribution of
administered bicarbonate do you use?
• 18. If a patient has renal failure and requires dialysis, does the presence of acidosis affect whether you choose
intermittent hemodialysis or a form of continuous renal replacement therapy?
• 19. If you use intermittent hemodialysis, do you adjust the dialysate bicarbonate concentration to reduce the
speed of rise in plasma bicarbonate concentration?
• 20. If you choose continuous renal replacement therapy, do you use bicarbonate-containing replacement fluids?

20. Kurtz et al,Clin Exp Nephrol (2006) 10:111–117
• Results. Although there was variability among individual physicians
from both specialties, a larger percentage of nephrologists than critical
care physicians queried recommended administration of base for the
treatment of lactic acidosis (86% vs 67%) and ketoacidosis (60% vs
28%). Also, critical care physicians in general used a lower level of
blood pH when deciding when to initiate treatment. Of the physicians
who gave base, most utilized sodium bicarbonate as the form of base
given.

21. As if that wasn’t enough…

22. Efficient Extra- and Intracellular Alkalinization Improves
Cardiovascular Functions in Severe Lactic Acidosis
Induced by Hemorrhagic Shock
(ANESTHESIOLOGY 2014; 120:926-34)
Kimmoun et al

23. determine the cardiovascular and metabolic
effects of an adapted sodium bicarbonate therapy,
including the prevention of carbon dioxide increase
and ionized calcium decrease, in a resuscitated rat
model of severe lactic acidosis induced by
hemorrhagic shock
clinical implication?
Buying time with bicarbonate

24. Material and Methods
- common animal preparation-
 Male wistar rats 300-400g
 Core body temperature maintained at 37C
 Infusion of equal amounts of fluids
 Sodium intake was equivalent for all experimental groups
ensuring a common denominator

25. Material and Methods
-Shock model-
 Hemorrhagic shock was induced by drawing blood in 10
min until a MAP of 40-45mmHG
 MAP was maintained during the remaining 50 min by
redrawing blood/transfusing the collected blood
 pH of less than 7.2 and a hyperlactatemia greater than
3mM defined shock at >1 hour

26. Material and Methods
-Group design-
 Standard resus: retransfusion in 10 min +/- NE (1-6mcg/kg/min) targeting
90% MAP (5 rats)
 Adapted group: Standard resus plus administration of sodium bicarbonate
8.4% 0.2mmol/100g over 5 min at time of shock and again at 30 min) and
calcium chloride 10% 2mg/100g over 5 min at time of shock and after 30
min. Targeting a PaCO2 of 38-42 mmHg (5 rats)
 Nonadapted group: Standard resus plus sodium bicarbonate at time of
shock without tailoring for PaCO2 or calcemia.(5 rats)
 Calcium group: Standard resus plus calcium chloride adm. 2mg/100g over 5
min at time of shock and after 30 min(5 rats)
 Hyperventilation group: Standard resus plus hyperventilation – RR-90 (5
rats) Sham group=5 rats

27. Material and Methods
-Sodium intake-
 Accounting for osmotic effects was realized by adm. NaCl
20% + glu 5% to achieve the same sodium load and
volume as the equivalent bicarbonate solution

28. Material and Methods
-time of in vivo measurements-
 Hemodynamic measurements, standard biological assays,
pHi, Pi/phosphocreatine were collected at baseline, at
time of shock, at 30 and 60 minutes after resus.
 For the catheter conductance study, experiments were
continued at 120 min and for the pHi 60 min after resus.

29. Material and Methods
-measurements-
 HD measurements: pressure-volume conductance catheter for
ESPVR quantification(Emax)-preload variation was assessed
by compression of the IVC.
 Spectroscopy(NMRS) based measurement of intracelular pHi,
Pi, phosphocreatine
 Exvivo vascular reactivity measurements-wire myograph
 Cytokine analyses-Il6, Il 10, TNF alfa
 NO2+NO3 measurement as an indicator of NO production
 RTPCR for NOSi RNA and HIF1 RNA

30. Results (1)
 Hyperlactatemia, extracellular acidosis in shock vs sham
 Impairment of load dependent and independent parameters of left ventricular
function

31. Results (2)
 Increased extracellular pH for AG rats in comparison with the other three groups
 Lactatemia tends to be higher in the bicarbonate groups on account of alkalosis induced
metabolic inertia
 For AG, PACO2 is significantly lower in comparison with NG
 ∆Emax is significantly higher for AG rats in comparison with the standard and NG

32. Results (3)
-intracellular pH-

33. Results (4)
-vasoreactivity-

34. Results (5)
-ESPVR-

35. Results (5)
-Pi/Pcr-
 No difference between the three groups

36. Author’s view on limitations and perspectives
 Small sample size in each group
 Rats were adm. neuromuscular-blocking agent, that
impeding their ability to hyperventilate. The implication
might be that the standard group did worse than it should
have.

37.  Acute situations in the expectation of specific therapeutic efficiency
► acute cardiogenic shock before reperfusion
► uncontrolled hemorrhagic shock before/during surgery
► septic shock with cardiac and vascular hyporesponsiveness
 Paralyzing agents should be avoided and PCO2 should be in the lower normal ranges.
 PCO2 should be monitored during bicarbonate adm.
 Monitor Ca2+ and administer calcium preemtively
Author’s view on clinical practice implications
Buying time with bicarbonate

38. 22 questions survey

39. • 1. Do you administer base to patients with acute metabolic acidosis?
• 2. Does the type of metabolic acidosis present, i.e. high vs normal (hyperchloremic) anion gap acidosis, affect
your decision to give base?
• 3. Do you ever administer base to patients with ketoacidosis?
• 4. Do you ever administer base to patients with lactic acidosis?
• 5. Does the cardiac status of the patient with metabolic acidosis modify your decision as to whether to
administer base therapy?
• 6. If your answer to question 5 is yes, do you administer base therapy only when the cardiac function appears to
be reduced or only when it appears to be normal?
Only when it is reduced Only when it is normal Either when it is reduced or normal
• 7. Do you use blood pH or blood bicarbonate concentration to decide when to give base?
Blood pH Blood bicarbonate Other, please specify
• 8. If you use blood bicarbonate, what value do you choose to begin base administration?
<20 mEq/l <15 mEq/l <10 mEq/l <5 mEq/l
• 9. Does the level of PaCO2 affect your decision about giving base?
• 10. What level of bicarbonate do you aim to achieve?
>20 mEq/l >15 mEq/l >10 mEq/l >5 mEq/l Other

40. • 11. If you use blood pH, what blood pH do you choose to begin therapy?
<7.3 <7.2 <7.1 <7.0 Other, please specify.
• 12. What blood pH do you try to achieve with base administration?
pH 7.4 or greater pH 7.3 or greater pH 7.2 or greater pH 7.1 or greater pH 7.0 or greater Other
• 13. How rapidly do you try to achieve your target blood pH or bicarbonate concentration?
<2 hours 2–4 hours 4–8 hours 8–12 hours 12–24 hours Other, please specify.
• 14. Do you give base in the form of bicarbonate?
• 15. If you administer base as bicarbonate, how do you give it?
Bolus Infusion Other, please specify
• 16. Do you give forms of base other than bicarbonate? If the answer is yes, specify what are they are
• 17. Do you calculate the amount of base to be administered and if so what volume of distribution of
administered bicarbonate do you use?
• 18. If a patient has renal failure and requires dialysis, does the presence of acidosis affect whether you choose
intermittent hemodialysis or a form of continuous renal replacement therapy?
• 19. If you use intermittent hemodialysis, do you adjust the dialysate bicarbonate concentration to reduce the
speed of rise in plasma bicarbonate concentration?
• 20. If you choose continuous renal replacement therapy, do you use bicarbonate-containing replacement fluids?
• 21. Do you administer calcium during bicarbonate infusion targeting a normal Ca2+? If higher , specify the value
• 22. Do you maintain normocapnia during bicarbonate administration?