pH DEPENDENT INOTROPIC

ENHANCEMENT

experimental observations from a rat study

ANESTHESIOLOGY, 2014

A plea for rat-derived studies

beginning of RAAS modulation era in clinical practice

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”

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?

Assigning a context -effects of bicarbonate on hemodynamics-

Assigning a context -effects of bicarbonate on hemodynamics-

Assigning a context -effects of bicarbonate on hemodynamics-

Assigning a context -effects of bicarbonate on hemodynamics-

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-

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

Assigning a context - getting a spur -

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

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 ?

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

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

Assigning a context - a 2006 context-

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

• 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

• 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?

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.

As if that wasn’t enough…

Efficient Extra- and Intracellular Alkalinization Improves Cardiovascular Functions in Severe Lactic Acidosis

Induced by Hemorrhagic Shock

(ANESTHESIOLOGY 2014; 120:926-34)

Kimmoun et al

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

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

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

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

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

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.

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

Results (1)

Hyperlactatemia, extracellular acidosis in shock vs sham Impairment of load dependent and independent parameters of left ventricular

function

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

Results (3)

-intracellular pH-

Results (4) -vasoreactivity-

Results (5) -ESPVR-

Results (5) -Pi/Pcr-

No difference between the three groups

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.

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

22 questions survey

• 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

• 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?