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The approach to a patient with acute polyuria and hypernatremia: a need for the physiology of McCance at the bedside
The Netherlands Journal of Medicine 2001;58:103–110
Original article
The approach to a patient with acute polyuria and hypernatremia: a need for the physiology of McCance at the bedside a b c, Mogamat Razeen Davids , Yeouda Edoute , Mitchell L. Halperin * a
Nephrology Unit, University of Stellenbosch, Cape Town, South Africa b Internal Medicine C, Rambam Medical Center, Haifa, Israel c Division of Nephrology, University of Toronto, St. Michael’ s Hospital Annex, Lab [1, Research Wing, 38 Shuter Street, Toronto, Ontario, Canada M5 B 1 A6 Received 12 December 2000; accepted 12 December 2000
Abstract We present a case to illustrate the importance of emphasizing elementary physiology to deduce the basis for the acute onset of polyuria and hypernatremia. An imaginary consultation with Professor McCance is utilized to illustrate how a clinician–physiologist would have explained why these abnormalities developed and how they should have been treated. His approach began with a consideration of the most impressive abnormality. His analysis relied heavily on deductions and the anticipation of the expected responses to a stimulus in quantitative terms. The goals of therapy became evident after he performed mass balance calculations. Professor McCance would not understand why modern clinicians abandoned this form of analysis. 2001 Elsevier Science B.V. All rights reserved. Keywords: Antidiuretic hormone; Hyponatremia; Neurosurgery; Sodium; Subarachnoid hemorrhage; Tonicity balance; Vasopressin; Water
There are two different, but not mutually exclusive ways to arrive at a clinical diagnosis and to initiate therapy for a patient who has a medical problem. In the more traditional approach, data are gathered from the history, physical examination and laboratory testing. A list of possible causes is derived from this information. This approach has stood the test of time. An imaginary consultation with Professor McCance, our central figure, is from a real patient, but we asked him to restrict his database to the years
preceding 1937. His emphasis, when dealing with problems in the fluid and electrolyte area, focuses on an application of principles of physiology [1,2]. In addition to relying on physiology, his analysis is deductive and is described in quantitative terms; it depends on a knowledge of the expected responses to a given perturbation. He begins by identifying a single, impressive abnormality.
Focus on the major abnormality *Corresponding author. Tel.: 11-416-864-5292; fax: 11-416864-5943. E-mail address: [email protected] (M.L. Halperin).
In the case to be considered (see Appendix A), the clinicians were faced with a patient who had a urine
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flow rate that was 10 ml / min. Professor McCance was amazed because when he extrapolated this flow rate to a 24-h period, it was equivalent to 14.4 l / day, a volume that exceeded the patient’s extracellular fluid (ECF) volume; and was virtually equal to half her total body water. Therefore, if this polyuria were not dealt with very promptly, it could create a lifethreatening situation. Faced with this medical emergency, we invite the reader to stop and consider the following question: ‘‘ What was responsible for the very large volume of urine produced by this patient?’’ We shall also ask Professor McCance the same question. He framed his response in the following context. Physiological principle: control of the urine flow rate Professor McCance would undoubtedly remind us that Eq. (1) describes urine flow rate. From this we learn that polyuria has two causes, a larger than normal daily solute excretion rate (osmotic diuresis) and an inability to raise the concentration of solutes in the urine (water diuresis). He deduced that for an osmotic diuresis to cause this degree of polyuria, each liter of urine would have to contain at least 300 mosmol of solute. The excretion of almost 4500 mosM of extra solutes (14.4 l per day 3 300 mosM / l) would require the presence of very high concentrations of these organic solutes in plasma. For example, with a glomerular filtration rate of 150 l per day, the concentration of glucose in the filtrate would have to be 30 mmol / l higher than the renal threshold of 10 mmol / l or be 40 mmol / l (540 mg / dl). If urea were the osmole responsible for the osmotic diuresis, its plasma concentration would have to be 60 mmol / l (BUN 168 mg / dl) because McCance knew that close to half of the filtered load of urea is normally absorbed [3].
that we would find a urine osmolality that was much lower than that of plasma to support his diagnosis. Indeed, the urine osmolality in our patient was 120 mOsm / kg H 2 O in the face of a plasma Na 1 concentration of 156 mmol / l. A full appreciation of those findings required our professor to review the control system for water and describe the expected response of an intact system to hypernatremia. Physiological principle: control system for water A control system may have a sensor that is in a different location from its response elements. If this occurs, there must also be a messenger that communicates between these two locations. For water (Fig. 1), the sensor is the volume of cells in a specialized area of the hypothalamus. They shrink and this leads to the release of more vasopressin when the plasma Na 1 concentration exceeds 140 mmol / l. At the response element level, vasopressin causes water to be reabsorbed in the distal segments of the nephron [3].
Urine flow rate (l / day) 5 Number of Solutes excreted / [Solutes] urine
(1)
Because our patient did not have an elevated glucose or urea concentration in plasma or a history of receiving an enormous quantity of mannitol, Professor McCance deduced that the basis of the polyuria was a water diuresis. He boldly predicted
Fig. 1. Control system for water excretion. The circles represent structures in the hypothalamus. The tonicity stat (stat) detects a change in the plasma Na 1 concentration. Because of hypernatremia (box on the left), this center leads to the release of vasopressin. This hormone acts on the distal nephron to cause it to become permeable to water (and urea) which when reabsorbed, thereby explains the excretion of a concentrated urine.
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Professor McCance then emphasized the importance of expected responses to stimuli and that the control system for water excretion should be ‘dissected’ at the bedside. Expected response to hypernatremia Vasopressin should cause the urine to become maximally concentrated. This means that at a minimum, the urine osmolality should be distinctly higher than the plasma osmolality. The fact that the urine osmolality was 120 mOsm / kg H 2 O indicates that there was a defect in the control system for water (Fig. 1). Probing the control system Because there was an acute procedure (neurosurgery) that could have compromised the hypothalamic area that releases vasopressin, and because there was a large water diuresis in the presence of a stimulus for the release of vasopressin (hypernatremia), the provisional diagnosis was central diabetes insipidus (DI). To confirm this diagnosis, the patient was given a preparation containing vasopressin to abort the polyuria. Clinical course The physicians in charge of the patient thanked Professor McCance for his help. They felt confident that they could interpret the renal response to vasopressin. They knew that vasopressin should act in a matter of minutes and cause a rapid fall in the urine flow rate along with a rise in the urine osmolality. The fall in flow rate could be observed promptly at the bedside, but a delay could be expected before the laboratory report returned with the urine osmolality. Therefore clinical decisionmaking would be made on the basis of the decline in the urine flow rate. To make their analysis quantitative as they had learned from their beloved professor, they relied on deductive reasoning. Normal subjects have a urine volume close to 1 l per day (Table 1). Since there are 1440 min in a day, the average urine flow rate is less than 1 ml / min. Accordingly, in response to vasopressin, they expected the urine volume to fall to less than 1 ml / min. A surprise was in store. The urine flow rate did decline, but only to 6 ml / min after vasopressin was given. Concluding
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Table 1 Composition of the 24-h urine in normal subjects a Volume Osmolality Urea Na 1 K1 Cl 2 Urea
l / day mosM / day mmol / day mmol / day mmol / day mmol / day % of osmoles
1.260.12 748644 345627 127611 5865 124611 4763
a
The number of subjects was 12, six males and six females (age 2862.6). They consumed their usual diet and performed all their usual activities. They did not take medications. Because their excretion rates for all items except creatinine were similar, their results were combined for simplicity. Results are presented as the mean6S.E.M.
that this represented only a partial renal response to this hormone, the patient was given extra doses of a long-acting form of vasopressin (dDAVP), but the urine flow rate did not decline further. The error made at this juncture was to rely on data obtained from one setting (normal subjects) and apply them to a patient in another setting (vide infra). This unfortunate mistake set into motion a series of compounding errors that had grave consequences for the patient. Part of the reason for this error was that the clinicians had failed to think like Professor McCance. Had the omniscient physiologist been consulted again, perhaps he would have provided the following simple and elegant answer. Quantitative analysis of the urine osmolality First, he would gently remind them that, had he not been so prematurely dismissed, he would have pointed out that the urine osmolality of 120 mOsm / kg H 2 O was not what he would have expected with a water diuresis and a flow rate of 10 ml / min. In fact, knowing that the typical Western diet yields a load of close to 800 mosM for excretion per day and that approximately half of them are urea and half are electrolytes (Table 1), he would expect a person in steady-state to excrete 0.5–0.6 mosM / min (800 mosM / 1440 min). With a flow rate of 10 ml / min, the osmolality should have been 50–60 mOsm / kg H 2 O (Eq. (1)). Professor McCance followed up this bit of deductive reasoning with data collection. He performed an experiment on the Fellows in his department. As
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keen as he was to participate fully in this selfexperimentation, he was mindful of the fact that he needed to select a study population that closely matched our patient, hence the data from the younger members of his team are provided in Table 2. Within 60 min after drinking a water load of 20 ml / kg, these healthy volunteers had a urine flow rate close to that of our patient. As our venerable professor had predicted, the urine osmolality was indeed predictable at 50–60 mOsm / kg H 2 O, close to half that of our patient. So both by deduction, and now by data that were easily obtained, McCance brought home to our team the fact that an excessive excretion of osmoles was present in the patient. During the water diuresis when there is a low urine osmolality, this high rate of excretion of osmoles would have no effect on the urine flow rate. Nevertheless, as soon as vasopressin acts, the osmole excretion rate will exert a major effect on the urine flow rate (Eq. (1)). So our team of physicians asked Professor McCance, ‘‘ How low should the urine flow rate be when vasopressin acts?’’ His answer caught them off guard. He said he did not expect it to fall to 1 ml / min because he took into account three important facts. First, the patient was excreting sodium (Na 1 ) and potassium (K 1 ) at 2.5 times the rate of the control subjects. Second, the huge water diuresis would have diminished the medullary interstitial osmolality and this would take time to be reconstituted. The maximum obtainable urine osmolality would therefore be similarly reduced. A third factor he considered was that the peak natriuresis following the intravenous Na 1 load that she had received may
not have been reached at the time that urine electrolytes were first measured. Indeed, the rate of excretion of Na 1 1K 1 continued to rise after vasopressin was given. Thus a flow rate after vasopressin that was more than 7-fold that of our control subjects was a more realistic expectation. McCance would also have dealt with an excellent question by one of his fellows: ‘‘ Does urea have the same influence on urine flow rate as electrolytes when vasopressin acts?’’ He would have relied on experiments conducted by Gamble in 1934 in human subjects [3]. When vasopressin acts, Gamble deduced that the terminal portion of the nephron becomes permeable to urea. This means that the concentration of urea in its lumen and in the inner medullary interstitial compartment approximate one another. Thus urea tends to become an ‘ineffective’ osmole in this nephron segment and does not directly cause water to be retained in its lumen. This theoretical impression was supported more than half a century later by experimental data in animals and in human subjects [4] providing that urea excretion rates were not excessively high. Comments In summary, up to this point, the clinical picture and the physiology pointed to a diagnosis of central DI. The apparent poor response to vasopressin did not reflect an additional diagnosis of nephrogenic DI. Rather, polyuria at this time reflected the expected renal response to an electrolyte-induced osmotic diuresis in the presence of a diminished medullary
Table 2 Parameters to assess the renal concentrating process a Parameter in urine
Flow rate Osmolality Osmole excretion Urea excretion Na 1 1K 1 excretion Urea
ml / min mOsm / kg H 2 O mosM / min mosM / min mosM / min % of osmoles
Control subjects
Patient
Water load
Before therapy
11.360.45 5763.6 645649 302622 377643 4862
10 120 1200 200 1000 17
a
The number of volunteer control subjects (age 3262) was 15, 10 males and five females. They ingested 20 ml of water per kg body weight and voided on request. Results are reported as the mean6S.E.M. The Netherlands Journal of Medicine 2001;58:103 – 110
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interstitial effective (non-urea) osmolality. The magnitude of the diuresis was larger than anticipated because the numerator of Eq. (1) in Na 1 1K 1 terms was 2.5-fold higher than in normal subjects and its denominator was half that of normal subjects (Table 2) given the time frame of the response. McCance might have been proud of the self-experimentation, the high reliance on elementary physiological principles defined in the 1930s [1–3], and a strong emphasis on a quantitative analysis. He would also have cautioned against using data derived in one setting (water-deprived normal subjects) and comparing them to the observed results in another setting (the acute administration of vasopressin to a patient undergoing a large water diuresis). Evidence-based medicine too requires the care exhibited by McCance in ensuring that the control group has similar characteristics to the experimental group.
Approach to hypernatremia using the principles of McCance The goal of therapy of hypernatremia in this patient should be to return the volume and composition of the body fluid compartments to normal. The first objective therefore is to decide whether hypernatremia was due to a higher value for the numerator (Na 1 content) and / or a lower value for the denominator (water in the ECF compartment) in our patient. Intuitively, and this was the opinion held by the attending physicians, it would seem that the basis of her hypernatremia was the water diuresis as is often the case in untreated central DI. They proudly presented their argument to Professor McCance, even including a quantitative analysis. They reasoned as follows. The urine volume was 5 l and its Na 1 concentration 50 mmol / l when the diagnosis of central DI was made. Hence sufficient pure water was excreted (2 / 3 of 5 or 3.3 l) to cause the observed slightly greater than 10% rise in the plasma Na 1 concentration (total body water was 30 l) [5]. Such logic, however, would never satisfy McCance who insisted on examining the mass balance for Na 1 1K 1 and for water. This simple analysis of all inputs and outputs is now called a tonicity balance [6,7] (Fig. 2A).
Fig. 2. Calculation of a tonicity balance. The box in the center of each figure represents total body water. The plasma Na 1 concentration before the infusion and excretion is shown at the top of the box, whereas this value at the end of the period is shown below. The period before vasopressin is depicted in the top portion of the figure (A), the initial response to therapy is shown in (B), and therapy to avoid the development of hyponatremia should be obvious from an examination of (C).
Calculate a tonicity balance Because the logic applied above began with water, its mass balance was examined first. The volume of water infused was equal to the urine volume. Therefore hypernatremia in our patient was NOT due to a water deficit despite the large water diuresis. On the other hand, the solution infused was isotonic saline (150 mmol Na 1 / l) while the urine was hypotonic saline (50 mmol Na 1 1K 1 / l). Accordingly, the patient gained 100 mmol Na 1 (1K 1 ) per liter of input and output, and 500 mmol of Na 1 in total. With a total body water of 30 l, the gain of 500
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mmol of Na 1 would cause the plasma Na 1 concentration to rise by 16.7 mmol / l (500 mmol / 30 l), a value closely approximating the observed value of 156 mmol / l. Use the tonicity balance for therapeutic decisions This clear demonstration by McCance that our patient’s hypernatremia was due to the gain of 500 mmol of Na 1 also made the required therapy equally obvious: he would cause the patient to lose 500 mmol of Na 1 while maintaining water balance. Our team of attending physicians once again thanked Professor McCance for his analysis and took charge of the case. The measured concentration of Na 1 1 K 1 in the urine was 175 mmol / l. Therefore, they infused half-isotonic saline (75 mmol Na 1 / l) at volumes equal to the urine output, which would result in a deficit of 100 mmol of Na 1 per liter. After the excretion of 5 l of urine, this resulted in the negative balance of 500 mmol of Na 1 and correction of the plasma Na 1 concentration along with restoration of the intracellular fluid (ICF) and ECF volumes and composition to normal (Fig. 2B). A successful clinical outcome was anticipated. Nevertheless, had McCance still been at the bedside, he would have predicted that this patient was not out of danger. ‘‘ A new and occult threat to survival was looming; what was this threat?’’
Anticipating the ‘occult’ threat to survival
(Fig. 2, bottom portion). A key concept now became relevant. Physiological principle: the plasma Na 1 concentration reflects the ICF volume Professor McCance stated that the volume of the ICF compartment is reflected by the plasma Na 1 concentration for three reasons (Fig. 3). First, water can cross cell membranes and it achieves osmotic equilibrium rapidly. Second, the number of effective osmoles in the ICF compartment remains constant in an acute setting (largely K 1 ). Third, in the absence of hyperglycemia and mannitol administration, the effective osmoles in the ECF compartment are Na 1 and its attendant anions, chloride (Cl 2) and bicarbonate. Should hyponatremia develop, cells will swell. The ‘target organ’ of clinical importance is the brain because it is in a confined rigid space and it cannot extrude intracellular particles in an acute setting. Clinical outcome Therapy with half-isotonic saline (Na 1 concentration 75 mmol / l) given at a rate equal to urine output caused a negative balance for Na 1 and a fall in her plasma Na 1 concentration (urine Na 1 concentration was 175 mmol / l). Nevertheless, the patient became progressively hyponatremic and ultimately died because of brain swelling that led to herniation due to the fact that this therapy was not
McCance knew that progressive hyponatremia from ongoing negative Na 1 balance was a real danger unless therapy was modified at this point to keep body composition constant. Urine Na 1 concentration This concentration can be as high as the medullary interstitial Na 1 1K 1 concentration when vasopressin acts. Since dDAVP was given in large amounts and the vast majority of urine osmoles were Na 1 1K 1 salts (Table 2), it is not surprising that the urine Na 1 concentration rose to 300 mmol / l. Therefore it is easy to anticipate why hyponatremia would develop
Fig. 3. Plasma Na 1 concentration reflects the ICF volume. The circle represents the ICF compartment. It contains macromolecular anions and the cation K 1 which is its major osmole. These osmoles (P) are restricted to the ICF compartment. Urea, shown on the left, is not an effective osmole here because it can cross cell membranes and achieve an equal concentration in the ECF and ICF compartments. The osmoles restricted to the ECF compartment are Na 1 and its attendant anions. Osmotic equilibrium is achieved because water can cross this cell membrane rapidly.
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modified. ‘‘ How could this fatal outcome have been avoided?’’ A quantitative approach would have allowed the attending physicians to recognize when the goal of therapy had been reached, i.e., when 500 mmol Na 1 had been lost and body composition and volumes had been restored to normal. At this point, it was necessary to match input with output, both in terms of volume and electrolyte content to keep the volumes and composition of the body compartments constant. Because the concentration of Na 1 1K 1 in the urine of our patient exceeded that of isotonic saline after administration of dDAVP, a loop diuretic, had it been available at that time, could have been employed to lower urine Na 1 1K 1 concentration to approximate that of plasma. At this point, giving isotonic saline at the same rate as the urine output could have replaced all renal losses other than K 1 while preventing a fall in the plasma Na 1 concentration. When the plasma Na 1 concentration was lower than 140 mmol / l, the attending physicians ignored the impassioned pleas of McCance to give hypertonic saline (300 mmol / l) to the patient. This infusion, if given at a rate equal to the urine flow rate, would have prevented a further decline in the plasma Na 1 concentration. He emphasized that this rate of infusion of hypertonic (300 mmol / l) NaCl would not cause the plasma Na 1 concentration to rise. To raise the plasma Na 1 concentration, the infusion of saline (300 mmol / l) must exceed the urine flow rate or the concentration of Na 1 in the infusate would have to be greater than 300 mmol / l. The attending physicians opted to only change the intravenous fluids to isotonic saline and this error caused our patient to die of brain cell swelling when her plasma Na 1 concentration reached 124 mmol / l. At any point before the tragic end, her Na 1 concentration could have been raised to a non-threatening level easily by the administration of 1 mmol Na 1 (in a very hypertonic form) per liter of total body water times the desired change in the plasma Na 1 concentration. Raising her Na 1 concentration from 124 to 130 mmol / l would have required a positive balance of 180 mmol of Na 1 , i.e., the rapid infusion of close to 400 ml of 3% NaCl. It is important to recognize that a reasonably rapid rate of correction of hyponatremia is not a risk factor for osmotic
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demyelination in a patient with acute hyponatremia (reviewed in Ref. [8]).
Concluding remarks The process of the analysis of the imaginary consult pitted Professor McCance against modern clinicians, but the playing field was not level. He was deprived of the entire medical literature written after 1936, he was not exposed to molecular biology, and he was not taught with a modern medical curriculum. Despite these handicaps, he excelled by using his knowledge of whole body physiology, deductive reasoning, a quantitative analysis with mass balance, and simple self-experimentation. For diagnosis, the basis of the polyuria was clearly a water diuresis. By calculating the osmole excretion rate and deducing that the nature of the excessive excretion of osmoles was electrolytes rather than urea (or glucose), he could predict that the urine flow rate might only decline to around 5 ml / min after vasopressin was given. Armed with these insights, he would not have given the patient excessive amounts of this hormone and avoided ‘pitfall 1’. In the area of therapy, he set out his objectives clearly — return the body compartment volumes and composition to normal. He defined the abnormality with data rather than innuendo. Using what we now call a tonicity balance, he recognized that the basis of hypernatremia was a positive balance of 500 mmol of Na 1 (and Cl 2). Accordingly, he designed therapy to create a negative balance for Na 1 (2500 mmol) and no more while maintaining water balance. Moreover, he could anticipate the danger in this setting. Once the plasma Na 1 concentration returned to normal, he insisted on maintaining Na 1 and water or a tonicity balance. Because the urine Na 1 concentration was high and the urine flow rate was also large, he insisted on giving an intravenous solution at the same rate as the urine flow rate while ensuring its Na 1 concentration was equal to that of the urine. Thus he avoided pitfall 2. Had loop diuretics been discovered, he might have used them to convert the composition of the urine to isotonic saline, a solution that would easily be matched in volume and composition by intravenous fluids. Perhaps the simple take-home message is that the thinking process and approach of
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Professor McCance should represent the present and the future rather than simply the good old days.
mOsm / kg H 2 O, urine Na 1 37 mmol / l, and urine K 1 13 mmol / l.
Appendix A
References
Case synopsis A 42-year-old previously healthy woman (weight 52 kg) presented with the sudden onset of severe headache, nausea and vomiting. Drowsiness and neck stiffness were the only abnormalities on physical examination. Computed tomography scan confirmed the presence of Berry aneurysms of the anterior communicating, right posterior communicating and left ophthalmic arteries. Plasma urea, creatinine and electrolytes were normal at the outset. Pre-operatively, she was given carbamazepine (800 mg) and dexamethasone (4 mg) and then had a successful clipping of the bleeding aneurysm. She was transferred to the neurosurgical intensive care unit where polyuria was first noted. The urine flow rate was 10 ml / min 10 h after her admission. She had passed a total of 5 l of urine during this time and received 5 l of isotonic saline. Laboratory results at the 10-h time revealed the following: plasma Na 1 concentration 156 mmol / l, urine osmolality 120
[1] McCance RA. Experimental sodium chloride deficiency in man. Proc R Soc London 1936;119:245–68. [2] McCance RA. Medical problems in mineral metabolism. III. Experimental human salt deficiency. Lancet 1936;230:823– 30. [3] Gamble JL, McKhann CF, Butler AM, Tuthill E. An economy of water in renal function referable to urea. Am J Physiol 1934;109:139–54. [4] Gowrishankar M, Lenga I, Cheung RY, Cheema-Dhadli S, Halperin ML. Minimum urine flow rate during water deprivation: Importance of the permeability of urea in the inner medulla. Kidney Int 1998;53:159–66. [5] Spital A, Sterns RD. The paradox of sodium’s volume of distribution: why an extracellular solute appears to distribute over total body water. Arch Intern Med 1989;149:1255–7. [6] Mallie J-P, Bichet DG, Halperin ML. Effective water clearance and tonicity balance: the excretion of water revisited. Clin Invest Med 1997;20:16–24. [7] Halperin ML, Goldstein MB. In: Fluid, electrolyte and acidbase physiology; a problem-based approach. Philadelphia, PA: W.B. Saunders; 1998. [8] Soupart A, Decaux G. Therapeutic recommendations for management of severe hyponatremia: current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol 1996;46:149–69.
The Netherlands Journal of Medicine 2001;58:103 – 110
Original article
The approach to a patient with acute polyuria and hypernatremia: a need for the physiology of McCance at the bedside a b c, Mogamat Razeen Davids , Yeouda Edoute , Mitchell L. Halperin * a
Nephrology Unit, University of Stellenbosch, Cape Town, South Africa b Internal Medicine C, Rambam Medical Center, Haifa, Israel c Division of Nephrology, University of Toronto, St. Michael’ s Hospital Annex, Lab [1, Research Wing, 38 Shuter Street, Toronto, Ontario, Canada M5 B 1 A6 Received 12 December 2000; accepted 12 December 2000
Abstract We present a case to illustrate the importance of emphasizing elementary physiology to deduce the basis for the acute onset of polyuria and hypernatremia. An imaginary consultation with Professor McCance is utilized to illustrate how a clinician–physiologist would have explained why these abnormalities developed and how they should have been treated. His approach began with a consideration of the most impressive abnormality. His analysis relied heavily on deductions and the anticipation of the expected responses to a stimulus in quantitative terms. The goals of therapy became evident after he performed mass balance calculations. Professor McCance would not understand why modern clinicians abandoned this form of analysis. 2001 Elsevier Science B.V. All rights reserved. Keywords: Antidiuretic hormone; Hyponatremia; Neurosurgery; Sodium; Subarachnoid hemorrhage; Tonicity balance; Vasopressin; Water
There are two different, but not mutually exclusive ways to arrive at a clinical diagnosis and to initiate therapy for a patient who has a medical problem. In the more traditional approach, data are gathered from the history, physical examination and laboratory testing. A list of possible causes is derived from this information. This approach has stood the test of time. An imaginary consultation with Professor McCance, our central figure, is from a real patient, but we asked him to restrict his database to the years
preceding 1937. His emphasis, when dealing with problems in the fluid and electrolyte area, focuses on an application of principles of physiology [1,2]. In addition to relying on physiology, his analysis is deductive and is described in quantitative terms; it depends on a knowledge of the expected responses to a given perturbation. He begins by identifying a single, impressive abnormality.
Focus on the major abnormality *Corresponding author. Tel.: 11-416-864-5292; fax: 11-416864-5943. E-mail address: [email protected] (M.L. Halperin).
In the case to be considered (see Appendix A), the clinicians were faced with a patient who had a urine
0300-2977 / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0300-2977( 01 )00078-X
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flow rate that was 10 ml / min. Professor McCance was amazed because when he extrapolated this flow rate to a 24-h period, it was equivalent to 14.4 l / day, a volume that exceeded the patient’s extracellular fluid (ECF) volume; and was virtually equal to half her total body water. Therefore, if this polyuria were not dealt with very promptly, it could create a lifethreatening situation. Faced with this medical emergency, we invite the reader to stop and consider the following question: ‘‘ What was responsible for the very large volume of urine produced by this patient?’’ We shall also ask Professor McCance the same question. He framed his response in the following context. Physiological principle: control of the urine flow rate Professor McCance would undoubtedly remind us that Eq. (1) describes urine flow rate. From this we learn that polyuria has two causes, a larger than normal daily solute excretion rate (osmotic diuresis) and an inability to raise the concentration of solutes in the urine (water diuresis). He deduced that for an osmotic diuresis to cause this degree of polyuria, each liter of urine would have to contain at least 300 mosmol of solute. The excretion of almost 4500 mosM of extra solutes (14.4 l per day 3 300 mosM / l) would require the presence of very high concentrations of these organic solutes in plasma. For example, with a glomerular filtration rate of 150 l per day, the concentration of glucose in the filtrate would have to be 30 mmol / l higher than the renal threshold of 10 mmol / l or be 40 mmol / l (540 mg / dl). If urea were the osmole responsible for the osmotic diuresis, its plasma concentration would have to be 60 mmol / l (BUN 168 mg / dl) because McCance knew that close to half of the filtered load of urea is normally absorbed [3].
that we would find a urine osmolality that was much lower than that of plasma to support his diagnosis. Indeed, the urine osmolality in our patient was 120 mOsm / kg H 2 O in the face of a plasma Na 1 concentration of 156 mmol / l. A full appreciation of those findings required our professor to review the control system for water and describe the expected response of an intact system to hypernatremia. Physiological principle: control system for water A control system may have a sensor that is in a different location from its response elements. If this occurs, there must also be a messenger that communicates between these two locations. For water (Fig. 1), the sensor is the volume of cells in a specialized area of the hypothalamus. They shrink and this leads to the release of more vasopressin when the plasma Na 1 concentration exceeds 140 mmol / l. At the response element level, vasopressin causes water to be reabsorbed in the distal segments of the nephron [3].
Urine flow rate (l / day) 5 Number of Solutes excreted / [Solutes] urine
(1)
Because our patient did not have an elevated glucose or urea concentration in plasma or a history of receiving an enormous quantity of mannitol, Professor McCance deduced that the basis of the polyuria was a water diuresis. He boldly predicted
Fig. 1. Control system for water excretion. The circles represent structures in the hypothalamus. The tonicity stat (stat) detects a change in the plasma Na 1 concentration. Because of hypernatremia (box on the left), this center leads to the release of vasopressin. This hormone acts on the distal nephron to cause it to become permeable to water (and urea) which when reabsorbed, thereby explains the excretion of a concentrated urine.
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Professor McCance then emphasized the importance of expected responses to stimuli and that the control system for water excretion should be ‘dissected’ at the bedside. Expected response to hypernatremia Vasopressin should cause the urine to become maximally concentrated. This means that at a minimum, the urine osmolality should be distinctly higher than the plasma osmolality. The fact that the urine osmolality was 120 mOsm / kg H 2 O indicates that there was a defect in the control system for water (Fig. 1). Probing the control system Because there was an acute procedure (neurosurgery) that could have compromised the hypothalamic area that releases vasopressin, and because there was a large water diuresis in the presence of a stimulus for the release of vasopressin (hypernatremia), the provisional diagnosis was central diabetes insipidus (DI). To confirm this diagnosis, the patient was given a preparation containing vasopressin to abort the polyuria. Clinical course The physicians in charge of the patient thanked Professor McCance for his help. They felt confident that they could interpret the renal response to vasopressin. They knew that vasopressin should act in a matter of minutes and cause a rapid fall in the urine flow rate along with a rise in the urine osmolality. The fall in flow rate could be observed promptly at the bedside, but a delay could be expected before the laboratory report returned with the urine osmolality. Therefore clinical decisionmaking would be made on the basis of the decline in the urine flow rate. To make their analysis quantitative as they had learned from their beloved professor, they relied on deductive reasoning. Normal subjects have a urine volume close to 1 l per day (Table 1). Since there are 1440 min in a day, the average urine flow rate is less than 1 ml / min. Accordingly, in response to vasopressin, they expected the urine volume to fall to less than 1 ml / min. A surprise was in store. The urine flow rate did decline, but only to 6 ml / min after vasopressin was given. Concluding
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Table 1 Composition of the 24-h urine in normal subjects a Volume Osmolality Urea Na 1 K1 Cl 2 Urea
l / day mosM / day mmol / day mmol / day mmol / day mmol / day % of osmoles
1.260.12 748644 345627 127611 5865 124611 4763
a
The number of subjects was 12, six males and six females (age 2862.6). They consumed their usual diet and performed all their usual activities. They did not take medications. Because their excretion rates for all items except creatinine were similar, their results were combined for simplicity. Results are presented as the mean6S.E.M.
that this represented only a partial renal response to this hormone, the patient was given extra doses of a long-acting form of vasopressin (dDAVP), but the urine flow rate did not decline further. The error made at this juncture was to rely on data obtained from one setting (normal subjects) and apply them to a patient in another setting (vide infra). This unfortunate mistake set into motion a series of compounding errors that had grave consequences for the patient. Part of the reason for this error was that the clinicians had failed to think like Professor McCance. Had the omniscient physiologist been consulted again, perhaps he would have provided the following simple and elegant answer. Quantitative analysis of the urine osmolality First, he would gently remind them that, had he not been so prematurely dismissed, he would have pointed out that the urine osmolality of 120 mOsm / kg H 2 O was not what he would have expected with a water diuresis and a flow rate of 10 ml / min. In fact, knowing that the typical Western diet yields a load of close to 800 mosM for excretion per day and that approximately half of them are urea and half are electrolytes (Table 1), he would expect a person in steady-state to excrete 0.5–0.6 mosM / min (800 mosM / 1440 min). With a flow rate of 10 ml / min, the osmolality should have been 50–60 mOsm / kg H 2 O (Eq. (1)). Professor McCance followed up this bit of deductive reasoning with data collection. He performed an experiment on the Fellows in his department. As
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keen as he was to participate fully in this selfexperimentation, he was mindful of the fact that he needed to select a study population that closely matched our patient, hence the data from the younger members of his team are provided in Table 2. Within 60 min after drinking a water load of 20 ml / kg, these healthy volunteers had a urine flow rate close to that of our patient. As our venerable professor had predicted, the urine osmolality was indeed predictable at 50–60 mOsm / kg H 2 O, close to half that of our patient. So both by deduction, and now by data that were easily obtained, McCance brought home to our team the fact that an excessive excretion of osmoles was present in the patient. During the water diuresis when there is a low urine osmolality, this high rate of excretion of osmoles would have no effect on the urine flow rate. Nevertheless, as soon as vasopressin acts, the osmole excretion rate will exert a major effect on the urine flow rate (Eq. (1)). So our team of physicians asked Professor McCance, ‘‘ How low should the urine flow rate be when vasopressin acts?’’ His answer caught them off guard. He said he did not expect it to fall to 1 ml / min because he took into account three important facts. First, the patient was excreting sodium (Na 1 ) and potassium (K 1 ) at 2.5 times the rate of the control subjects. Second, the huge water diuresis would have diminished the medullary interstitial osmolality and this would take time to be reconstituted. The maximum obtainable urine osmolality would therefore be similarly reduced. A third factor he considered was that the peak natriuresis following the intravenous Na 1 load that she had received may
not have been reached at the time that urine electrolytes were first measured. Indeed, the rate of excretion of Na 1 1K 1 continued to rise after vasopressin was given. Thus a flow rate after vasopressin that was more than 7-fold that of our control subjects was a more realistic expectation. McCance would also have dealt with an excellent question by one of his fellows: ‘‘ Does urea have the same influence on urine flow rate as electrolytes when vasopressin acts?’’ He would have relied on experiments conducted by Gamble in 1934 in human subjects [3]. When vasopressin acts, Gamble deduced that the terminal portion of the nephron becomes permeable to urea. This means that the concentration of urea in its lumen and in the inner medullary interstitial compartment approximate one another. Thus urea tends to become an ‘ineffective’ osmole in this nephron segment and does not directly cause water to be retained in its lumen. This theoretical impression was supported more than half a century later by experimental data in animals and in human subjects [4] providing that urea excretion rates were not excessively high. Comments In summary, up to this point, the clinical picture and the physiology pointed to a diagnosis of central DI. The apparent poor response to vasopressin did not reflect an additional diagnosis of nephrogenic DI. Rather, polyuria at this time reflected the expected renal response to an electrolyte-induced osmotic diuresis in the presence of a diminished medullary
Table 2 Parameters to assess the renal concentrating process a Parameter in urine
Flow rate Osmolality Osmole excretion Urea excretion Na 1 1K 1 excretion Urea
ml / min mOsm / kg H 2 O mosM / min mosM / min mosM / min % of osmoles
Control subjects
Patient
Water load
Before therapy
11.360.45 5763.6 645649 302622 377643 4862
10 120 1200 200 1000 17
a
The number of volunteer control subjects (age 3262) was 15, 10 males and five females. They ingested 20 ml of water per kg body weight and voided on request. Results are reported as the mean6S.E.M. The Netherlands Journal of Medicine 2001;58:103 – 110
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interstitial effective (non-urea) osmolality. The magnitude of the diuresis was larger than anticipated because the numerator of Eq. (1) in Na 1 1K 1 terms was 2.5-fold higher than in normal subjects and its denominator was half that of normal subjects (Table 2) given the time frame of the response. McCance might have been proud of the self-experimentation, the high reliance on elementary physiological principles defined in the 1930s [1–3], and a strong emphasis on a quantitative analysis. He would also have cautioned against using data derived in one setting (water-deprived normal subjects) and comparing them to the observed results in another setting (the acute administration of vasopressin to a patient undergoing a large water diuresis). Evidence-based medicine too requires the care exhibited by McCance in ensuring that the control group has similar characteristics to the experimental group.
Approach to hypernatremia using the principles of McCance The goal of therapy of hypernatremia in this patient should be to return the volume and composition of the body fluid compartments to normal. The first objective therefore is to decide whether hypernatremia was due to a higher value for the numerator (Na 1 content) and / or a lower value for the denominator (water in the ECF compartment) in our patient. Intuitively, and this was the opinion held by the attending physicians, it would seem that the basis of her hypernatremia was the water diuresis as is often the case in untreated central DI. They proudly presented their argument to Professor McCance, even including a quantitative analysis. They reasoned as follows. The urine volume was 5 l and its Na 1 concentration 50 mmol / l when the diagnosis of central DI was made. Hence sufficient pure water was excreted (2 / 3 of 5 or 3.3 l) to cause the observed slightly greater than 10% rise in the plasma Na 1 concentration (total body water was 30 l) [5]. Such logic, however, would never satisfy McCance who insisted on examining the mass balance for Na 1 1K 1 and for water. This simple analysis of all inputs and outputs is now called a tonicity balance [6,7] (Fig. 2A).
Fig. 2. Calculation of a tonicity balance. The box in the center of each figure represents total body water. The plasma Na 1 concentration before the infusion and excretion is shown at the top of the box, whereas this value at the end of the period is shown below. The period before vasopressin is depicted in the top portion of the figure (A), the initial response to therapy is shown in (B), and therapy to avoid the development of hyponatremia should be obvious from an examination of (C).
Calculate a tonicity balance Because the logic applied above began with water, its mass balance was examined first. The volume of water infused was equal to the urine volume. Therefore hypernatremia in our patient was NOT due to a water deficit despite the large water diuresis. On the other hand, the solution infused was isotonic saline (150 mmol Na 1 / l) while the urine was hypotonic saline (50 mmol Na 1 1K 1 / l). Accordingly, the patient gained 100 mmol Na 1 (1K 1 ) per liter of input and output, and 500 mmol of Na 1 in total. With a total body water of 30 l, the gain of 500
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mmol of Na 1 would cause the plasma Na 1 concentration to rise by 16.7 mmol / l (500 mmol / 30 l), a value closely approximating the observed value of 156 mmol / l. Use the tonicity balance for therapeutic decisions This clear demonstration by McCance that our patient’s hypernatremia was due to the gain of 500 mmol of Na 1 also made the required therapy equally obvious: he would cause the patient to lose 500 mmol of Na 1 while maintaining water balance. Our team of attending physicians once again thanked Professor McCance for his analysis and took charge of the case. The measured concentration of Na 1 1 K 1 in the urine was 175 mmol / l. Therefore, they infused half-isotonic saline (75 mmol Na 1 / l) at volumes equal to the urine output, which would result in a deficit of 100 mmol of Na 1 per liter. After the excretion of 5 l of urine, this resulted in the negative balance of 500 mmol of Na 1 and correction of the plasma Na 1 concentration along with restoration of the intracellular fluid (ICF) and ECF volumes and composition to normal (Fig. 2B). A successful clinical outcome was anticipated. Nevertheless, had McCance still been at the bedside, he would have predicted that this patient was not out of danger. ‘‘ A new and occult threat to survival was looming; what was this threat?’’
Anticipating the ‘occult’ threat to survival
(Fig. 2, bottom portion). A key concept now became relevant. Physiological principle: the plasma Na 1 concentration reflects the ICF volume Professor McCance stated that the volume of the ICF compartment is reflected by the plasma Na 1 concentration for three reasons (Fig. 3). First, water can cross cell membranes and it achieves osmotic equilibrium rapidly. Second, the number of effective osmoles in the ICF compartment remains constant in an acute setting (largely K 1 ). Third, in the absence of hyperglycemia and mannitol administration, the effective osmoles in the ECF compartment are Na 1 and its attendant anions, chloride (Cl 2) and bicarbonate. Should hyponatremia develop, cells will swell. The ‘target organ’ of clinical importance is the brain because it is in a confined rigid space and it cannot extrude intracellular particles in an acute setting. Clinical outcome Therapy with half-isotonic saline (Na 1 concentration 75 mmol / l) given at a rate equal to urine output caused a negative balance for Na 1 and a fall in her plasma Na 1 concentration (urine Na 1 concentration was 175 mmol / l). Nevertheless, the patient became progressively hyponatremic and ultimately died because of brain swelling that led to herniation due to the fact that this therapy was not
McCance knew that progressive hyponatremia from ongoing negative Na 1 balance was a real danger unless therapy was modified at this point to keep body composition constant. Urine Na 1 concentration This concentration can be as high as the medullary interstitial Na 1 1K 1 concentration when vasopressin acts. Since dDAVP was given in large amounts and the vast majority of urine osmoles were Na 1 1K 1 salts (Table 2), it is not surprising that the urine Na 1 concentration rose to 300 mmol / l. Therefore it is easy to anticipate why hyponatremia would develop
Fig. 3. Plasma Na 1 concentration reflects the ICF volume. The circle represents the ICF compartment. It contains macromolecular anions and the cation K 1 which is its major osmole. These osmoles (P) are restricted to the ICF compartment. Urea, shown on the left, is not an effective osmole here because it can cross cell membranes and achieve an equal concentration in the ECF and ICF compartments. The osmoles restricted to the ECF compartment are Na 1 and its attendant anions. Osmotic equilibrium is achieved because water can cross this cell membrane rapidly.
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modified. ‘‘ How could this fatal outcome have been avoided?’’ A quantitative approach would have allowed the attending physicians to recognize when the goal of therapy had been reached, i.e., when 500 mmol Na 1 had been lost and body composition and volumes had been restored to normal. At this point, it was necessary to match input with output, both in terms of volume and electrolyte content to keep the volumes and composition of the body compartments constant. Because the concentration of Na 1 1K 1 in the urine of our patient exceeded that of isotonic saline after administration of dDAVP, a loop diuretic, had it been available at that time, could have been employed to lower urine Na 1 1K 1 concentration to approximate that of plasma. At this point, giving isotonic saline at the same rate as the urine output could have replaced all renal losses other than K 1 while preventing a fall in the plasma Na 1 concentration. When the plasma Na 1 concentration was lower than 140 mmol / l, the attending physicians ignored the impassioned pleas of McCance to give hypertonic saline (300 mmol / l) to the patient. This infusion, if given at a rate equal to the urine flow rate, would have prevented a further decline in the plasma Na 1 concentration. He emphasized that this rate of infusion of hypertonic (300 mmol / l) NaCl would not cause the plasma Na 1 concentration to rise. To raise the plasma Na 1 concentration, the infusion of saline (300 mmol / l) must exceed the urine flow rate or the concentration of Na 1 in the infusate would have to be greater than 300 mmol / l. The attending physicians opted to only change the intravenous fluids to isotonic saline and this error caused our patient to die of brain cell swelling when her plasma Na 1 concentration reached 124 mmol / l. At any point before the tragic end, her Na 1 concentration could have been raised to a non-threatening level easily by the administration of 1 mmol Na 1 (in a very hypertonic form) per liter of total body water times the desired change in the plasma Na 1 concentration. Raising her Na 1 concentration from 124 to 130 mmol / l would have required a positive balance of 180 mmol of Na 1 , i.e., the rapid infusion of close to 400 ml of 3% NaCl. It is important to recognize that a reasonably rapid rate of correction of hyponatremia is not a risk factor for osmotic
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demyelination in a patient with acute hyponatremia (reviewed in Ref. [8]).
Concluding remarks The process of the analysis of the imaginary consult pitted Professor McCance against modern clinicians, but the playing field was not level. He was deprived of the entire medical literature written after 1936, he was not exposed to molecular biology, and he was not taught with a modern medical curriculum. Despite these handicaps, he excelled by using his knowledge of whole body physiology, deductive reasoning, a quantitative analysis with mass balance, and simple self-experimentation. For diagnosis, the basis of the polyuria was clearly a water diuresis. By calculating the osmole excretion rate and deducing that the nature of the excessive excretion of osmoles was electrolytes rather than urea (or glucose), he could predict that the urine flow rate might only decline to around 5 ml / min after vasopressin was given. Armed with these insights, he would not have given the patient excessive amounts of this hormone and avoided ‘pitfall 1’. In the area of therapy, he set out his objectives clearly — return the body compartment volumes and composition to normal. He defined the abnormality with data rather than innuendo. Using what we now call a tonicity balance, he recognized that the basis of hypernatremia was a positive balance of 500 mmol of Na 1 (and Cl 2). Accordingly, he designed therapy to create a negative balance for Na 1 (2500 mmol) and no more while maintaining water balance. Moreover, he could anticipate the danger in this setting. Once the plasma Na 1 concentration returned to normal, he insisted on maintaining Na 1 and water or a tonicity balance. Because the urine Na 1 concentration was high and the urine flow rate was also large, he insisted on giving an intravenous solution at the same rate as the urine flow rate while ensuring its Na 1 concentration was equal to that of the urine. Thus he avoided pitfall 2. Had loop diuretics been discovered, he might have used them to convert the composition of the urine to isotonic saline, a solution that would easily be matched in volume and composition by intravenous fluids. Perhaps the simple take-home message is that the thinking process and approach of
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Professor McCance should represent the present and the future rather than simply the good old days.
mOsm / kg H 2 O, urine Na 1 37 mmol / l, and urine K 1 13 mmol / l.
Appendix A
References
Case synopsis A 42-year-old previously healthy woman (weight 52 kg) presented with the sudden onset of severe headache, nausea and vomiting. Drowsiness and neck stiffness were the only abnormalities on physical examination. Computed tomography scan confirmed the presence of Berry aneurysms of the anterior communicating, right posterior communicating and left ophthalmic arteries. Plasma urea, creatinine and electrolytes were normal at the outset. Pre-operatively, she was given carbamazepine (800 mg) and dexamethasone (4 mg) and then had a successful clipping of the bleeding aneurysm. She was transferred to the neurosurgical intensive care unit where polyuria was first noted. The urine flow rate was 10 ml / min 10 h after her admission. She had passed a total of 5 l of urine during this time and received 5 l of isotonic saline. Laboratory results at the 10-h time revealed the following: plasma Na 1 concentration 156 mmol / l, urine osmolality 120
[1] McCance RA. Experimental sodium chloride deficiency in man. Proc R Soc London 1936;119:245–68. [2] McCance RA. Medical problems in mineral metabolism. III. Experimental human salt deficiency. Lancet 1936;230:823– 30. [3] Gamble JL, McKhann CF, Butler AM, Tuthill E. An economy of water in renal function referable to urea. Am J Physiol 1934;109:139–54. [4] Gowrishankar M, Lenga I, Cheung RY, Cheema-Dhadli S, Halperin ML. Minimum urine flow rate during water deprivation: Importance of the permeability of urea in the inner medulla. Kidney Int 1998;53:159–66. [5] Spital A, Sterns RD. The paradox of sodium’s volume of distribution: why an extracellular solute appears to distribute over total body water. Arch Intern Med 1989;149:1255–7. [6] Mallie J-P, Bichet DG, Halperin ML. Effective water clearance and tonicity balance: the excretion of water revisited. Clin Invest Med 1997;20:16–24. [7] Halperin ML, Goldstein MB. In: Fluid, electrolyte and acidbase physiology; a problem-based approach. Philadelphia, PA: W.B. Saunders; 1998. [8] Soupart A, Decaux G. Therapeutic recommendations for management of severe hyponatremia: current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol 1996;46:149–69.
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