Coagulation

Coagulation


6 thrombophilias (hypercoagulability) of major interest:

• Activated protein C resistance (APCR)
• Factor V Leiden mutation
• Hyperprothrombinemia
• Factor II G20210A mutation
• Antithrombin (ATIII) deficiency
• Protein C deficiency
• Protein S deficiency
• Hyperhomocysteinemia*

Major Causes of Inherited Hypercoagulability

http://drtedwilliams.net/kb/index.php?pagename=Platelet%20Aggregation

Hemostasis

Dr. Scariano -  Hemostasis




Secondary Hemostasis
• Goal: generation of massive amounts of fibrin by thrombin
• Activation of (serine protease) zymogens (inactive enzymes) by injury
– Damaged endothelium
– Activated platelets 
– Tissue Factor
• “Thrombin burst” and fibrin generation
• Simultaneous activation of natural anticoagulant and fibrinolytic systems
• Players must assemble and be oriented on a phospholipid membrane
– Importance of vitamin K in post-translational modification of factors 2, 7, 9 & 10 (procoagulent factors)
• Restriction to injured areas

• everything in blood has negative charge (repels other components)
• thrombin circulates in inactive form - activated by factor 10

Fibrinogen: plasma protein synthesized in liver (nl 200-400 mg/dL)

• Soluble fibrinogen is converted to insoluble fibrin by thrombin, an active serine protease 

• The fibrin monomer assembly is covalently cross-linked to form a mature blood clot (13a)

• Prothrombin zymogen circulates in an inactive conformation

• Factor 10a converts prothrombin to its active form

• Factor 10 zymogen circulates in an inactive conformation

• How is factor 10 activated?

Initiation of the clotting cascade

Tissue factor (TF): integral membrane protein cofactor normally expressed on most extravascular cells

• During injury, circulating factor 7 (zymogen and pre-activated form) bind TF

• Factors 7 and 10: reciprocal activation amplification loop

• When factor 7a activity reaches a threshold level, it converts factor 9 zymogen to 9a

Sustained amplification of the clotting cascade

Factor 9a: 50x more catalytically efficient than factor 7a in generating factor 10a 

– Dependency on cofactor (VIIIa)

• 10a converts prothrombin to thrombin – Dependency on cofactor (5a)

• Thrombin cleaves fibrinopeptides from fibrinogen

• Factor 13a transglutaminase crosslinks fibrin monomers

PATHWAYS - 2 OR 1????   MOST SAY ONE.

Vitamin K dependence

• Vutamin K dependent : factors 2, 7, 9, 10, Protein C and Protein S 

• Cofactor for gamma carboxylation of critical glutamate residues

• Allows calcium dependent bridging of factors to phospholipid membranes

• Undercarboxylation results in their inactivity (reduced binding to PL)

• Active form of vitamin K must be regenerated (VKORs)

• Warfarin (Coumadin) inhibits regeneration of the active reduced form of vitamin K and quantitatively reduces K-dependent factors(7a = shortest half-life)

Clotting time tests

1) The prothrombin time (PT) is a common 

clotting time test that uses 

supraphysiological amounts of tissue factor 

(thromboplastin + calcium) as an activator 

of the “extrinsic pathway” , bypassing the 

need for factor 9a.

• The INR is calculated from the prothrombin 

time test: INR = [patient PT/controlPT]

ISI

• Measures the integrity and activity of the 

following factors: 7, 10, 5, prothrombin (2) 

and fibrinogen (1)

• INR is normally 0.8 – 1.2

• Used as a general coagulation screen and 

also to monitor warfarin therapy 

(INR goal 2-4)

• Bleeding risk with elevated INR

2) The activated partial thromboplastin time (aPTT) is another common clotting time test that uses an anionic polymer as an activator of the “intrinsic pathway” 

• The measures the integrity and activity of the following factors: 12, 11, 9, 8, 10, 5, 2 

and 1

• aPTT is normally 25-39 seconds (depends on reagents)

• Used as a general coagulation screen and also as a crude measure of heparin therapy

• Newer heparin activity assay is available

• Bleeding risk with elevated aPTT

Naturally circulating anticoagulants

• On a molar basis, the inhibitors of the clotting cascade are in excess compared with the active procoagulant proteases. Why is this so?

• Important players:

– Antithrombin

– Activated Protein C and Protein S

– Tissue Factor Pathway Inhibitor (TFPI)

– PGI2: (Prostacyclin): Platelet antagonist

– Α-1-antitrypsin, α-2-macroglublin, etc.

• Deficiencies of naturally circulating anticoagulants tip balance toward clotting

FIBRINOLYSIS

• Local Augmentation

• Systemic inhibition

• Fibrin stimulates release of tPA from endothelial cells

• Fibrin is a cofactor for plasminogen activation by tPA

• α-2-antiplasmin & PAI-1 are not effective inhibitors of thrombus-bound plasmin and plasminogen activator

• α-2-antiplasmin & PAI-1 are effective inhibitors of plasmin and plasminogen activator in circulation

D-Dimer

• Specific byproduct of mature crosslinked fibrin degradation

• Quantitative levels available in most labs

• Normal levels < 0.5 μg/mL

• Longer circulating half life than other FSPs

• Increased in patients with acute thromboembolism

• Increased in malignancy and infections

• Sensitive but nonspecific test for thrombi

• Reliable negative predictive value

– if d-dimer is < 0.5 μg/dL, clot (i.e., PE, DVT) is unlikely 

Dr. Ahmed  --Myocardial Oxygen Supply/Demand

simple calculus - supply vs demand

LAD and Circumflex perfuse 80% of the heart


Coronary artery anatomy
 Left main arises from aorta distal to the left coronary cusp of aortic valve
 Bifurcates into left anterior descending (LAD) and circumflex (LCX) arteries
 Can also trifurcate to give off Ramus Intermedius
 LAD runs down anterior portion of the heart and gives off septal (S) and diagonal branches (D)
 LCX runs down lateral and posterior parts of the LV and gives off obtuse marginals (OM) branches



Right coronary artery (RCA)
 Comes off the right coronary cusp of the aorta
 Will first give rise to SA node artery to supply SA Node
 As it courses in right AV groove, gives off acute marginal (RV) branches to RV
 Continues posteriorly to give off posterior left ventricular branches (PLV) and posterior descending artery (PDA) in most individuals (70-85%)


Coronary Dominance
 Determined by which artery supplies the posterior descending artery 
– 85% RCA (right dominant)
– 7% Circumflex (left dominant)
– 8% both (co-dominant)

Blood flow x arterial O2 = O2 delivery

Flow most important  (occurs mainly during diastole)

• Q = P/R
• R related to r^4

Flow Control

•  Most potent stimulus is myocardial hypoxia
•  Works through release of mediators such as adenosine and nitric oxide, as well as activation of the ATP-sensitive K+ channels.
• Other Determinants and Factors influencing flow:
• Vasodilation
• Neural Input
•  Alpha stimulation leads to vasoconstriction
•  Beta and vagal stimulation lead to vasodilatation
• Autoregulation
•  Ability to regulate constant flow at varying coronary pressures under basal conditions
•  Multiple factors such as paracrine factors, neurohormonal agonists, neural tone and shear stress modulate coronary vasomotor tone autoregulate coronary flow.

Oxygen Content


Arterial oxygen content (CaO2) (ml/O2/dl) = (Hgb x 1.36 x SaO2 

) + (0.0031 x 

PaO2

)

SaO2 = % of hemoglobin saturated with oxygen
(Normal range: 93-100%)
Hgb = hemoglobin
Normal range(Adults): Male: 13-18 g/dl Female: 12-16 g/dl
PaO2= Arterial oxygen partial pressure 

(Normal range: 80-100 mm hg)

Concepts:
 CaO2

: Directly reflects the total number of oxygen molecules in 

arterial blood (both bound and unbound to hemoglobin)

 Supply can be reduced by anemia, carbon monoxide poisoning, 

hypoxia

 Oxygen extraction is the difference between what comes in and 

what goes out (i.e. CaO2 –CvO2)

Oxygen Demand

1. Wall Tension

Related to intracavitary pressure and volume by the 

Law of Laplace

 Law of Laplace: 

– Wall tension = pressure X radius/

wall thickness

 Increased cavitary pressure and increased
ventricular size both increase wall tension, while 

increased thickness decreases wall tension.

Concept: Law of Laplace determines wall tension and is directly related
to intra-cavitary pressure and size and inversely related to wall
thickness.

dioesn't talk about overall mass - wall thicker = more myocytes consuming oxygen
2. Contractility

• shifts of Starling Curves
  
  

3. Heart rate

Supply Demand Problems

Supply problems

– Nonocclusive thrombus on preexisting plaque

– Dynamic obstruction (spasm)

– Progressive mechanical 

obstruction

– Inflammation and/or infection

- Acute coronary syndrome

Demand problems

– Secondary angina

 Fever, tachycardia, anemia

Medications - Acute Coronary Syndrome = supply problem

"MONA"

• morphine
• oxygen
• nitroglycerine
• aspirin - morbity & mortality decreases

 Increase supply

– Nitrates – coronary vasodilators

– Calcium channel blockers - vasodilators

 Decrease demand

– Beta blockers – decrease HR, 

contractility, BP

– Calcium channel blockers – decrease HR, 

contractility, BP (limited role)

Dr. Spaulding 

- Hypertension

Dr. Valenzuela - Pharmacology of RAAS

ACE = endothelial enzyme - abundant in lungs
ACE inhibitors

• vasodilator effects

• cardiac benefits = decrease in remodelling
• Indications
• Congestive heart failure (CHF)
• Hypertension monotherapy (young caucasians)
• Hypertension associated with CHF or diabetes
• Cardioprotective after acute myocardial infarction - block remodel pathways
• Delay the progression of kidney disease, including diabetic nephropathy
• side effects

• cough
• angioedema
• hyperkalemia
• hypopolarization
• faster repolarization - peaked T wave
• slows upstroke - wide QRS
• bradycardia - inc K conductance = keeps sa node cells polarized = low slope of phase 4.
• renal failure in pts. with renal artery stenosis - AT2 constricts efferent arteriole

• Drug Interactions
• NSAIDS

• Diuretics
• Thiazides - cause K loss= good interaction since ACE inhibitors can cause hyperkalemia
• e.g., lisinopril/hydrochlorothiazide for HTN

Angiotensin 2 receptor blockers (ARBs)

Aldosterone Blockers

Spironolactone, Eplerenone

Antagonize effect of high aldosterone levels in heart failure, renal disease, 

and post-myocardial infarction:

1. Antagonize fibrotic and inflammatory effects of aldosterone

2. Prevent aldosterone escape (or aldosterone breakthrough) phenomenon:

• ACE inhibitors and ARBs initially cause a decrease aldosterone levels but 

these then gradually increase in some patients, decreasing effectiveness 

of these medications

• Incidence can be as high as 10-50% over 12 months

• Should test for it in refractory cases (i.e., measure aldosterone levels)

• 

Mechanisms: non-ACE enzymes can cleave angiotensin-I into 

angiotensin II? Other factors can increase aldosterone (corticotropin, 

vasopressin) 

Toxicity:

1. Hyperkalemia in patients with renal disease or

those taking ACE inhibitors, angiotensin II receptor 

antagonists or b-blockers

2. Gynecomastia, impotence and menstrual abnormalities (not 

reported with eplerenone). (structure similar to cholesterol-inhibits testosterone production; increases estrogen)

Pathophysiology of valve disease

Dr. Roldan  pathophysiology of valve disease

aortic valve 

• tricuspid leaflets
• aortic regurgitation = diastolic (ARD) starts at S2
• acute - endocarditis, aortic dissection, trauma, valve implant malfunction
• chronic - Bicuspid aortic valve, Aortic root/annular dilatation, Previous endocarditis, Rheumatic disease, Connective tissue diseases
• aging, infection, inflammation

• large pulse pressure > 100 mm Hg
• systolic murmur may also be hearddue to large stroke volume - 3-4 left IC space
• increased with hand grip maneuver (increases diastolic P)

• aortic stenosis = systolic (ASS)  starts after S1

• only chronic
• crescendo - decresendo as turbulent flow increases then decreases
• 2nd right intercostal space with pt. leaning forward  (increases periph. vasc. resist.)
• causes
• < 70 y/o = congenital bicuspid valve
• > 70 y/o = degenerative (calcified, sclerosed)
• 
  

mitral valve

• bicuspid leaflets
• MI can damage papillary muscles = regurgitation
• mitral stenosis = diastolic (MSD) starts after S2
• rheumatic fever > 95%
• high risk for stroke (LA clot)

• mitral regurgitation = systolic  (MRS) starts at S1 - best heard at apex

murmurs memory tool:  hARD ASS MSD MRS

tricuspid valve

• 3 leaflets
• allow tivial nl regurg (lower closing pressures)
• the trivial to mild regurgitation % refers to percent of the population who show this, not the % regurgitation.

pulmonic valve

• 2 leaflets (SEMILUNAR)
• allow trivial nl regurg (lower closing pressures)
• the trivial to mild regurgitation % refers to percent of the population who show this, not the % regurgitation.

PRESSURE VOLUME LOOPS

AS - compensated

AS - decompensated

AR - compensated

AR Chronic Compensated  (dilated LV)

• similar to elite athletes

AR -decompensated  - systolic failure

MR acute compensated

• Incomplete closure 
• of mitral valve
• Flow regurgitates 
• back into the LA
• LA pressure
• LA size
• LV size
• LV end-diastolic 
• pressure

MR chronic compensated

MR chronic decompensated

MS 

• "happy left ventricle" = low EDP
• "sad right ventricle" = pressure overload RV failure

Summary Figure (looks like great MCQ for exams)

Pressure–volume loops in patients with valvular heart disease. A, normal; B, mitral stenosis; C, aortic stenosis; D, mitral regurgitation (chronic); E, aortic regurgitation (chronic). LV, left ventricular.

(Reproduced, with permission, from Jackson JM, Thomas SJ, Lowenstein E: Anesthetic management of patients with valvular heart disease. Semin Anesth 1982;1:239.)

Dr. Andrews

MS

• Acute, immunologically mediated, multisystem inflammatory disease that occurs a few weeks after an episode of group A streptococcal pharyngitis
• Pathogenesis
• Antibodies directed against the M proteins of streptococci have been shown to cross react with self antigens in the heart
• CD4+ T-cells specific for streptococcal peptides also react with self proteins in the heart, and produce cytokines that activate macrophages

Infective Endocarditis

• Infection characterized by colonization of the heart valves or 
  

  mural endocardium by a microbe
• Leads to vegetations
• Most cases caused by bacterial infections – bacterial endocarditis
• Acute infective endocarditis
• Infection of a previously normal heart valve by a highly virulent organism
  • that produces necrotizing, ulcerative, destructive lesions
• Subacute infective endocarditis
• Organisms of lower virulence
• Organisms cause insidious infections of deformed valves
• Janeway lesions (nontender, macular lesions most commonly involving the palms and soles). Janeway lesions occur more frequently in endocarditis caused by Staphylococcus aureus. Janeway lesions are caused by septic emboli. Subcutaneous abscesses are found on histologic examination.

FAQs Cardiovascular, Respiratory and Renal Physiology

Asthma

Question

When as pt has and asthma attack due to it being an obstructive problem , I thought the pt would be hypercapnic .. The PBL had the ABGS that showed hypocapnic. I dont follow the rational. Also, when A beta 2 agonist is given , does it initially cause hypoxemia because the vessels were vasodilated and when the beta agonist was given it caused vasoconstriction and this caused a Ventilation/respiration mismatch? 

Answer

the asthma attack caused a big-time mismatch in V/Q  by lowering V to alveoli downstream from constricted and mucus filled airways.

this caused a drop in arterial PO2

this caused stimulation of carotid PO2 receptor leading to hyperventilation (= decreased PCO2).  this would increase PO2 but not enough to compensate for the regions of the lung with low V/Q.

An arterial PO2 < 60 is defined as respiratory failure.  there are two types of respiratory failure:

type 1 = PO2 < 60 with normal or low PCO2 (patients can hyperventilate in response to hypoxia but still have low PO2)

type 2 = PO2 < 60 with high PCO2 (patients are unable to increase ventilation enough to lower PCO2)

memory tool:  type 2 = CO2

A beta 2 agonist may initially cause a drop in saturation by dilating arterioles more than airways, thus worsening V/Q mismatch.

Potassium
I'm finding a few little discrepancies between the currents discussed in class and those in Physiology by Costanzo, and was wondering what to go by. For example, regarding Phase 3, Costanzo never mentions an I(k1), only an I(k), but we had talked about both in class for this phase. Also for phase 4, Costanzo says for action potentials in the ventricles and atria, there is an outward I(k1) current and inward i(Na) and i(Ca-T), but in class we said it was an outward i(k) and inward i(Ca-T) and i(f). The only time Costanzo mentions i(f) is with the SA node action potential. Are these differences really important?

Answer

In contractile myocytes that exhibit fast-response action potentials and a stable phase 4, membrane permeability to potassium is high, largely due a high open probability of inwardly rectifying K channels (these channels carry the IK1 current).  Consequently, phase 4 membrane potential is close to the K equilibrium potential, and there is only a small outward K current.  Permeability to Na+ and Ca2+ is very low, so the inward currents associated with these ions are small.  Neither T-type channels nor channels that mediate the funny current (if) in pacemaker cells are involved here.

In pacemaker cells (e.g. SA node), there are 3 primary currents that are responsible for the phase 4 pacemaker potential:

a. An inward current (if) carried mainly by Na+.  

b. An inward Ca2+ current (iCa) that becomes activated toward end of phase 4, mediated by both L-type and T-type VGCC.  L-type channels are activated near the end of phase 4 and contribute not only to this pacemaker potential, but also phase 0 (i.e. upstroke of the action potential; see attached review). These L-type channels are also those activated by catecholamines, which increase the inward Ca2+ current, thereby increasing the slope of the pacemaker potential.

c. A decreasing outward K+ current (iK) due to inactivation of Kdr (delayed rectifier K channels).

Although not mentioned in current physiology texts, there is also evidence that the sodium calcium exchanger plays an important role in the pacemaker potential by mediating an inward Na+ current (I think this is also mentioned in the attached review).  Also note that the statement in Costanzo that T-type calcium channels mediate phase 0 of the slow response action potential is a mistake.  T-type channels may be involved in the phase 4 pacemaker potential, but not phase 0, as Dr. Partridge mentioned.  Inward calcium current through L-type channels predominantly mediates the upstroke of the action potential in pacemaker cells.

Regarding phase 3:

In a fast response action potential, the rapid repolarization during phase 3 is caused by inactivation of the L-type Ca2+ channels and a relative increase in K+ permeability [mediated primarily via activation of delayed rectifier K+ channels (iK) and inwardly rectifying channels (iK1) ].

For slow-response action potentials, phase 3 is primarily mediated by increased outward K+ current (iK) due to activation of Kdr.

SVT vs. VT

Regarding the question which begins "This EKG was obtained from a 77 year old woman who was recently admitted to the Coronary Care Unit for an acute inferior myocardial infarction...." the question is accompanied by an EKG which shows a narrow complex tachycardia without discernable p-waves. It appears to have left axis deviation (Up in I, Down in aVF). The V leads are not concordant. The answer is keyed as V-tach, not SVT. If this is VT, what did I miss?

Answer 1
I can see why this is confusing. Looking at the QRS complexes they are not as wide and bizarre looking as we usually see in VT although they are definitely widened a little. The thing that really makes it VT is the AV dissociation with the appearance of p waves independent of the QRS complexes (indicated by the arrows). You cannot have AV dissociation with SVT because the atria (and SA node) are depolarized at the same rate as the ventricle, around 150 times/minute. That means that the SA node would never get a chance to depolarize normally and cause a p-wave. 


Answer 2
In short, SVT is an "above the ventricle" arrhythmia. Typical SVTs include: A-Fib, A-Flutter, AVRT, or AVNRT. VT is a ventricular initiated arrhythmia. This rhythm is often a medical emergency as it may digress to VF and significantly compromise systemic perfusion.


On the ECG one could often distinguish between the two by looking at the width of the QRS complexes. VT will be very broad suggesting ventricular delay, SVT tends to be narrow.


In the example question given the QRS complexes appear to be >100 msec (wide) but this is not clear given no little box detail and no print out of intervals. 

Rho Kinase

I just have a quick question I'm having a hard time answering. Does the RhoA/ROCK pathway stimulate or inhibit the MLCP pathway?

Answer

Activation of the RhoA-ROK pathway mediates increased smooth muscle Ca2+ sensitivity by inhibition of MLCP, and provides a major contribution to receptor-mediated Ca2+-sensitization of smooth muscle. Such inhibition of MLCP results in accumulation of phosphorylated MLC and thus greater contraction for a given [Ca2+]i.  

Myocyte Action Potentials and Ion Conductance

summative 2 had MCQ on this.  Figure was flawed.  Here is an accurate figure

Answer
"I think that the scale on the "Ion Conductivity" axis is incorrect. At the end of phase 4, all conductances shouldn't be the same. (It looks sort of like the figure is showing current rather than conductance.) In a graph of conductance, gK should be high, it falls during phase 0 and gradually rises again during phase 2 and 3. gNa is transient during phase 0 as shown and L-type gCa is at a peak during phase 2. Further confusing is the time scale, which is compressed with respect to that of the action potential. The figure below from makes this point. (This image is fromhttp://www.cvpharmacology.com/antiarrhy/cardiac_action_potentials.htm, which along with it's links, provides a pretty clear description of the cardiac action potential.)

Obstructive sleep apnea

Sleep Disorders - obstructive sleep apnea

independent risk factors

• obesity

Index of Suspicion for OSA?

• Step 1: History 

• S: "Do you snore loudly, loud enough to be heard 

through a closed door?"

• T: "Do you feel tired or fatigued during the 

daytime almost every day?"

• O: "Has anyone observed that you stop breathing 

during sleep?“ Awakening with choking.

• P: "Do you have a history of high blood pressure

with or without treatment?"

Step 2 : Physical Exam

• B: BMI greater than 35; body habitus

• A: Age older than 50 years

• N: Neck circumference greater than 43 cm (17 in)

• G: Gender, male (postmenopausal female)

Conditions associated with OSA

• Hypothyroidism – elderly females
• Neurologic syndromes –
• muscular dystrophies
• Stroke – cause vs effect
• Acromegaly - macroglossia
• Environmental exposures –second-hand smoke, environmental irritants or allergens

Obesity Hypoventilation Syndrome (Pickwickian Syndrome)

Joe the Fat Boy

• Type 1 – typical OSA (90%) 

- decrease of functional lung volume - airway compromise, V/Q mismatch – decreased O2 sat, and cor pulmonale.

• Type 2 – chronic hypercapnia, decreased noc O2 sat without simultaneous apnea or hypopnea (10%)

Risk of OSA based on palate (Mallampati Score)

Sleep Studies

done during nl sleep period

• Sleep stages - EEG, 
• electro-oculogram, and chin electromyogram (EMG).
• Heart rhythm - singlelead ECG.
• Leg movements -
• anterior tibialis EMG.
• Breathing pattern analyzed for the presence of apneas and hypopneas
• O2 saturation.
• Breathing - airflow at the nose and mouth (thermal sensors, nasal pressure transducer), effort - chest wall and abdomen (inductance plethysmography)

Tx choices

• CPAP
• Tracheostomy
• Weight loss
• Oral appliance
• Surgery
• Supplemental Oxygen

USMLE – Benefits of CPAP

• Decreased RDI

• Improved sleep architecture

• Improved nocturnal O2 sat

• Improved driving, daytime sleepiness, neurocognitive fn

• Improved perceived health status

• Decreased mortality, arrhythmia, HTN, noc ischemia, health care visits

• Improved LVH in CHF 

Central Sleep Apnea (CSA) - no breathing effort 

• Primary central apnea is rare

• Most cases occur with OSA (mixed apnea)

• During polysomnography a central apneic event is defined as cessation of airflow for 10 seconds or longer without an identifiable respiratory effort

• Causes: drug use, high altitude, Cheyne-Stokes breathing , stroke, other rare medical conditions

• unstable ventilatory control during sleep is the hallmark, the pathophysiology and prevalence of various forms of CSA vary

Basic Pathophysiology - CSA

• Brainstem chemoreceptors (neurons responding to CO2 via shifts in H+ concentration) and peripheral chemoreceptors (carotid body via Pao2 and Paco2 ) play a key role in 

modulating ventilation. 

• ventilatory output to a given change in Pao2 or Paco2 varies between individuals and with disease status. Highly sensitive chemoresponders are at risk for unstable breathing patterns because they over-respond to small changes in chemical stimuli. 

• delays in the negative feedback loop controlling ventilation also contribute to the risk for developing instability. E.g. increased PaCO2 will result in increased ventilation; increased ventilation leads to reduced PaCO2 due to chemoreceptor response; low PaCO2

then leads to hypoventilation and potential apnea

• Sleep generally characterized by elevation of PaCO2 and a higher PaCO2 apneic threshold, (PaCO2 below which apnea occurs). Very small reduction of PaCO2 can result in apneas. 

• Central apneic events commonly occur during the transition between wake and sleep, a 

period during which the PaCO2 set point adjusts.

Eckert, et al, Chest. 2007 February; 131(2): 595–607 

Treatment

• Non-pharmacologic methods vary, depending on underlying conditions: O2

(CHF), CPAP (CheyneStokes), increased dead space

• Drugs: acetazolamide - causes bicarbaturia and metabolic acidosis, which presumably shifts the apneic threshold of PaCO2 to a lower level 

• Theophylline 

• benzos, newer sedative-hypnotics (eg zolpidem) – non-hypercapnic CSA, believed to work by consolidating the sleep pattern, thus minimizing the instability in ventilation induced by sleepwake transitions