Secondary Responses to Altered Acid

Secondary Responses to Altered Acid-Base Status:
The Rules of Engagement
Horacio J. Adrogue´ *†‡ and Nicolaos E. Madias§

*Department of Medicine, Baylor College of Medicine, Houston, Texas; †
Department of Medicine, Methodist Hospital,
Houston, Texas; ‡
Renal Section, Veterans Affairs Medical Center, Houston, Texas; §
Department of Medicine, Tufts
University School of Medicine, Boston, Massachusetts; and

Department of Medicine, Division of Nephrology,
St. Elizabeth’s Medical Center, Boston, Massachusetts
The physiologicapproach toacid-basedisorders
views blood pH as determined by the
prevailing levels of carbonic acid (PaCO2, the
respiratory component) and plasma bicarbonate
concentration ([HCO3

], the metabolic
component), as stipulated by the
Henderson equation, [H] 24 
PaCO2/[HCO3

].1Thefour canonical acidbase
disorders include the respiratory
disorders (acidosis and alkalosis) and the
metabolic disorders (acidosis and alkalosis).
Whereas the respiratory disorders
are expressed as primary changes in
PaCO2, the metabolic disorders are expressed
as primary changes in plasma
[HCO3

].2,3
Each primary change in either the respiratory
or the metabolic component
elicits in vivo a secondary response in the
countervailing component that is directional
and proportional to the primary
change, albeit fractionally smaller, thus
tending to minimize the change in body
acidity. These secondary responses originate
from physicochemical buffering
and change in ventilation, organic-acid
metabolism, and renal acidification.
They have been quantified in dogs and humans,
are consistent in presence and predictableinmagnitude,
and are viewed as an
integral part of each canonical disorder.
Absence of an appropriate secondary response
denotes the coexistence of an additional
acid-base disturbance.1–3
A popular, alternative epithet of the
secondary responses is compensatory.
We discourage use of this term, because
it evokes confusing pronouncements
about partial versus complete compensation;
secondary responses generally ameliorate
the impact of primary changes on
blood acidity but never completely restore
blood acidity to control levels.
Moreover, under certain circumstances,
secondary responses yield a maladaptive
effect on blood pH (see next section).1,3
We term the secondary responses to respiratory
acidosis (primary increase in
PaCO2) and respiratory alkalosis (primary
decrease in PaCO2) secondary hyperbicarbonatemia
and secondary hypobicarbonatemia,
respectively. The alternative
terms secondary or compensatory metabolic
alkalosis and secondary or compensatory
metabolic acidosis, respectively, are
also confusing and objectionable. Similarly,
the secondary responses to metabolic
acidosis (primary decrease in plasma
[HCO3

]) and metabolic alkalosis (primary
increase in plasma [HCO3

]) are
termed secondary hypocapnia and secondary
hypercapnia, respectively; we discourage
use of the alternative terms secondary
or compensatory respiratory alkalosis and
secondary or compensatory respiratory acidosis,
respectively.3
MAGNITUDE AND TIME COURSE
OF THE SECONDARY RESPONSES
Here we examine the mean slope of the
secondary response to each cardinal acidbase
disorder (Table 1) and the time interval
required for each secondary response
to reach completion. Toward this
end, we reviewed all available human
Published online ahead of print. Publication date
available at www.jasn.org.
Correspondence: Dr. Nicolaos E. Madias, Department
of Medicine, St. Elizabeth’s Medical Center,
736 Cambridge Street, Boston, MA 02135. Phone:
617-562-7502; Fax: [phone]; E-mail: nicolaos.
[e-mail]
Copyright © 2010 by the American Society of
Nephrology
ABSTRACT
Each of the four canonical acid-base disorders expresses as a primary change in
carbon dioxide tension or plasma bicarbonate concentration followed by a secondary
response in the countervailing variable. Quantified empirically, these secondary
responses are directional and proportional to the primary changes, run a
variable time course, and tend to minimize the impact on body acidity engendered
by the primary changes. Absence of an appropriate secondary response denotes
the coexistence of an additional acid-base disorder. Here we address the expected
magnitude of the secondary response to each cardinal acid-base disorder in
humans and offer caveats for judging the appropriateness of each secondary
response.
J Am Soc Nephrol 21: 920 –923, 2010. doi: 10.1681/ASN.2009121211
SCIENCE IN RENAL MEDICINE www.jasn.org
920 ISSN : 1046-6673/2106-920 J Am Soc Nephrol 21: 920–923, 2010
studies for each disorder and weighed
study design, methods, and evidence of a
steady state. One can think of these as
general rules for secondary responses.
Because of space constraints, we cite only
limited references.
Respiratory Acidosis
Hypercapnia acidifies body fluids and titrates
nonbicarbonate buffers, yielding a
small increase in plasma [HCO3

]. This
secondary hyperbicarbonatemic response
is completed within 5 to 10 minutes and
remains stable for several hours. Observations
in unanesthetized normal humans
studied in an environmental
chamber (inspired CO2 7 and 10%) reveal
a mean[HCO3

]/PaCO2 slope of 0.1
mEq/L per mmHg; expected [HCO3

]
24 [(current PaCO2
40)  0.1].4 An
essentially identical slope is obtained in
humans in whom respiratory acidosis is
induced by endogenous hypercapnia.5
Sustained hypercapnia causes an additional,
larger increase in plasma [HCO3

]
owing to stimulation of renal acidification.
In dogs, a new steady state emerges
within 3 to 5 days.6,7 Whether this temporal
pattern applies to humans is unknown.
In patients, chronic hypercapnia often reflects
gradual deterioration in pulmonary
function; consequently, the secondary response
might keep pace with the slowly rising
PaCO2 without a perceptible delay.
Careful observations of patients with
chronic hypercapnia as a result of chronic
obstructive pulmonary disease allowed estimation
of a mean [HCO3

]/PaCO2
slope of 0.35 mEq/L per mmHg; expected
[HCO3

] 24 [(current PaCO2

40)  0.35]. This slope functions up to a
PaCO2 of approximately 70 mmHg. Beyond
that level, the slope of [HCO3

]/
PaCO2 seems toflatten.8,9More recently, a
substantially larger slope was reported, but
the small number of blood gas measurements,
onefor each of 18 patients, callsinto
question the validity of the conclusion
reached.10
Respiratory Alkalosis
Hypocapnia alkalinizes body fluids and titrates
nonbicarbonate buffers, yielding a
decreasein plasma [HCO3

]. This secondary
hypobicarbonatemic response is completed
within 5 to 10 minutes and remains
stable for several hours. Hypocapnia of 20
to 120 minutes’ duration resultingfrom either
voluntary hyperventilation in normal
individuals or controlled hyperventilation
in anesthetized patients undergoing minor
surgical procedures yielded a mean
[HCO3

]/PaCO2 slope of 0.2 mEq/L
per mmHg; expected [HCO3

] 24

[(40
current PaCO2)  0.2].11,12
Sustained hypocapnia causes an additional
decrease in plasma [HCO3

] owing
to suppression of renal acidification.
A new steady state emerges within 2 to 3
days.13,14 Studies of normal volunteers
who were exposed to hypobaric hypoxia
(6 days) and unanesthetized patients
who had spinal cord or head injuries and
were undergoing controlled hyperventilation
(7 to 11 days) revealed a mean
[HCO3

]/PaCO2 slope of 0.4 mEq/L
per mmHg; expected [HCO3

] 24

[(40
current PaCO2)  0.4].14,15
Metabolic Acidosis
Primary hypobicarbonatemia engenders acidemia
that stimulates central and peripheral
chemoreceptors, causing increases in tidal
volume and, usually, respiratory rate. This
secondary hypocapnic response consistently
attends metabolic acidosis, whether induced
in normal volunteers who are administered
ammonium chloride or observed in patients
with various disorders, such as diarrhea, disturbancesofintermediarymetabolism,or
renal
failure. Although the magnitude of the
ventilatory response varies considerably
among studies, it seems to be independent
of the cause of the acidosis. Compiling
most published studies, a mean PaCO2/
[HCO3

] slope of 1.2 mmHg per
mEq/L is obtained; expected PaCO2
40
[(24
current HCO3)  1.2].16 –20
The secondary response appears within
30 to 120 minutes from onset of metabolic
acidosis; the time interval for its
completion (and its disappearance after
correction of the metabolic acidosis) depends
on the pace of development of the
disorder.21,22 In patients with cholera,
when plasma [HCO3

] falls or corrects
slowly, such as by 6 mEq/L in 24 hours,
the ventilatory response keeps pace with
the level of plasma [HCO3

]. Conversely,
when metabolic acidosis develops
or corrects rapidly, 11 to 24 hours is
required for the ventilatory response to
reach completion or vanish.16
Metabolic Alkalosis
Contrary to the wide recognition of metabolic
acidosis–induced secondary hypocapnia,
the very existence of secondary
hypercapnia in response to metabolic alkalosis
is controversial.23,24 Absence of
hypercapnia in some early studies can be
traced to methodologic problems and inclusion
of patients who have disorders
that stimulate ventilation.23 In addition,
confusion arises from the seemingly
paradoxic stimulation of ventilation observed
during rapid intravenous infusion
of sodium bicarbonate, a model of acute
metabolic alkalosis; this hyperventilatory
response, caused by decomposition of bicarbonateintoCO2,is
short-lived and converts
to alkalemia-induced hypoventilation.25
Subsequent studies established that
the alkalemia engendered by metabolic
alkalosis consistently suppresses alveolar
ventilation, an effect primarily caused by
Table 1. Secondary responses to alterations in acid-base status
Disorder Primary
Change
Secondary
Response Mean Slope of the Secondary Response
Respiratory acidosis 1PaCO2 1HCO3


acute HCO3

/PaCO2 0.1 mEq/L per mmHg
chronic HCO3

/PaCO2 0.35 mEq/L per mmHg
Respiratory alkalosis 2PaCO2 2HC

Kết quả (Việt) 1:

Trung học hồi đáp tới thay đổi axit-bazơ tình trạng:Sự tham gia của quy tắcHoracio J. Adrogue´ * †‡ và Nicolaos E. Madias§* Vùng y học, Baylor College of Medicine, Houston, bang Texas; †Vùng y khoa, bệnh viện Methodist,Houston, bang Texas; ‡Phần thận, cựu chiến binh Trung tâm y tế vấn đề, Houston, bang Texas; §Vùng y học TuftsTrường đại học y khoa, Boston, Massachusetts; vàCác bộ phận của Nephrology, vùng y họcSt Elizabeth của Trung tâm y tế, Boston, MassachusettsPhysiologicapproach toacid-basedisordersSố lần xem máu pH được xác định bởi cáccác cấp độ hiện hành của axit cacbonic (PaCO2, cácthành phần đường hô hấp) và bicacbonat plasmatập trung ([HCO3], sự trao đổi chấtthành phần), theo quy định của cácPhương trình Henderson, [H] 24PaCO2 / [HCO3] .1Thefour kinh điển acidbaserối loạn bao gồm các đường hô hấprối loạn (toan và alkalosis) và cácrối loạn chuyển hóa (toan và alkalosis).Trong khi các chứng rối loạn hô hấpđược biểu thị dưới dạng các thay đổi chính trongPaCO2, các rối loạn chuyển hóa được thể hiệnnhư các thay đổi chính trong huyết tương[HCO3] .2,3Mỗi thay đổi chính trong hai sự hô hấphoặc các thành phần trao đổi chấtelicits trong vivo một phản ứng phụ trong cácthành phần đó là hướng đối khángvà với chínhthay đổi, mặc dù fractionally nhỏ hơn, do đóChăm sóc để giảm thiểu sự thay đổi trong cơ thểđộ chua. Các phản ứng phụ có nguồn gốctừ hóa lý đệmvà thay đổi trong thông gió, axít hữu cơtrao đổi chất, và quá trình axit hóa thận.Họ có được định lượng ở chó và con người,phù hợp trong sự hiện diện và predictableinmagnitude,và được xem như là mộtphần không thể thiếu của mỗi rối loạn kinh điển.Sự vắng mặt của một phản ứng trung học thích hợpbiểu thị cùng tồn tại của một bổ sungaxit-bazơ disturbance.1–3Một danh hiệu phổ biến, thay thế của cácphản ứng thứ hai là đền bù.Chúng tôi không khuyến khích sử dụng thuật ngữ này, bởi vìnó gợi lên khó hiểu tuyên bốvề phần so với bồi thường hoàn chỉnh;phản ứng phụ thường phục hồitác động của các thay đổi chính trênnồng độ axit máu nhưng không bao giờ hoàn toàn khôi phụcmáu chua để kiểm soát mức độ.Hơn nữa, trong một số trường hợp,phản ứng phụ mang lại một maladaptivecó hiệu lực vào máu pH (xem phần kế tiếp) .1,3Chúng tôi hạn các phản ứng phụ để hô hấptoan (chính tăng trongPaCO2) và hô hấp alkalosis (tiểugiảm PaCO2) thứ cấp hyperbicarbonatemiavà trung học hypobicarbonatemia,tương ứng. Việc thay thếđiều khoản trung học hoặc đền bù trao đổi chấtalkalosis và trung học hoặc đền bùtrao đổi chất toan, tương ứng,cũng khó hiểu và gây khó chịu. Tương tự như vậy,Các phản ứng phụ để trao đổi chấttoan (chính giảm trong tương[HCO3]) và trao đổi chất alkalosis (tiểutăng trong plasma [HCO3])gọi là trung học hypocapnia và trung họchypercapnia, respectively; we discourageuse of the alternative terms secondaryor compensatory respiratory alkalosis andsecondary or compensatory respiratory acidosis,respectively.3MAGNITUDE AND TIME COURSEOF THE SECONDARY RESPONSESHere we examine the mean slope of thesecondary response to each cardinal acidbasedisorder (Table 1) and the time intervalrequired for each secondary responseto reach completion. Toward thisend, we reviewed all available humanPublished online ahead of print. Publication dateavailable at www.jasn.org.Correspondence: Dr. Nicolaos E. Madias, Departmentof Medicine, St. Elizabeth’s Medical Center,736 Cambridge Street, Boston, MA 02135. Phone:[phone]; Fax: [phone]; E-mail: [e-mail] © 2010 by the American Society ofNephrologyABSTRACTEach of the four canonical acid-base disorders expresses as a primary change incarbon dioxide tension or plasma bicarbonate concentration followed by a secondaryresponse in the countervailing variable. Quantified empirically, these secondaryresponses are directional and proportional to the primary changes, run avariable time course, and tend to minimize the impact on body acidity engenderedby the primary changes. Absence of an appropriate secondary response denotesthe coexistence of an additional acid-base disorder. Here we address the expectedmagnitude of the secondary response to each cardinal acid-base disorder inhumans and offer caveats for judging the appropriateness of each secondaryresponse.J Am Soc Nephrol 21: 920 –923, 2010. doi: 10.1681/ASN.2009121211SCIENCE IN RENAL MEDICINE www.jasn.org920 ISSN : 1046-6673/2106-920 J Am Soc Nephrol 21: 920–923, 2010studies for each disorder and weighedstudy design, methods, and evidence of asteady state. One can think of these asgeneral rules for secondary responses.Because of space constraints, we cite onlylimited references.Respiratory AcidosisHypercapnia acidifies body fluids and titratesnonbicarbonate buffers, yielding asmall increase in plasma [HCO3
]. Thissecondary hyperbicarbonatemic responseis completed within 5 to 10 minutes andremains stable for several hours. Observationsin unanesthetized normal humansstudied in an environmentalchamber (inspired CO2 7 and 10%) reveala mean[HCO3
]/PaCO2 slope of 0.1mEq/L per mmHg; expected [HCO3
]24 [(current PaCO2
40)  0.1].4 Anessentially identical slope is obtained inhumans in whom respiratory acidosis isinduced by endogenous hypercapnia.5Sustained hypercapnia causes an additional,larger increase in plasma [HCO3
]owing to stimulation of renal acidification.In dogs, a new steady state emergeswithin 3 to 5 days.6,7 Whether this temporalpattern applies to humans is unknown.In patients, chronic hypercapnia often reflectsgradual deterioration in pulmonaryfunction; consequently, the secondary responsemight keep pace with the slowly risingPaCO2 without a perceptible delay.Careful observations of patients withchronic hypercapnia as a result of chronicobstructive pulmonary disease allowed estimationof a mean [HCO3
]/PaCO2slope of 0.35 mEq/L per mmHg; expected[HCO3
] 24 [(current PaCO2
40)  0.35]. This slope functions up to aPaCO2 of approximately 70 mmHg. Beyondthat level, the slope of [HCO3
]/PaCO2 seems toflatten.8,9More recently, asubstantially larger slope was reported, butthe small number of blood gas measurements,onefor each of 18 patients, callsintoquestion the validity of the conclusionreached.10Respiratory AlkalosisHypocapnia alkalinizes body fluids and titratesnonbicarbonate buffers, yielding adecreasein plasma [HCO3
]. This secondaryhypobicarbonatemic response is completedwithin 5 to 10 minutes and remainsstable for several hours. Hypocapnia of 20to 120 minutes’ duration resultingfrom eithervoluntary hyperventilation in normalindividuals or controlled hyperventilationin anesthetized patients undergoing minorsurgical procedures yielded a mean[HCO3
]/PaCO2 slope of 0.2 mEq/Lper mmHg; expected [HCO3
] 24
[(40
current PaCO2)  0.2].11,12Sustained hypocapnia causes an additionaldecrease in plasma [HCO3
] owingto suppression of renal acidification.A new steady state emerges within 2 to 3days.13,14 Studies of normal volunteerswho were exposed to hypobaric hypoxia(6 days) and unanesthetized patientswho had spinal cord or head injuries andwere undergoing controlled hyperventilation(7 to 11 days) revealed a mean[HCO3
]/PaCO2 slope of 0.4 mEq/Lper mmHg; expected [HCO3
] 24
[(40
current PaCO2)  0.4].14,15Metabolic AcidosisPrimary hypobicarbonatemia engenders acidemiathat stimulates central and peripheralchemoreceptors, causing increases in tidalvolume and, usually, respiratory rate. Thissecondary hypocapnic response consistentlyattends metabolic acidosis, whether inducedin normal volunteers who are administeredammonium chloride or observed in patientswith various disorders, such as diarrhea, disturbancesofintermediarymetabolism,orrenalfailure. Although the magnitude of theventilatory response varies considerablyamong studies, it seems to be independentof the cause of the acidosis. Compilingmost published studies, a mean PaCO2/[HCO3
] slope of 1.2 mmHg permEq/L is obtained; expected PaCO240
[(24
current HCO3)  1.2].16 –20The secondary response appears within30 to 120 minutes from onset of metabolicacidosis; the time interval for itscompletion (and its disappearance aftercorrection of the metabolic acidosis) dependson the pace of development of thedisorder.21,22 In patients with cholera,when plasma [HCO3
] falls or correctsslowly, such as by 6 mEq/L in 24 hours,the ventilatory response keeps pace withthe level of plasma [HCO3
]. Conversely,when metabolic acidosis developsor corrects rapidly, 11 to 24 hours isrequired for the ventilatory response toreach completion or vanish.16Metabolic AlkalosisContrary to the wide recognition of metabolicacidosis–induced secondary hypocapnia,the very existence of secondaryhypercapnia in response to metabolic alkalosisis controversial.23,24 Absence ofhypercapnia in some early studies can betraced to methodologic problems and inclusionof patients who have disordersthat stimulate ventilation.23 In addition,confusion arises from the seeminglyparadoxic stimulation of ventilation observedduring rapid intravenous infusionof sodium bicarbonate, a model of acutemetabolic alkalosis; this hyperventilatoryresponse, caused by decomposition of bicarbonateintoCO2,isshort-lived and convertsto alkalemia-induced hypoventilation.25Subsequent studies established thatthe alkalemia engendered by metabolicalkalosis consistently suppresses alveolarventilation, an effect primarily caused byTable 1. Secondary responses to alterations in acid-base statusDisorder PrimaryChangeSecondaryResponse Mean Slope of the Secondary ResponseRespiratory acidosis 1PaCO2 1HCO3
acute HCO3
/PaCO2 0.1 mEq/L per mmHgchronic HCO3
/PaCO2 0.35 mEq/L per mmHgRespiratory alkalosis 2PaCO2 2HC