COMMON

 CAUSES  OF  HYPOXEMIA 2015

Common  Causes  of  Hypoxemia  

Instructor:    Dr.  Dawn  Cooper,  MSc,  PhD  

 Department  of  Cellular  &  Physiological  Sciences,  University  of  British  Columbia  
 Office:  LSC  1547  
 Email:  d.cooper@ubc.ca  

Suggested  Readings  
1) Respiratory  Physiology:  A  Clinical  Approach,  Shwartzstein  &  Parker,  Ch.  5.
2) Respiratory  Physiology:  The  Essentials.  John  B.  West.  Ninth  Edition.  Chapter  5.
3) Pulmonary  Circulation  and  the  Ventilation-­‐Perfusion  Ratio.  Rodney  A.  Rhodes.  Medical
Physiology.  Chapter  20.

Learning  Objectives  

1. Define  and  distinguish  between  hypoxia  and  hypoxemia

2. Be  able  to  calculate  the  A-­‐a  gradient,  define  its  normal  range,  and  describe  its
significance  in  distinguishing  between  the  common  causes  of  hypoxemia.
3. Describe  the  clinically  important  causes  of  arterial  hypoxemia.

1. Definitions
• Hypoxia:  Failure  of  oxygenation  at  the  tissue  and  cellular  level
• Hypoxemia:   Low   partial   pressure   of   oxygen   in   the   blood.   Specifically,   hypoxemia
is   determined   by   measuring   partial   pressure   of   oxygen   in   the   arterial   blood
[PaO2]
 COMMON  CAUSES  OF  HYPOXEMIA 2015

2. A-­‐a  gradient:  Alveolar-­‐arterial  Difference  in  Oxygen  (A-­‐a  DO2)

In  the  perfect  lung,  the  PaO2  of  arterial  blood  would  be  the  same  as  that  in  the  alveolar  gas.  In  
reality   however,   the   blood   that   traverses  the   pulmonary   capillary   never   quite   reaches   that   of  
PAO2.   There   will   always   be   a   small   difference   between   PAO2   and   PaO2   (~10-­‐20   mmHg).   This  
natural,  small  decrease  in  PaO2  is  due  to  three  factors:  1)  incomplete  diffusion  (immeasurably  
small),   2)   ventilation   and   perfusion   are   not   perfectly   matched   even   in   healthy   individuals  
(ventilation  and  perfusion  are  best  matched  at  the  base  of  the  lungs),  and  3)  a  small  percentage  
of   bronchial   arterial   blood   is   collected   by   the   pulmonary   veins   after   it   has   perfused   the   bronchi  
and  its  O2  has  been  partly  depleted.  When  the  difference  between  the  calculated  PAO2  and  PaO2  
measured  from  a  sample  of  blood  is  greater  than  10-­‐20  mmHg,  the  lungs  are  not  transferring  
oxygen  properly.  

Clinically,  the  A-­‐a  DO2  can  be  used  to  identify  potential  causes  of  hypoxemia.  The  formula  takes  
into   account   the   partial   pressure   of   oxygen   in   the   alveoli   and   the   arterial   blood   and   can   be  
determined  as  follows:  
(1)  Obtain  PaO2  and  PaCO2  levels  by  sampling  arterial  blood  gases  
(2)  Use  PaCO2  and  the  Alveolar  Air  Equation  to  calculate  PAO2  
(3)  Calculate  A-­‐a  DO2  =  PAO2  (determined  using  alveolar  air  equation)  –  PaO2  (from        
           the  arterial  blood  gases)  
Note:  Large  values  for  A-­‐a  DO2  point  to  problems  with  gas  exchange.  

• Normal  range:  ≤ 10  mmHg  breathing  room  air  [FlO2  -­‐  0.21]  in  young  adults.  The  normal
A-­‐a  DO2  exists  due  to  venous  admixture.  In  the  healthy  individual,  the  normal  anatomic
shunt  and  the  regional  differences  in  VA/Q  in  the  lungs  result  in  venous  admixture.
The  normal  range  for  A-­‐a  DO2  increases  with  age  [an  approximate  formula:  A-­‐a  gradient
=(Age/4)+4].  This  increase  is  due  to  the  age-­‐dependence  of  normal  PaO2.     PaO2  declines
slightly  over  the  years  and  reflects  the  change  in  VA  /Q  ratio  of  the  aging  lungs.

Normal  A-­‐a  gradient:    A-­‐a  gradient  –  (Age/4)  +4  

Increased  age  affects  A-­‐a  gradient  (at  sea  level  on  room  air)  
1. Age  20  years:  4  to  17  mmHg
2. Age  40  years:  10  to  24  mmHg
3. Age  60  years:  17  to  31  mmHg
4. Age  80  years:  25  to  38  mmHg
 COMMON  CAUSES  OF  HYPOXEMIA 2015

3. Five  Causes  of  Hypoxemia  [↓PaO2  ]

The   mechanisms   that   cause   hypoxemia   can   be   divided   into   those   that   increase   A-­‐a   DO2   and  
those  where  A-­‐a  DO2  is  preserved.  

1. Low  inspired  oxygen  [↓Pio2]  Pio2  =  (PB  –  PH20)  FIO2

• A-­‐a  DO2  normal  (PAO2  and  PaO2  will  be  decreasing  at  the  same  rate)

Examples  
• A  decrease  in  barometric  pressure  [e.g.  breathing  at  high  altitude].
• A   decrease   in   FIO2   –   accidental   [e.g.   anesthetist   does   not   supply   enough   oxygen   or
improper  installation  of  oxygen  supply  lines  in  a  leak  in  the  breathing  circuit].

In  situations  of  low  inspired  oxygen,  PaCO2  is  decreased.  This  reduction  in  PaCO2  (hypocapnia)  is  
due   to   hyperventilation   in   response   to   hypoxemia.   Peripheral   chemoreceptors   sense   the   low  
arterial   PO2   and   initiate   and   increase   in   ventilation   through   their   input   to   the   medullary  
respiratory  centre.  

2. Alveolar  Hypoventilation  (low  alveolar  ventilation)

o A-­‐a  DO2  is  normal  (PAO2  and  PaO2  will  be  decreasing  at  the  same  rate)
o PaCO2  is  elevated  (hypercapnia)

The  body’s  primary  means  of  eliminating  carbon  dioxide  is  through  the  lungs  (via  the  alveoli).  
The  relationship  between  alveolar  ventilation  and  carbon  dioxide  elimination  can  be  described  
by  the  alveolar  ventilation  equation:  

   PaCO2  ~  V�CO2  
     VA�  

This  equation  states  alveolar  PACO2  is  directly  proportional  to  the  amount  of  CO2  produced  by  
metabolism   and   delivered   to   the   lungs   (V" CO2)   and   inversely   proportional   to   the   alveolar  
ventilation  (V, A).  

Alveolar   Hypoventilation   (reduced   alveolar   ventilation)   is   always   associated   with   elevated  

PaCO2   (hypercapnia).   If   you   look   back   at   the   alveolar   ventilation   equation,   a   reduction   in  
alveolar   ventilation   means   the   volume   of   gas   entering   and   exiting   the   alveoli   per   unit   time   is  
reduced.  This  will  cause  an  increase  in  the  alveolar  PCO2   (PACO2)  because  the  gas  is  not  being  
exchanged  at  a  normal  rate.  In  turn,  the  carbon  dioxide  in  the  blood  perfusing  the  alveoli  will  
begin  to  accumulate  and  increase  the  partial  pressure  of  carbon  dioxide  in  the  blood  (PaCO2).  
 COMMON  CAUSES  OF  HYPOXEMIA 2015

Supplemental   oxygen:   Increasing   the   fraction   of   inspired   oxygen   (FIO2)   can   alleviate   the  
hypoxemia   and   the   hypercapnia   can   be   corrected   by   mechanically   ventilating   the   patient   to  
eliminate  CO2.  

3. Diffusion  Impairment  (Diffusion  Abnormality)

• A-­‐a  DO2  is  normal  at  rest  but  may  be  elevated  during  exercise.
• A  rare  observation  in  the  clinical  setting

In  healthy  individuals,  a  transit  time  for  red  blood  cells  in  the  pulmonary  capillary  exceeds  that  
required   for   the   PO2   in   the   mixed   venous   blood   to   reach   equilibrium   with   the   alveolar   gas.  
During  exercise,  when  there  is  an  increase  blood  flow,  this  transit  time  is  decreased  but  there  
remains   sufficient   time   for   the   PO2   in   the   mixed   venous   blood   to   reach   equilibrium   with   the  
alveolar  gas.  The  exception  to  this  is  the  elite  athlete  who  achieves  very  high  cardiac  outputs  
during  exercise  resulting  in  a  large  decrement  in  pulmonary  transit  time.  

In  disease  states,  impaired  diffusion  may  occur  when  there  is  an  increase  in  the  thickness  of  the  
physical   separation   between   alveolar   gas   and   pulmonary   capillary   blood   and   a   shortened  
pulmonary   transit   time.   Both   of   these   conditions   exist   in   a   patient   with   an   interstitial   lung  
disease  performing  exercise.    

Supplemental   oxygen:   Increasing   the   fraction   of   inspired   oxygen   (FIO2)   can   alleviate   the  
hypoxemia  because  it  increases  the  partial  pressure  gradient  driving  oxygen  across  the  altered  
blood  air  barrier.  

4. Ventilation-­‐perfusion  inequality  [Ventilation-­‐perfusion  mismatch]:  V/Q  mismatch

• A-­‐a  DO2  is  elevated
• Can  be  treated  with  supplemental  oxygen

For   efficient   gas   exchange   to   occur,   air   must   reach   the   regions   of   the   lung   that   are   being  
appropriately  perfused.  The  relationship  between  ventilation  and  perfusion  is  described  by  the  
V/Q  ratio.  On  average,  alveolar  ventilation  is  4  L/min  and  cardiac  output  is  5  L/min  (pulmonary  
blood  flow).  The  normal  range  for  the  V/Q  ratio  for  the  lung  is  0.8 - 1.    

Even  in  healthy  lungs,  the  matching  of  ventilation  and  blood  flow  is  not  perfect.  Ventilation  and  
blood   are   both   gravity-­‐dependent;   with   both   increasing   as   you   move   down   the   lungs.   Blood  
flow  shows  about  a  5-­‐fold  difference  between  the  top  and  bottom  of  the  lung,  while  ventilation  
shows  about  a  2-­‐fold  difference.  This  causes  gravity-­‐dependent  regional  variations  in  the  V/Q  
ratio  that  range  from  0.7  at  the  base  of  the  lungs  to  3.0  at  the  apex.  
• At   the   top   of   the   lungs,   where   the   V/Q   ratio   is   high,   there   is   relatively   more
ventilation  compared  to  perfusion
• At   the   base,   where   the   V/Q   ratio   is   low,   there   is   more   perfusion   compared   to
ventilation
 COMMON  CAUSES  OF  HYPOXEMIA 2015

This  normal  pattern  of  ventilation  and  perfusion  accounts  for  approximately  2/3  of  the  normal  
A-­‐a  DO2  seen  in  healthy  individuals  and  does  not  present  any  gas  exchange  problem.  

Please  note  that  the  physiology  of  V/Q  mismatching  is  significantly  more  complicated  than  has  
been   summarized   here;   however,   a   significant   proportion   of   that   information   is   clinically  
relevant  (meaning  it  won’t  help  you  at  the  bed  side).  What  you  do  need  to  understand  is  that  
even  in  healthy  individuals,  matching  of  airflow  and  blood  flow  is  not  perfect  but  that  significant  
deviations   from   0.8   represent   problems   with   gas   exchange   and   will   decrease   the   PO2   in   arterial  
blood.   Deviations   from   0.8   will   occur   with   age   (due   to   a   number   of   factors   including   the  loss   of  
elastic  recoil  in  the  lungs)  and  be  exacerbated  in  certain  disease  states.  

Supplemental   oxygen:   Supplemental   oxygen   will   help   correct   hypoxemia   due   to   V/Q   mismatch  
because  it  will  provide  additional  oxygen  to  the  low  V/Q  regions  of  the  lung.  If  we  look  back  at  
our   oxyhemoglobin   dissociation   curve,   we   can   see   that   supplemental   oxygen   will   have   very  
little  affect  on  the  high  V/Q  regions  of  the  lung  because  the  blood  coming  from  these  regions  
will  be  nearly  fully  (95-­‐98%)  saturated.  If  you  refer  back  to  the  plateau  phase  of  the  dissociation  
curve,   increasing   supplemental   oxygen   will   not   significantly   improve   the   saturation   of   blood  
that   is   already   nearly   fully   saturated.   However,   supplemental   oxygen   will   improve   both   the  
saturation  and  PaO2  of  the  blood  coming  from  the  regions  of  the  lung  with  low  V/Q  ratios.    

5. Shunting
A  shunt  is  a  condition  in  which  deoxygenated  blood  from  the  venous  system  is  directed  to  the  
arterial  system  without  receiving  oxygen  from  the  lungs.  Shunts  occur  naturally  and/or  can  be  
the  result  of  a  disease  process.    
• A-­‐a  DO2  is  elevated
• Hypoxemia  will  not  be  corrected  by  supplemental  oxygen

Common   causes   of   shunting   include   congenital   abnormalities,   such   as   intra-­‐cardiac   shunts   (e.g.  
Tetralogy  of  Fallot:  ventricular  septal  defect  +  pulmonary  artery  stenosis)  and  intrapulmonary  
fistulas   (direct   communication   between   a   branch   of   the   pulmonary   artery   and   a   pulmonary  
vein).  Each  will  contribute  deoxygenated  blood  to  the  venous  admixture.  

Supplemental   oxygen:   The   key   clinical   feature   of   the   shunt   is   that   the   accompanying  
hypoxemia  cannot  be  corrected  with  administration  of  supplemented  oxygen.  This  is  because  
the  shunted  blood,  by  definition,  will  never  be  exposed  to  the  supplemental  oxygen.  
 COMMON  CAUSES  OF  HYPOXEMIA 2015

Table  1:  Summary  Table:  Common  Causes  of  Hypoxemia  and  Response  to  Supplemental  Oxygen  

Responds  to  Supplemental  

Causes  of  Hypoxemia   A-­‐a  DO2  
Oxygen  

Low  FIO2   Normal   Yes  

Alveolar  Hypoventilation   Normal   Yes  

Diffusion  Abnormality   Can  be  elevated   Yes  

Shunt   Elevated   No  

V/Q  Mismatch   Elevated   Yes