1. What is the cause and pathophysiology of this patient s metabolic acidosis?

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1 The Clinical Physiologist Section Editors: John W. Kreit, M.D., and Erik Swenson, M.D. Hypo-Hypo: A Complex Metabolic Disorder Brian L. Block 1, Samuel Bernard 1, and Richard M. Schwartzstein 2 1 Department of Medicine, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York; and 2 Department of Medicine, Carl J. Shapiro Institute for Education and Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts In Brief A young man was hospitalized with severe sepsis in the setting of a diarrheal illness. Laboratory studies revealed evidence of metabolic acidosis with a normal serum anion gap, which persisted after diarrhea resolved. An understanding of renal acid base physiology allowed a diagnosis to be made and provided the basis for pharmacological intervention. The Clinical Challenge A 26-year-old man with poorly controlled type 1 diabetes mellitus, bipolar disorder, and recurrent Clostridium difficile infection presented to the emergency department with fever and diarrhea. In the emergency department, he had an oral temperature of 398C, a blood pressure of 98/64 mm Hg, a heart rate of 107 beats/min, a respiratory rate of 20 breaths/min, and an oxygen saturation of 98% measured by pulse oximetry while he breathed ambient air. Physical examination revealed an agitated but conversant, thin man with a dry oropharynx, normal heart and lung findings, nontender abdomen with normal bowel sounds, and warm extremities. Initial laboratory data are presented in Table 1 and were most remarkable for a venous ph of 7.22; serum potassium, 5.1 mm; total CO 2, 16 mm; blood urea nitrogen, 54 mg/dl; creatinine, 3.0 mg/dl; and glucose, 477 mg/dl. The patient reported he had not used any insulin in more than 24 hours, raising concern for diabetic ketoacidosis. However, the serum anion gap of 9 mm was not elevated, and ketones were not present in urine or serum. Despite relative hypotension, a measured venous lactate level was normal at 1.3 mm. The patient was treated by intravenous fluid administration and given empiric oral vancomycin for presumed severe, recurrent C. difficile infection. Examination of a stool sample by PCR confirmed the presence of C. difficile. Diarrhea, fever, and hypotension resolved with antibiotics, and his hyperglycemia was treated with insulin. Despite this clinical improvement, however, metabolic acidosis persisted and the patient remained hyperkalemic. Urine studies were obtained, revealing a urine sodium concentration (U Na ) of 31 mm, a urine potassium concentration (U K ) of 24 mm, a urine chloride concentration (U Cl )of24mm,and a urinary anion gap of 31 (Table 1). Questions 1. What is the cause and pathophysiology of this patient s metabolic acidosis? 2. How does the urinary anion gap help determine the cause of metabolic acidosis with a normal serum anion gap? (Received in original form July 20, 2015; accepted in final form October 9, 2015 ) Correspondence and requests for reprints should be addressed to Brian L. Block, M.D., New York Presbyterian Hospital-Columbia, Milstein Hospital 6C-12, 177 Fort Washington Avenue, New York, NY brianlblock@gmail.com Ann Am Thorac Soc Vol 13, No 1, pp , Jan 2016 Copyright 2016 by the American Thoracic Society DOI: /AnnalsATS CC Internet address: Case Conferences: The Clinical Physiologist 127

2 Table 1. Laboratory values Laboratory Test Reference Range Initial Value 30 h after Admission Sodium, mm Potassium, mm Chloride, mm Carbon dioxide, mm Urea nitrogen, mg/dl Creatinine, mg/dl Glucose, mg/dl Albumin, g/dl Anion gap, mm Expected anion gap, mm Variable* Venous ph x Venous pco 2,mmHg x Arterial ph x 7.16 Arterial pco x 40 Venous lactate, mm x Serum ketones (qualitative) Negative Negative x Urine ketones (qualitative) Negative Negative Negative Urine ph Urine sodium, mm Variable x 31 Urine potassium, mm Variable x 24 Urine chloride, mm Variable x 24 Given is a summary of pertinent laboratory studies on arrival at the emergency department, and on the second hospital day. X denotes result unavailable. *The normal anion gap is 1012 mm, and the expected anion gap, corrected for the patient s hypoalbuminemia, is calculated according to the following equation: Expected anion gap = normal anion gap 2 ([4.0 2 serum albumin] 3 2.5). [Continue onto next page for answers] 128 AnnalsATS Volume 13 Number 1 January 2016

3 Table 2. Causes of metabolic acidosis with a normal serum anion gap Gastrointestinal loss of bicarbonate d Diarrhea d Intestinal, pancreatic, or biliary fistulae d Ureterosigmoidostomy d Ureteroileostomy Impaired renal acid excretion d Distal (type 1) RTA d Hyperkalemic (type IV) RTA d Low GFR/hypovolemia d Adrenal insufficiency d ACEi, ARB, potassium-sparing diuretics, carbonic-anhydrase inhibitors d Cyclosporine, NSAIDs, amphotericin, trimethoprim, pentamidine d Chronic heparin administration d Pseudohypoaldosteronism type I d Pseudohypoaldosteronism type II (Gordon s syndrome) Renal loss of bicarbonate d Proximal (type II) RTA d Carbonic anhydrase inhibitors Addition of HCl or substances metabolized to HCl d Administration of TPN (cationic amino acids) d Direct ingestion of HCI d Direct ingestion of NH 4 CI Urinary organic anion loss with replacement by chloride d Toluene intoxication Resuscitation with chloride-rich solution d Normal saline administration Definition of abbreviations: ACEi = angiotensinconverting enzyme inhibitor; ARB = angiotensin receptor blocker; GFR = glomerular filtration rate; NSAIDs = nonsteroidal antiinflammatory drugs; RTA = renal tubular acidosis; TPN = total parenteral nutrition. Clinical Reasoning and Diagnosis The serum anion gap is typically calculated as the difference between concentrations Table 3. Laboratory studies before and after initiation of fludrocortisone Laboratory Test Reference Range of plasma sodium cations and plasma chloride plus bicarbonate anions. Healthy individuals have an anion gap of mm, largely composed of albumin as the unmeasured anion. An elevated anion gap indicates the presence of a pathological unmeasured anion, for example, ketones or lactate. In this patient, the normal anion gap argued against the presence of another anion and suggested the acidosis was caused by either (1) gastrointestinal or pancreatic loss of bicarbonate, (2) renal loss of bicarbonate, or (3) impaired renal acid excretion. See Table 2 for a summary of causes of metabolic acidosis with a normal serum anion gap. Severe diarrhea suggested gastrointestinal bicarbonate loss as the cause of acidosis. That the acidemia persisted despite the resolution of his diarrhea, however, made it necessary to consider other etiologies, including renal tubularacidoses(rta). The urinary anion gap (UAG) is the sum of urinary Na 1 plus K 1 minus Cl.Inthe setting of a metabolic acidosis with a normal serum anion gap, the kidneys should augment acid excretion in the form of ammonium. To maintain electroneutrality, Before Fludrocortisone ammonium is excreted with an anion typically chloride. Therefore the urinary chloride concentration is a surrogate marker for urinary ammonium, and is expected to be elevated (exceeding the sum of sodium plus potassium) in the setting of an acidosis. This results in a negative urine anion gap. Failure to excrete the excess acid as ammonium, evinced by low urinary chloride and therefore a positive urine anion gap, suggests RTA. Given the patient s positive UAG and concurrent hyperkalemia, type IV RTA associated with hypoaldosteronism was suspected. Assessment of plasma renin activity and serum aldosterone level, both of which were low, confirmed the diagnosis to be hyporeninemic hypoaldosteronism. The Clinical Solution 60 h after Fludrocortisone Sodium, mm Potassium, mm Chloride, mm Carbon dioxide, mm Urea nitrogen, mg/dl Creatinine, mg/dl Glucose, mg/dl Shown is a summary of pertinent chemistries before and after the initiation of mineralocorticoid replacement therapy (fludrocortisone). Given the patient s hypoaldosteronism and hyperkalemic RTA, he was started on fludrocortisone, a potent mineralocorticoid with lesser glucocorticoid activity. Within 2 days of starting this therapy, potassium Table 4. Characteristics of cardinal subtypes of renal tubular acidosis Type Mechanism Urinary ph Serum Serum K 1 I (distal) Inability to generate H 1 gradient:.5.5 d Defective H 1 - d Leak of H 1 out of lumen because of increased membrane permeability II (proximal) Decreased bicarbonate reabsorption in PCT Variable, high when filtered bicarbonate exceeds that which can be absorbed, otherwise ph,5.5 IV True or functional hypoaldosteronism,,5.5 or voltage defect Definition of abbreviation: PCT = proximal convoluted tubule. Shown are the characteristics of the three major types of renal tubular acidosis. z 10 z 1215 z 1520 Usually low Normal High Case Conferences: The Clinical Physiologist 129

4 Tubular Lumen PCT Cell Capillary + H + H 2 CO 3 (CA IV) NHE normalized and the metabolic acidosis resolved (Table 3). Unfortunately, in the setting of chronic kidney disease, the volume expansion that accompanied initiation of fludrocortisone led to hypertension. Ultimately, fludrocortisone was discontinued and the patient was started on hydrochlorothiazide. The Na + 3 Na + 2 K+ H + OH + CO 2 HCO 3 (CA II) H 2 O + CO 2 H 2 O + CO 2 Na/ HCO3 Figure 1. Mechanisms of sodium and bicarbonate reabsorption in the proximal convoluted tubule. The Tubular Lumen describes the interior of the nephron, the Capillary represents the systemic circulation, and PCT Cell indicates the cell lining the proximal convoluted tubule. NHE = sodiumhydrogen exchanger; Na/ = sodium/bicarbonate cotransporter; = sodiumpotassium pump; PCT = proximal convoluted tubule; CA IV = carbonic anhydrase IV; CA II = carbonic anhydrase II. Angiotensin II (not depicted) stimulates the sodiumhydrogen exchanger. See text for details. Na + patient was discharged shortly after discontinuation of fludrocortisone and we do not have further laboratory data to determine how his acidbase and potassium concentrations reequilibrated thereafter. However, with resolution of his diarrheaandanimprovedglomerular filtration rate, he would have been expected to reequilibrate with only mild Tubular Lumen PCT Cell Capillary NH 3 + Reabsorbed or directly excreted NHE Na + 3 Na + 2 K + NH α-ketoglutarate Glutamine Na/ HCO3 Figure 2. Mechanism of ammonia generation in the proximal convoluted tubule. The Tubular Lumen describes the interior of the nephron, the Capillary represents the systemic circulation, and PCT Cell indicates the cell lining the proximal convoluted tubule. NHE = sodiumhydrogen exchanger; Na/ = sodium/bicarbonate cotransporter; = sodiumpotassium pump; PCT = proximal convoluted tubule. See text for details. Na + acidosis (see Table 4 for features of the three cardinal forms of RTA). The Science behind the Solution Renal Tubular Acidoses In steady state, acid intake plus acid generation must equal acid elimination. Most acid is generated from cellular metabolism of carbohydrate and fat to CO 2, which, although it is not itself an acid, is hydrated to form carbonic acid (H 2 CO 3 ). H 2 CO 3 is termed a volatile acid because it can dissociate into H 2 O 1 CO 2, with the gaseous CO 2 being eliminated by the lungs. Fixed or metabolic acid, by contrast, is the consequence of protein metabolism and exists primarily as phosphoric and sulfuric acids. Metabolic acid cannot be exhaled, and instead must be buffered and subsequently eliminated by the kidney. On a typical Western diet, we produce roughly 70 meq of fixedacidper day. At the physiological ph of 7.4, this acid exists largely in the deprotonated form, having donated its proton to bicarbonate and to other buffers, as follows: 2HA 1 Na 1 X NaA 1 H 2 CO 3 1 HX where HA represents fixed acid, and X represents nonbicarbonate buffers, including HPO 4 2,H 2 PO 4,SO 4 2,NH 3, and albumin, among others. Note that the equation is simplified, as H 2 CO 3 and HX are not formed in a 1:1 ratio. The kidneys must accomplish three tasks in the setting of this daily acid load. First, they must eliminate the hydrogen ions and sodium salts (NaA) of the fixed acid. Second, they must reclaim as much of the filtered bicarbonate as possible. Finally, they must also regenerate new bicarbonate to both replace that which had been consumed in the process of buffering the acid load, and to titrate nonbicarbonate buffers back to their original state of protonation. Renal tubular acidosis describes the situation in which acidosis develops because of a defect in bicarbonate generation, bicarbonate reabsorption, or acid elimination. Because sodium salts are still adequately eliminated, unmeasured anions do not accumulate, and the anion gap remains normal. 130 AnnalsATS Volume 13 Number 1 January 2016

5 Tubular Lumen α-intercalated Cell Capillary NH 4 + NH 3 + Trapped and excreted with Chloride H + H + H/K H + Renal Bicarbonate Reabsorption and Generation Our kidneys filter approximately 4,320 meq of bicarbonate daily (180 L of plasma filtered/d 3 24 meq of bicarbonate/l). Nearly all of this bicarbonate is reabsorbed; 85% of it in the proximal TCA ATP H K + 2 O + CO 2 2 K + OH + CO 2 (CA II) CI / CI 3 Na + Figure 3. Mechanism of acid excretion in alpha-intercalated cells of the distal tubule. The Tubular Lumen describes the interior of the nephron and the Capillary represents the systemic circulation. H 1, proton pump; H/K, hydrogenpotassium pump; /Cl = bicarbonate/chloride exchanger; = sodiumpotassium pump; CA = carbonic anhydrase; TCA = tricarboxylic acid cycle. Aldosterone (not depicted) stimulates the activity of the apical H 1 -, the basolateral, and also enzymes of the TCA cycle, generating more energy to drive the s. Notably, the luminal H 1 can combine with ammonia to form ammonium (as shown) or titratable acid such as phosphate, which is not shown for simplicity. See text for details. convoluted tubule (PCT) (Figure 1). There, bicarbonate combines with hydrogen to form CO 2 and H 2 Oina reaction catalyzed by a brush-border carbonic anhydrase (CA-IV). The CO 2 then diffuses into PCT cells where a cytosoliccarbonicanhydrase(ca-ii) Tubular Lumen Principal Cell Capillary Na + ENaC ROMK K + 2 K + 3 Na + Figure 4. Mechanism of sodium reabsorption and potassium elimination in the distal tubule. The Tubular Lumen describes the interior of the nephron, the Capillary represents the systemic circulation. ENaC = epithelial sodium channel; ROMK = renal outer medullary potassium channel. Aldosterone (not depicted) promotes insertion and stabilization of apical sodium and potassium channels, and also stimulates the basolateral sodiumpotassium pump. generates bicarbonate for reabsorption, while the Na 1 /H 1 exchanger (NHE) excretes protons into the lumen to reclaim further bicarbonate. A similar process occurs more distally in the thick ascending limb of the loop of Henle(TAL)andcollectingduct(CD), such that ultimately only 25 meqof bicarbonate is eliminated in the urine each day. In addition to this reabsorption of filtered bicarbonate, new bicarbonate is also generated in the PCT and CD to replace losses due to buffering of acid. Proximally, the amino acid glutamine is metabolized into ammonium and a-ketoglutarate in cells of the PCT. The a-ketoglutarate is then converted into bicarbonate, which is taken into the circulation via a basolateral sodium/bicarbonate symporter. Meanwhile, the cationic ammonium is secreted into the lumen by the aforementioned NHE (Figure 2). Distally, an H 1 - in the a-intercalated cells of the CD pumps protons into the lumen, where they bind filtered anions and ammonia. Intracellular bicarbonate, liberated from the secreted proton, is then absorbed via a basolateral bicarbonate/chloride exchanger on the a-intercalated cell (Figure 3). Importantly, ammoniagenesis is impaired by reduced glomerular filtration rate, and hyperkalemia both of which were present in our patient. Renal Acid Elimination: Ammonia and the Urinary Anion Gap In the setting of acidemia, the nephron augments acid elimination. To achieve this, protons must be secreted and then quickly buffered or titrated to maintain an electrochemical gradient for further proton secretion. Phosphate and other filtered anions provide some buffering capacity. However,theamountofacidthatmust be eliminated exceeds the buffering capacity of these titratable acids. Ammonia provides large urinary buffering capacity, and its production can be enhanced to accommodate increased acid elimination. Ammonia is generated from glutamine metabolism in cells lining the PCT, and secreted into the lumen by the NHE. Although some is directly excreted in the urine, most is protonated to form ammonium and then reabsorbed into the interstitium of the TAL via the Na 1 /K 1 /2Cl cotransporter. Interstitial ammonium exists in equilibrium Case Conferences: The Clinical Physiologist 131

6 Chronic, poorly-controlled Diabetes Renal artery (afferent/efferent) hyalinization Diarrhea and Glycosuria Diabetic Nephropathy Chronic Volume Retention Volume Depletion Prorenin conversion Urine ph Reduced GFR Ammoniagenesis Renin Angiotensin II Aldosterone Atrial Natriuretic Peptide Normal Anion Gap Metabolic Acidosis Renal H + secretion intracellular ph (H + shift) Hyperkalemia Urine CI Positive Urine Anion Gap Figure 5. Overview of the case, tying together diagnoses, physiological processes, and laboratory findings. Underlying diagnoses/conditions are displayed in blue, and the cardinal findings of hyporeninemic hypoaldosteronism are displayed in red and major intermediate processes are displayed in black. The patient s longstanding uncontrolled diabetes likely led to chronic volume retention, which is thought to indirectly inhibit renin release by increasing levels of atrial natriuretic peptide. Low levels of renin lead to low levels of angiotensin II and, in turn, low levels of aldosterone, causing impaired renal acid and potassium elimination. At the same time, the patient s chronically reduced glomerular filtration rate (GFR) from diabetic nephropathy, paired with acute kidney injury from volume depletion and peripheral vasodilation in the setting of diarrhea and sepsis, further impaired renal acid elimination by reducing ammoniagenesis. In the setting of decreased urinary ammonium, less chloride was eliminated in the urine (recall that urinary chloride is a surrogate marker for urinary ammonium, as the two are normally eliminated together to maintain electroneutrality). The urinary anion gap, calculated as urine sodium plus urine potassium minus urine chloride, was therefore positive, indicating reduced renal acid elimination consistent with type IV renal tubular acidosis due to hyporeninemic hypoaldosteronism. See text for further details of these pathophysiological processes. with its conjugate base, ammonia, which is uncharged and, therefore, lipid soluble. Lipid-soluble ammonia diffuses into the lumen of the nephron distally, and buffers hydrogen being secreted by the a-intercalated cells. Importantly, once it binds hydrogen, it becomes positively charged and is trapped in the tubule, destined for elimination in the urine as ammonium. Given its positive charge, urinary ammonium is excreted along with an anion to maintain electroneutrality. When there is not a large amount of unmeasured anion this anion is chloride. Therefore, urinary chloride is a surrogate marker of urinary ammonium. High levels suggest robust ammonium (i.e., acid) elimination, whereas low levels suggest little acid elimination. This principle underlies the UAG: Urine cations ¼ urine anions U Na 1 U K 1 unmeasured cations ¼ U CI 1 unmeasured anions U Na 1 U K 2 U Cl ¼ UAG ¼ unmeasured anions 2 unmeasured cations In the setting of acidemia with a normal serum anion gap, a positive UAG indicates relatively low chloride elimination, suggesting inadequate acid elimination. Hypoaldosteronism and the Hyperkalemic RTA Aldosterone modulates both renal acid base balance and renal potassium handling. In the principal cell of the distal tubule, it stimulates sodium reabsorption and potassium wasting by causing insertion of apical sodium (ENaC) and potassium (ROMK [renal outer medullary potassium]) channels, andbasolateral Na 1 /K 1 -s (Figure 4). It also induces enzymes of the tricarboxylic acid cycletoincreaseatpgeneration, 132 AnnalsATS Volume 13 Number 1 January 2016

7 Table 5. Etiologies of hyperkalemic (type IV) renal tubular acidosis Hyporeninemic hypoaldosteronism d Chronic kidney disease d Diabetic nephropathy d Chronic interstitial nephritis d Medications d NSAIDs d Calcineurin inhibitors d Heparin d Acute glomerulonephritis d Pseudohypoaldosteronism type II (Gordon9s syndrome) Hyperreninemic hypoaldosteronism d Primary adrenal insufficiency d Severe illness d Medications d ACEi d ARB Functional hypoaldosteronism d Pseudohypoaldosteronism type 1 d Medications d Potassium-sparing diuretics, inhibit the mineralocorticoid receptor (spironolactone, eplerenone) d Inhibition of ENaC (amiloride, triamterene, trimethoprim, pentamidine) Definition of abbreviations: ACEi = angiotensinconverting enzyme inhibitor; ARB = angiotensin receptor blocker; ENaC = epithelial sodium channel; NSAIDs = nonsteroidal antiinflammatory drugs. providing additional energy to drive the sodiumpotassium pump. In the a-intercalated cell, aldosterone stimulates an H 1 - that pumps hydrogen into the lumen. Recall that this pumping of hydrogen into the lumen generates new bicarbonate, as discussed previously and displayed in Figure 3. Given its role in potassium and hydrogen elimination, it is easy to understand why decreased aldosterone signaling causes hyperkalemia and acidosis. The picture is more complicated, however, as hyperkalemia itself further worsens acidosis by inhibiting ammoniagenesis (presumablybyincreasingintracellularph as it enters PCT cells in exchange for hydrogen ions) and interfering with ammonia cycling (by competing with ammonium to be pumped into the interstitium via the TAL s Na 1 /K 1 /2Cl cotransporter). Upstream of aldosterone, other components of the reninangiotensin aldosterone cascade also impact renal acid elimination. Angiotensin II normally stimulates the NHE of PCT cells (Figure 1), augmenting proximal bicarbonate reclamation. Without angiotensin II, proximal bicarbonate reclamation is reduced, worsening acidosis. A concept map (Figure 5) has been generated to tie together the mechanistic and physiological relationships between clinical processes for the described patient with hyporeninemic hypoaldosteronism. Other forms of hyperkalemic RTA are presented in Table 5. Answers 1. What is the cause and pathophysiology of this patient s metabolic acidosis? This patient s metabolic acidosis was due to type IV renal tubular acidosis, specifically hyporeninemic hypoaldosteronism. The lack of aldosterone led to deficits in potassium and hydrogen elimination, resulting in hyperkalemia and acidemia. See text for further details. 2. How does the urinary anion gap help determine the cause of metabolic acidosis with a normal serum anion gap? Calculating the urinary anion gap provides a means for assessing whether the kidneys are adequately eliminating acid. If the urinary anion gap is negative, it suggests a nonrenal cause of acidosis. If the urinary anion gap is positive, it suggests renal tubular acidosis. Treatment Treatment of hyporeninemic hypoaldosteronism is most often aimed at reducing serum potassium, as hyperkalemia is typically more significant than acidemia. Mineralocorticoid replacement effectively treats both hyperkalemia and acidosis, but as was seen in this patient, can precipitate or worsen hypertension and edema a particular concern given that many patients with hyporeninemic hypoaldosteronism have chronic kidney disease. Those patients who cannot be treated by mineralocorticoid replacement can instead be managed with either loop diureticsorpotassiumbinding resins. n Author disclosures are available with the text of this article at Recommended Reading Berend K, de Vries AP, Gans RO. Physiological approach to assessment of acidbase disturbances. N Engl J Med 2014;371: Clark BA, Brown RS, Epstein FH. Effect of atrial natriuretic peptide on potassium-stimulated aldosterone secretion: potential relevance to hypoaldosteronism in man. J Clin Endocrinol Metab 1992;75: Karet FE. Mechanisms in hyperkalemic renal tubular acidosis. J Am Soc Nephrol 2009;20: Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2007;2: Kraut JA, Madias NE. Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol 2010;6: Kraut JA, Madias NE. Differential diagnosis of nongap metabolic acidosis: value of a systematic approach. Clin J Am Soc Nephrol 2012;7: Lush DJ, King JA, Fray JC. Pathophysiology of low renin syndromes: sites of renal renin secretory impairment and prorenin overexpression. Kidney Int 1993;43: Phelps KR, Lieberman RL, Oh MS, Carroll HJ. Pathophysiology of the syndrome of hyporeninemic hypoaldosteronism. Metabolism 1980;29: Richards J, Schwartzstein R, Irish J, Almeida J, Roberts D. Clinical physiology grand rounds. Clin Teach 2013;10:8893. White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med 1994;331: Case Conferences: The Clinical Physiologist 133