John W. Severinghaus

Respiratory insensitivity to hypoxia in chronically hypoxic man

Abstract Respiratory chemosensitivity was studied in Cerro de Pasco, Peru (4330 m) in 5 normal highlanders (H), 6 highlanders with chronic mountain polycythemia (CMP) without right heart failure, and 7 lowlanders (L) acclimatized for 1–40 weeks. Mean age of groups was 35 and pulmonary function was normal. Hematocrit averaged 51.7 in L, 60.1 in H and 75.4 in CMP. P aco 2 was 27.8 ±0.6 mm Hg (s.e.) in L, 31.9±0.7 in H and 34.8±0.9 in CMP. Similarity of CO2 response curve slopes of 2.6 1/min/m2/mm Hg in L, 2.5 in H and 2.2 in CMP suggested that medullary chemoreceptor sensitivity was normal although set chemically, by CSF HCO3− adjustment, to operate at differing P co 2 levels in the 3 groups. However, the ventilatory response to hypoxia ( Pa co 2 =40 mm Hg ) at control Pa co 2 differed, being 211/min/m3 in L, 5.6 in H and only 2.4 in CMP, and PaO2 as low as 22 mm Hg failed to induce hyperpnea in either H or CMP. It is postulated that chronic hypoxia results in desensitization of the carotid body hypoxia chemoreceptors, and the reduced stimulus permits ventilation to fall and P co 2 to rise. This process may be etiologic in chronic mountain sickness.

Cerebral Blood Flow In Man at High Altitude: Role of Cerebrospinal Fluid pH in Normalization of Flow in Chronic Hypocapnia

Cerebral blood flow was determined by an N2O method in 7 normal men at sea level and after 6 to 12 hr and 3 to 5 days at 3810 m altitude. An infrared N2O analyzer was used both to measure end-tidal PN2O so that it could be kept constant for 15 min and to determine blood N2O, for which a simple gas extraction method was devised. In addition, acute changes in cerebral blood flow were estimated from cerebral A-V O2 differences. Control cerebral blood flow was 43 ml per 100 g per min; it increased 24% at 6 to 12 hours and 13% at 3 to 5 days at altitude. After 3 to 5 days, pH of cerebrospinal fluid was normal (7.31) in four subjects while arterial blood pH was alkaline (7.47); arterial blood Pco2 had fallen from 41 to 30 mm Hg. Acute correction of hypoxia restored cerebral blood flow to control while mean Pco2 was still 31 mm Hg. Addition of O2 and CO2 to inspired air raised cerebral blood flow 34% above control at Pao2 = 170, Paco2 = 35 mm Hg. Values obtained by extrapolation suggest that if arterial Pco2 was raised to control (41 mm Hg), cerebral blood flow would have been 60% above control. Cerebral blood flow thus appears to return to normal at the prevailing Paco2, probably because the pH of cerebrospinal fluid and of the extracellular fluid of cerebral vascular smooth muscle is kept normal by active transport across the ‘blood-brain’ barrier. It is postulated that an ion-impermeable barrier separates the blood stream from extracellular fluid of the smooth muscle of cerebral arterioles.

Accuracy of response of six pulse oximeters to profound hypoxia.

Oxygen saturation, Spo2%, was recorded during rapidly induced 42.5 ± 7.2-s plateaus of pro found hypoxia at 40–70% saturation by 1 or 2 pulse oximeters from each of six manufacturers (NE = Nellcor N10O®, OH = Ohmeda 3700®, NO = Novametrix 500® versions 2.2 and 3.3 (revised instrumentation), CR = Criticare CSI 501+® version .27 and version .28 in 501 & 502 (revised instrumentation), PC = PhysioControl Lifestat 1600®, and MQ = Marquest/Minolta PulseOx 7®). Usually, one probe of each pair was mounted on the car, the other on a finger. Semi-recumbent, healthy, normotensive, non-smoking Caucasian or asian volunteers (age range 18–64 yr) performed the test six to seven times each. After insertion of a radial artery catheter, subjects hyperventilated 3% CO2, 0–5% O2, balance N2. Saturation Sco2, computed on-line from mass spectrometer end-tidal Po2 and Pco2, was used to manually adjust Flo2 breath by breath to obtain a rapid fall to a hypoxic plateau lasting 30–45s, followed by rapid resaturation. Arterial Hbo2% (Radiometer OSM-3®) sampled near the end of the plateau averaged 55.5 ± 7.5%. Sco2% (from the mass spectrometer) and Sao2% (from pH and Po2, by Corning 178®) differed from Hbo2% by + 0.2 ± 3.6% and 0.4 ± 2.8%, respectively. The mean and SD errors of pulse oximeters (vs. Hbo2%) were: The plateaus were always long enough to permit instruments to demonstrate a plateau with ear probes, but finger probes sometimes failed to provide plateaus in subjects with peripheral vasoconstriction. Nonetheless, Spo2 read significantly too low with finger probes at 55% mean Sao2. The mean error with car probes was not significant. Several instruments occasionally defaulted to zero saturation during rapid desaturation. Precision was independent of probe location, but differed widely between instruments. The studies provided data with which manufacturers could improve function, as illustrated by subsequent series with CR and NO. The authors conclude that square-waves of hypoxia can assess both the transient and the steady-state profound hypoxic responses of pulse oximeters, disclosing a variety of problems, and facilitating their resolution. An addendum follows the article.

Effect of Carotid Endarterectomy on Carotid Chemoreceptor and Baroreceptor Function in Man

Abstract The ventilatory response to inhaled carbon dioxide was measured during hyperoxia (Pao2 over 200 torr) and hypoxia (Pao2 of 40 torr) in 14 patients before and one to nine weeks after caroti...

REGIONS OF RESPIRATORY CHEMOSENSITIVITY ON THE SURFACE OF THE MEDULLA

The hyperventilation produced by increasing H+ concentration in the cerebrospinal fluid of dogs was first described by Leusenl-s and confirmed by Winterstein and Gokhan.4m They thought that the hyperventilation resulted from direct stimulation of the respiratory centers. Loeschcke and co-workerss confirmed their results and attempted to locate the site of the stimulation. They found the maximum acid-sensitivity to be in the region of the lateral recesses of the 4th ventricle or in the adjacent subarachnoid space near the roots of the 8th-10th cranial nerves. They also demonstrated that dilute solutions of veratradine in this region also caused hyperventilation, whereas lobeline, cyanide, or procaine depressed ~entilation.T-~ Sergievski and Okuneva,lo who also produced hyperventilation in dogs by introducing acidic cerebrospinal fluid into the ventricles, concluded that the reactive area was on the surfaces of the lateral ventricles. However, the respiratory responses in their studies were much smaller than those described by other workers. Our investigaton is an examination of the hypothesis that the superficial int,racranial chemoreceptors may be the site of the respiratory response to inhaled C02. We have attempted to localize the region of chemosensitivity and to determine its quantitative relationship to the respiratory response to inhaled CO2.

Step Hypocapnia to Separate Arterial from Tissue Pco2 in the Regulation of Cerebral Blood Flow

The change in cerebral blood flow was determined after a step decrease in the Pco2 of arterial blood from 40 to 25 mm Hg in awake man. Subjects monitored their own end-tidal Pco2 (infrared analyzer) and adjusted their voluntary ventilation to produce the step change, which they maintained for at least 1 hour. Cerebral blood flow relative to control was determined from the arterial-jugular venous oxygen saturation differences. After the step change, arterial Pco2 fell in less than 30 sec to a plateau, cerebral blood flow fell with a time constant (to 1/e) of 0.3 min to a plateau of 68% of control, while jugular venous Pco2 fell with a time constant for the fast component of 3.5 min. Base excess rose 1.2 mEq/liter within 1 min and remained at that level. It is concluded that CO2 affects cerebral blood flow by direct diffusion into arteriolar walls, rather than by its effect on brain tissue Pco2 or pH. It is postulated that the pH of the extracellular fluid of arteriolar smooth muscle is the common controlled variable through which CO2, and possibly hypoxia and blood pressure, determine vascular tone.

Errors in 14 pulse oximeters during profound hypoxia

The accuracy of pulse oximeters from fourteen manufacturers was tested during profound brief hypoxic plateaus in 125 subject sets using 50 normal adult volunteers, of whom 29 were studied two to nine times. A data set usually consisted of 10 subjects, and 13 sets were collected between August 1987 and July 1988. In the first 6 sets, six 30-second hypoxic plateaus were obtained per subject at 55±6% oxyhemoglobin (O2Hb) (range, 40 to 70%). In the last 7 sets, three hypoxic plateaus were obtained at each of four levels, approximately 86, 74, 62, and 50% O2Hb, for the purpose of linear regression analysis. Inspired oxygen was adjusted manually breath by breath in response to arterial oxygen saturation computed on-line from end-tidal oxygen and carbon dioxide tensions. End-plateau arterial blood O2Hb was analyzed by a Radiometer OSM-3 oximeter, and plateau pulse oximeter saturation (SpO2) was read by cursor from a computer record of the analog output. Three to 13 instruments were tested simultaneously by using 1 to 3 duplicate instruments from each of one to seven manufacturers. Variations introduced by manufacturers were tested on subsequent sets in several instruments. An index of error, “ambiguity” (α) of oxygen saturation, was defined as the absolute sum of bias and precision (mean and SD of SpO2−O2Hb) at O2Hb=55.8±4.5%, preserving the sign when bias was significant atP<0.05. Ambiguity values for finger probes (unless specified) with latest data were: Physio-Control, 3.9 (ear, 3.3); Puritan-Bennett, −4.4; Criticare, 5.8 (forehead, 4.7); Kontron, 5.9 (infant probe) and 6.1 (ear, 5.8; forehead, 7.1); Biochem, −6.0; Datex 6.4 (ear, 6.9; forehead, 6.8); Critikon, 8.4; SiMed, 8.6; Marquest, 9.0; Novametrix, 10.2; Invivo, −12.2 (ear, −14.3); Nellcor, −15.1; Ohmeda, −21.2; and Radiometer, −21.2 (ear, −9.6). Linear regression slopes of 36 instruments from twelve manufacturers generally deviated from 1 in proportion to α. The data showed substantial differences in bias and precision between pulse oximeters at low saturations, the most common problems being underestimation of saturation and failing precision.

Effect of a vecuronium-induced partial neuromuscular block on hypoxic ventilatory response.

BackgroundA previous study has demonstrated a decrease in the hypoxic ventilatory response in volunteers partially paralyzed with vecuronium. However, in this study, hypocapnia was allowed to occur. Because hypocapnia counteracts the ventilatory response to hypoxia during partial vecuronium-induced neuromuscular block and isocapnia, the hypoxic ventilatory response (HVR) was tested in 10 awake volunteers. MethodsTo avoid hypocapnia, the resting hyperoxic control end-tidal PCO2 was increased to 43.3 ± 2.4 mmHg, raising inspiratory minute ventilation (&OV0312;1) to 140 ml·kg-1·min-1·Hypoxic ventilatory response (Δ&OV0312;1 /ΔSpO2, L·min-1·%-1) was measured during a 5-min isocapnic step reduction to a mean arterial hemoglobin oxygen saturation (SpO2) of 84.8 ± 1.4%. Immediately thereafter, hypercapnic ventilatory response (HCVR; δ&OV0312;1/ΔPetCO2, L·min-1·mmHg-1) was determined at the end of a 6-min step increase of PetCO2 to 50.5 ± 2.7 mmHg. During a subsequent 30–40-min pause, an intravenous infusion of vecuronium was adjusted to reduce the adductor pollicis train-of-four ratio to 0.70, as monitored using mechanomyography. Ventilatory parameters, HVR and HCVR, were then re-determined. ResultsResting &OV0312;1, PetCO2, and SpO2 were unchanged by drug infusion. Hypoxic ventilatory response decreased from control (a) of 0.97 ± 0.43 to 0.74 ± 0.41 L·min-1·%-1 (P < 0.02) during drug infusion (b), while HCVR was unchanged (a = 1.91 ± 0.82, b = 1.62 ± 0.46 L·min-1·mmHg-1; NS). To correct HVR for possible vecuronium-induced respiratory muscle weakness or otherwise altered central nervous system reactivity, the drug/control ratio (HVRb/a) was divided by the associated HCVRb/a ratio. This HVR index, FHVR was 0.84 ± 0.12 (P < 0.01). ConclusionsWe conclude that a vecuronium-induced partial neuromuscular block impairs HVR more than it does HCVR In humans, suggesting an effect of vecuronium on carotid body hypoxic chemosensitivity.

History of blood gas analysis. VII. Pulse oximetry

Pulse oximetry is based on a relatively new concept, using the pulsatile variations in optical density of tissues in the red and infrared wavelengths to compute arterial oxygen saturation without need for calibration. The method was invented in 1972 by Takuo Aoyagi, a bioengineer, while he was working on an ear densitometer for recording dye dilution curves. Susumu Nakajima, a surgeon, and his associates first tested the device in patients, reporting it in 1975. A competing device was introduced and also tested and described in Japan. William New and Jack Lloyd recognized the potential importance of pulse oximetry and developed interest among anesthesiologists and others concerned with critical care in the United States. Success brought patent litigation and much competition.

Pulse Oximeter Failure Thresholds in Hypotension and Vasoconstriction

The degree of systolic hypotension causing failure and recovery were tested simultaneously with three oximeters (CSI 504US, Nellcor N-200, and Ohmeda 3740) in nine normal male volunteers. Perfusion of the right hand was slowly reduced and restored by 1) elevation of the hand plus systemic hypotension with nitroprusside if needed (EL); 2) clamp compression of the brachial artery (CL); 3) brachial cuff inflation (CU); and 4) intraarterial norepinephrine (NE). With EL, pulse pressure was normal whereas right radial arterial systolic pressure (SP) was 25.3 +/- 12.4 mmHg at failure and 34.1 +/- 13.3 at recovery (mean of three oximeters, n = 189). With CL, pulse pressure fell more than did mean pressure, and failure occurred at 37.3 +/- 9.8 and recovery at 46.8 +/- 17.6 mmHg, n = 84. With CL, threshold of function, defined as the average of failure SP and recovery SP, was 47.1 +/- 13.5, n = 41 for Nellcor, higher than for either CSI (38.7 +/- 14.5, n = 17) or Ohmeda (36.0 +/- 3.4, n = 26) (P less than 0.05). With EL, no difference among instruments was found (mean 29.7 +/- 12.8, n = 189). Threshold was 58.2 +/- 8.4, n = 17 with CU if cuff inflation was slow (filling veins), but recovery was similar to EL after rapid cuff occlusion. With NE, SP threshold was increased to 58.3 +/- 21.0 with CL but only to 41.0 +/- 13.8 with EL.(ABSTRACT TRUNCATED AT 250 WORDS)