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wing ed of the Art THE tlYPERVENTILATION syn- drome is a common, often disabling, and frequently inadequately treated clinical problem. Diagnosis ls often missed, perhaps because physicians are no! sufficiently aware of it or ~ecause patients rarely demonstrate the classic textbook picture of obvious overbreathing, paresthesia, and teta- ny. More commonly, symptoms are subtle and of 1 en mimic those of other clinical conditions, either, organic or functional. Indeed, many patients with this affliction wander from one physician to another either vainly undergoing increasingly complex di- agnostic procedures or being dis- missed as a,,,.xious or neurotic. The purpose of this brief review is to emphasize the clinical importance of this syndrome, its common clinical signs and symptoms, and its metabol- ic and physiologic consequences, and to define effective management. DEFINITION AND INCIDENCE Hyperventilation is defined as ven- tilation in excess of that required to maintain normal blood Pao: and Paco~. It may be produced either by an increase in frequency or depth of respiration or by a combination of the two/ From the Section of Cardiovascular Medicine, New England Deaconess.Hospital (are Miasri and Alexander:} and Lehey Clinic Foundation (Or Alex- ander). Boston. Reprint requests to Sectloct of Cardiovascular Medicine. I. ahey CiVic Foundation, F.05 Co~m~oc~- wealth Ave, Boston, MA 02215 (Dr Alex~tnder). JAMA, Nov 3, 1978~Vol 240, No. 19 Hyperventilation Syndrome Jose C. Missri~MD, A Brief Review Sidney Alexander,. MD The hy~)erventilation syndrome was diagnosed in 6% of patients who attended specialty clinirs~ and in 10% of those seen in the office of a general physician.' The syndrome does not seem to occur prepnnderant- ly in women; at least in one large series the sex incidence was almost equal.' The syndrome is frequently overlooked. One author' reported tha~ 40% of his office patients had no apparent organic cause for their symptoms; he listed their presenting complaints, which were identical to those produced by hyperventilation, but he neglected to mention hyper- ventilation as a p¢~ssible cause for them. Organic causes for hyperventilation include pain,: metabolic acidosis,~ drug into×ication,' hypereapnia,~ cir- rhosis,'~" and organic CNS disorders." Our remarks are confined to the hyperventilation syndrome as it oc- curs in patients with no apparent organic cause. SYMPTOMS AND SIGNS While episodes of hyperventilation seem commonest in visibly anxious persons and are often precipitated by obvious stress, sometimes patients appear outwardly calm and may be totally unaware, frequently disbeliev- ing, that they are hyperventilating. :Nor is the patient likely to be convinced of this unless the physician has the patient hyperventilate, repro- dueing a typical episode, preferably Symptoms of Hyperventilation Generei ...... Fatigue Weakness Exhaustion Cardiovascular Palpitations Ta chycardla Precordial pain Raynaud's phenomenon Neurologto Dizziness Li~hthe~dedness Disturbance of consciousness or vision Numbnees and tingling of the extremities Tetany (rare) Respiratory Shortness of breath Cheat pain Dryness of the mouth Yawning Gastrointestinal Globua hyatetlcua Epigastrio pain Aefophsgla Muacul0akelet al Muscle paine end cramps Slilfness Tetaey Paycholog{¢ Tension Anxiety Insomnia Nightmares with another member of the family present. The total clinical picture appears to be a composite of symptoms produced not only by Ihe physiologic derange- ments caused by hyperventilation i~self but often more prominently by underlying anxiety. Not surprisingly, when normal subjects hyperventi|ate, Hyperventitation Syndrorne--Missri & Alexander 20~3 T109570363

few symptoms are produced, and a good correlation cannot be found between the clinical findings in these normal volunteers and the magnitude of changes in arterial pH and Pace:.'~ Only rarely do patients have the classic clinical picture of tetany, paresthesia, and greatly accelerated respiratory rate. The diverse, com- mon presenting symptoms are out- lined by system in the Table. While symptoms vary greatly from one patient to another, they generally are fairly constaut in a given patient. Commonly the major complaint is just an ill-defined lightheadedness or vague "out-of-touch" feeling. Some patients complain only of episodic breathlessness or a need to "fill the lungs a little better." This usually occurs during periods of rest, not with exertion, and may be accompanied by pounding of the heart. In other persons, cardiac symptoms, such as palpitations and pounding, come first. The resultant anxiety provokes hy- perventilation. Even when watched closely, some patients who hyperven- tilate- exhibit apparently normal breathing patterns, at least between attacks, but many exhibit deep or sighing respiration, even during rela- tively symptom-free periods. Some authorities believe that bad breathing habits may be primarily responsible for the hyperventilation syndromeS and that anxiety is second- ary. It is our impression, however, that acute or chronic anxiety is the causal factor in the majority of patients. Once initiated in such patients, the hyperventilation syn- drome becomes increasingly frequent and often self-perpetuating. PHYSIOLOGIC CONSEQUENCES Body Fluids The pH of body fluids is governed by the relation described by the Henderson-Hasselbalch equation: HCO, pH=B.l+log -- H:CO~ Carbonic acid (H~CO,) concentra- tions are directly proportional Pace: so that during hypervevtilation, as increased amounts of CO., are expired, Paco~ falls, increasing the ratio of HCO~/II~CO, Blood pH is thereby elevated, and acute resplra- tory alkalosis is produced. "re restore pH to normal, compensatory renal mechanisms are employed. These tend to return the HCO~/H~CO.~ ratio to normal by increasing urinary" bicarbonate excretion. However, these changes occur much more slow- ly and cannot produce the immediate compensation necessary to prevent symptoms. If hyperventilation is chronic, however, compensation can occur. Plasma bicarbonate concentration is reduced both by increased renal excretion and apparent transfer of bicarbonate to intracellular stores. The pH may then return toward normal levels despite the pers;sting hypocapnia. The respiratory center maintains the Pace., at this lower level, presumably to maintain normal arterial blood pH. Thus, compensa- tory mechanisms tend to perpetuate the lowered Paco~.:"" However, the continual low Pace., mak÷s such patients susceptible to the develop- ment of the hyperventilation syn- drome. If they increase their ventila- tion even slightly, for example, in response to trivial emotional stress or during light exercise, the already low Pace: is further reduced, and symp- toms are produced. Tissue oxygenation may be affected by hyperventilation. The acute respi- ratory alkalosis displaces the oxyhe- moglobin dissociation curve to the left (Bohr effect). Oxygen becomes more tightly bound to hemoglobin and is less easily released to the tissues at any given level of oxygen tension. Total serum calcium level appears not to be substantially changed, but the ionized calcium concentration has not been measured systematically,m' Therefore, the role of calcium in the production of tetany, paresthesia, skeletal muscle irritability, and pain- ful visceral spasm is uncertain. Some believe these symptoms may be caused by the direct effect of alkalosis on peripheral nerve function rather than on altered calcium metabolism." Sodium, potassium, am] magnesium concentrations are unchange~l, but substantial reduction in organic phos- phate levels has been reportedJ~ The mechanism is uncertain, but this change may b~) related in part to the increased muscular activity associ- ated with the act of byperveutilation itselL Lactate and pyruvate concen- 2094 JAMA, Nov 3, t978--Vol 240, No 19 trations lnay increase2~ Animal data suggest that hepatic lactate metabo- lism is reduced during hyperventila- tion, perhaps because of reduced hepatic blood flow.': Cardiovascular Changes Price~' has reviewed the effects of CO: on the cardiovascular system. Severe vasoconstriction of the cere- bral arteries occurs when Pa~;o: is abruptly reduced, and some evidence exists that cerebral anoxia may be ~produced by this means. Many of the symptoms of the CNS associated with hyperventilation may be caused by the resultant decrease in cerebral blood fl~w. The Bohr effect also ser~'es to reduce oxygenation of the CNS. Arteriolar constriction occurs in skin, intestines, and kidneys. The effect in other regional circulation is uncertain. Burnum et a}:: measured cardiac output, forearm blood flow, and ar- terial blood pressure during hyper- ventilatiou in normal subjects and in patients who had undergone upper limb sympathectomy. In both groups, when Pace: fell to 20 mm Hg, forearm blood flow (largely to muscle) more than doubled, while cardiac output increased by 50% and heart rate by about 70%. Systemic arterial pres- sure fell similarly in both groups of patients, suggesting that arteriolar vasodilation is independent of direct sympathetic nervous control. Neill and HattenhaueP~ have shown that hyperventilation in- creases coronary artery vascular re- sistance. This effect, coupled with the shift of the oxyhemoglobin dissocia- tion curve to the left, might reduce myocardial oxygen supply and z:~ay have obvious clinical importance in patients with coronary disease. Chest pain occurs commvnly in patienis who chronically hyperventi- late. The pain is usually described as shooting or stabbing in nature but sometimes may be difficult to distin- guish from angina pectoris. Evans and Lure~' recently described 50 patienis who were referred to a cardiac clinic for confirmation or exclusion of angina pectoris and were found to be habitual hyperventilators. In 37 no evidence for organic heart disease could be found; the pain seemed unrelated to hemodynamic factors. Simple physiotherapy aimed Hypervontilation Syndrome--Missri & Alexander Ti09570364

at restoring normal breathing pat- terns dramatically reduced the fre- quency and severity of the pain, suggesting that it was in some way related to the vigorous respiratory effort itself. ECG Changes The ECG changes caused by hyper- ventilation seem related to alteration of autonomic nervous system tone, both sympathetic and parasympa- thetic)" rather tlmn to hemodynamic changes. Less likely, local changes in e]ectrcdyte concentration, particular- ly potassium, may play a role.2'~ In the Figure, great downward depression of the ST segment and flattening and inversion of the T waves can be noted. This response is fairly typical, but ST segment depression or T wave changes alone have also been de- scribed both in the resting and exercise ECG. Unlike ischemic ST Sitting ...V.~I:::'I.-::I ..... I.:-L,~.:..+ .... ,.---,.::.,,,,,,.,.:,:~~ .... ..... V5 segment cha.nges, those caused, by ~~:~..~.:=. " "=: :=:~:: I:-.~5"~-- ~ i=_'-~'-.[ a.t]on.u ~al '~ ,pea~ ~, rly ~:.._:-~,...._,.,.:.....:.z~.~ ga, an~ ;e~ .t dis, ~[~ar a control or resting ECG ~;~z&~£...~ hyperventilation usually appear early during exercise, in the absence of any other symptoms or signs of myocar- dial ischemia, and tend to disappear as exercise continues.:'"' Many exer- cise laboratories, therefore, routinely record before a'ad after hypervent.ilation to document these benign changes. Paroxysmal arterial arrhythmias during hyperventilation have been reported*: but are rare in our experi- ence. More frequently sirras tachycar- din is present, usually produced by anxiety. In fact, many patients relate that it is their awareness of a rapid, forceful heart beat that makes them byperventilate. The direct effects of hyperventila- tion on the CNS are difficult to disso- ciate from those caused by reduction in cerebral blood flow. Electroen- cephalographic changes are unpre- dictable; even when characteristic slow-wave activity is produced, this change is often transient and disap- pears, though the level of Pac{b remains constantY Changes In Respiration The role of CO: in the regulation of respiration has recently been re- viewed in detailJ~ Ordinarily, changes in Paro~ provoke'prompt responses from both central and peripheral chemoreceptors, which alter respira- tion to return Paco~ to normal levels. Hyperventilation I aV~ V5 Effect of hyperventilation on resting EGG. Left, Simultaneous leeds l, aVe, and V~ taken at rest in sitting position. Right, Same leads, sitting position, after 30 seconds of hyperventi* letion. Note great ST-T changes. Thus, after acute hyperventilation, the rate and depth of respiration will fall until Paco~ returns to normal. ttowever, if Paeo: is more chronically reduced by hyperventilation, the sen- sitivity of the carotid body to hypox- emia is reduced. Equally important, the sensitivity of the respiratory center to CO: nmy be blunted as well. For example, some subjects who chronically hyperventilate do not re- spond to inhalation of 5% CO.,, ordi- narily a potent respiratory stimulus. DIAGNOSIS AND TREATMENT Diagnosis is easy if clinical suspi- cion is high, It can usually be inferred if voluntary hyperventilation repro- duces typical symptoms. In some patients, presumably those who chronically hypervcnti]ate, just a few deep brvaths will dramatically pro- yoke the usual signs and symptoms. In others, rapid breathing for a minute or more may he required. Ordinarily we ask our patients to hypervcntilate in the sitting position for at least one minute and then request that they remain silent and still for the next several minutes. We then ~void leading questions but rather ask in a casual manner what symptoms they have experienced. Only after these are related do we ask more leading questions, eg, if these symptoms are similar to those experi- enced during a typical attack. Voluntary hyperventilation is best performed in the presence of a friend or relative. We often can convince the patient that hyperventilation is re- sponsible for the symptoms while the patient is still sitting in the office, but this may quickly be forgotten when the next attack occurs. Most patients need constant reminding by both family and physicians of the cause of their problem. Weeks of constant reinforcement may be re- quired before these patients finally JAMA. Nov 3, 1978~VoI 240. No. 19 Hyperventilation Syndrome--Missal & Alexander 2095 T109570365

accept that such severe symptoms can be provoked by so apparently innocu- ous a habit: The classic remedy, breathing into a paper bag, rarely seems to help. Rather, understanding the mecha- nism by which symptoms are pro- duced forms the best foundation for effective therapy. For some this is enough; whenever an attack begins, patients can consciously control the rate and depth of respiration. Others may be helped by learning proper respiratory techniques that empha- size diaphrah~natic breathing Some may require sedation. In patients who hyperventilate in response to rapid or irregular beating of the heart, control of cardiac arrhythmias or reduction of the sinus rate works best, and propranolol hydrochloride, a potent #3-adrenergic blocking agent, is often the drug of choice. It ~nay be particu- larly helpful at night since anxious patients frequently seem most sensi- tive to their pulse rate and rhythm at this time~ Constant reassurance, encourage- ment, and follow-up visits are neces- sary. If these measures are employed, treatment of this common clinical problem is usually effective. 1. Eicbenholz A: Respiratory alkalosis. Arch Intern Mud 116:699-708, t9~6. 2. McKeli TE, Sullivan A J: Hyperventi]atiun syndrome in gastroevtsro]ogy. Gastrovateroloyy 9:.6-16, 1947. 3. Yu PN, Yim JB, Stanfi~ld CA: Hyperventi- lation syndrome: Changes in the electrocardio- gram, blmxl gases, and electrolytes during voluno tary hyp~rventilation: Poeelble mechaniems and clinical implications. Arch In~'n Med 103:902- 913, 1959. 4. Rice RL: Symptom patterns of hyperventi- ]*tJon syndrome. Am J Meal 8:691-700, 1950. 5. Lure LC: Hyperventilation: The tip and the iceberg. JP~c~ Ben llk375-3M, 1975. 6. Gottlieb B: Non-organic disease in medical outpatients. M~d [[pdate 1:917.92"2, 19~9. 7. Aronson PR: Hypervontilstion from orgsn- ie disease. Ann Intern Med 50:554-559, 1959. 8. Beveridge GW, Forshall W, Munro JF, et al: Acute salicylate poisoning in adults. Laurel 1:1406-1409, 1964. 9. Elkluton JR: ClJnlca] disorders of acld-b~se regulntion: A suwey of 17 years' diagnostic expe- References • rlonce. Mud CHn North Am 50:1325-1350, 1966. I0. Knretzky MS, Mithoefer JC: The cause of hyperventilation and arterial hypoxia in pa- tlents with cirrhosis of the ~iver..4m J Mud 254:79%804, 1962. 11. Cohn JE, Kuida H: Primary alveolar hypoventilatlon associated with Western equine encephalitis. Ann Intern Mud ~;:633-644, 1962. 12. Saltzman HA, Heyman A. Sieker He: Correlation of clinical and physio]oglc manifes- tations of sustained hyperventilation. N Engl J Mud '268:14~1-1436, 1963. 13. Okel BB, Iiurst JW: Prolonged hyperventi- htion in man: A~seclated electrolyte changes and subjective symptoms. Arch [~tern Mud 108:757-762, 1961. 14. Brown EB Jr: Physiological effects of hyperventilatlon. Phvsiol Rvr 33:445-471, 1953. 15. B~ck AV. Dill DB, Edwards HT: Lactic acid in the blood of resting man. J Clin Invest I h775-788, 1932. 16. Price HL: Effects of carbon dioxide on the cardiovascular system. A~esfhesiolol.pd 21:652- 663, 17. Burnum JF, Hickam JB, Mclntosh HD: Effect of hypocapnia on arterial blood pressure. Circ~dati~n 9:89-95, 1954. 18. Nei]l WA, Hattenhauer M: Impah'ment of myocardial O, supply due to hyperventilation. Cir~latian 52=854-858, 1975. 19. Evans DW, Lum LC: Hyperventilation: An important cause of pseudoanglna. Lan~e~ I:155- 157, 1977. 20. McHenry PL0 Cogan O J, E1Hott WC, et al: False positive ECG response to exercise second- a~" to hyperventilation: Cineangiogrsphic corre- lation Am He~r~ J 79.'683-687, 1970. 21. McHenry PL, Stowe DE, Lancaster MC: Computer quantitation of the ST-segment response during maximal treadmill exercise: Clinical correlation. Circulation 38:691-70~ 1968. 22. Wildenthal K, Fuller DS, Shapiro W: Paroxysmal atrial arrhythmias induced by hypt, rventilation. Am J Cardlo121;436-441, 1968. 23. Berger A J, Mitchell RA, Severinghaus JW: Regulation of respiration. N Engl J Mud 297:92- 97, 138-143, 194-201. 1977. Jules Gonin was born on Ang 10, 1870, in Lausanne, Switzerland. While sti]l a medi- cal student, he was allowed ~o substitute "for the resident physician at l'HSpital de ]'Asile des Aveugles, where he was intro- duced to ophthalmology. He rereived his medical degree from the University of I,aasanne in 1894. Later, hc stvdicd at the Institute of Pathologic Anatomy and then at ]'HSpital Ophtalmique d~, Lausanne nndcr Professor Mark Dnfonr. Gon[n was asked hy Professor Dufour to help write a chapter on diseases of the retina and optic nerve, This led him ~o the study of detach- ment of the retina. Gonin was the first to on the cure of retinal detachment by ther- mal cautery was published in 19~, but ophthalmologists paid little or no atten- tion to his work until his presentation in 19~ at the Amsterdam International Congress. At that time, he had succeeded realize that there was a causal relation- ship between tears or runts in the retina and detachment. Detachment of the retina with a tear was cnnsidercd incurable, but Gonln asserted that such detachment was curable by thermal cantery. Ile had writ- ten his first paper on retinal detachment in 1908, and ten years later, he wrote his second paper entitled "The Anatomical Causes of Retinal Detachment." His paper in curing more than two thirds of }]is patients who had retinal detachments of recent origin, whereas other experienced ophthalmologists had seen only an occa- sional isolated cure. He became the surgeon in charge of l'lt6pital de ]'Asile des Aveugles in 1918 and professor of ophthalmology at the University of Lausanne in 1920. He also contributed to other areas in ophthalmolo- gs". including stndies of the anmdar scoto- ma of retinitis pigmentosa, em~cleation of the eye. amaurosis, and amblyopia. His final work was his large book Detachment of the Re/in,. which was published in 1934. It is said that one must go hack 70 years in the history of ophthalmology to yon Graefe's irideetomy for glaucoma to find an event as important as Gonin's surgery for the detached retina. When asked why it took so long for European ophthalmologists to adopt his methods, Gonin is reported to have said that "'sometimes recognition is easier in Eur,pe when it arrives via Amp'tics." He died on June 10, 1935, of a cerebral hemorrhage and was honored philatelicaL ly by Switzerland (Scott No. 537) in 1971 and by Hungary (Scott N~*. 2143) in 1972. --RoBSRT A. KYLZ, MD, and MARC A. SHAMI'O, })lid 2096 JAMA. Nov 3, t978~Vol 240, No. 19 Hyperventilation Syndrome--Missri & Alexander TI09570366