Q J Med 2003; 96: 531-540
© 2003 Association of Physicians
Masterclasses in medicine |
An integrative physiological approach to polyuria and hyponatraemia: a ‘double-take’ on the diagnosis and therapy in a patient with schizophrenia
From the 1Department of Internal Medicine C, Rambam Medical Center, Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel, 2Nephrology Unit and Department of Internal Medicine, University of Stellenbosch, Cape Town, South Africa, 3Division of Nephrology, University of Alberta Hospital, Edmonton, Canada, and 4Division of Nephrology, St. Michael’s Hospital, University of Toronto, Toronto, Canada
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Summary |
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 Top Summary IntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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A patient with a history of schizophrenia was brought to the emergency department with extensive self-inflicted soft tissue injuries. Primary polydipsia was evident on admission, because he had a maximally dilute urine, a urine flow rate of 10 ml/min, and hyponatraemia (100 mmol/l). During an imaginary consultation with Professor McCance in which he applied basic principles of integrative physiology and a deductive analysis in quantitative terms, other reasons for the polyuric state were considered. Moreover, based on the very low value for the concentration of urea in plasma (< 0.7 mmol/l, BUN 1 mg /dl), the goals of therapy to prevent osmotic demyelination became evident. Applying this simple approach, a more comprehensive and accurate differential diagnosis, and a plan for therapy to avoid serious complications was compiled.
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Introduction |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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This is the sixth article in our series on the application of principles of integrative physiology at the bedside that begin with a problem in the fluid, electrolyte, acid-base, and/or energy metabolism area. Once again, we use an imaginary consultation with the integrative physiologist, Professor McCance (whom we have transported to the present), to help clarify the interpretation of information from an actual case. We begin with an analysis of the most pressing abnormality, profound polyuria. Elements that could contribute to the diagnosis and treatment of this polyuria are considered in a quantitative fashion. This analysis is dependent upon a broad understanding of whole-body physiology, along with an anticipation of the responses to a series of perturbations. Professor McCance is also informed of molecular discoveries, so that our understanding of modern physiology can be advanced. His emphasis is on concepts. To avoid overwhelming readers with details, only key facts are provided when necessary. The article demonstrates how the application of physiological principles at the bedside leads to a better-formulated differential diagnosis and design of treatment.
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The consultation |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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The medical team were asked to see a patient in the emergency department who had a urine flow rate of 10 ml/min. Recalling a previous consult with Professor McCance,1 they began their clinical analysis using physiology principle 1 and equation 1, which deals with the urine flow rate (Table 1).
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| (1) |
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Physiology principle 1: control of the urine volume
Because > 99% of the glomerular filtration rate (GFR) is usually reabsorbed, control of the urine flow rate should depend on regulation of water reabsorption. There are two essential features that permit this water reabsorption, water permeability and an osmotic driving force across the distal nephron (Figure 1). Therefore the urine flow rate can be very high if the distal nephron is poorly permeable to water (a water diuresis due to a lack of actions of vasopressin). Alternatively, when this nephron segment is permeable to water, a diminished osmotic driving force in the distal nephron, along with a high rate of excretion of solutes, will cause an osmotic diuresis, because urinary osmoles ‘hold’ water osmotically in the lumen of the collecting duct (equation 1 and Figure 1).
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Return to the bedside: To differentiate between a water and an osmotic diuresis, the urine osmolality (Uosm) was examined. The expected Uosm was deduced by knowing both the urine flow rate and the estimated osmole excretion rate (usually half as urea and half as electrolytes). For example, if this patient had a typical osmole excretion rate of 900 mOsm/day and an extrapolated daily urine volume of close to 15 l/day (10 ml/minx1440 min in a day), his Uosm should be approximately 60 mOsm/kg H2O. Because his minimum Uosm was 37 mOsm/kg H2O, his polyuria represented a water diuresis along with a low osmole excretion rate. The importance of this latter observation will become evident when therapy is considered.
The next step was to establish whether the control system for the excretion of a dilute urine was functioning in an appropriate fashion. We ask the reader to pause and answer the first question: ‘What information is needed to decide whether this large water diuresis was appropriate?’
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Question 1: What information is needed to decide whether the large water diuresis was appropriate? |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Physiology principle 2: the control system for the excretion of water
A control system has a sensor, with a messenger that links the sensor to its response element. For water, the sensor is in the cells of the hypothalamus that become activated by a shrinkage of their intracellular fluid (ICF) volume2—this almost always requires the presence of hypernatraemia (Figure 2). The messenger is vasopressin and the response element is the distal nephron, which becomes permeable to water when vasopressin acts (Figure 1).
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Return to the bedside: A water diuresis should occur, because of hyponatraemia and a low plasma osmolality (Posm), which inhibits the release of vasopressin. Therefore the information needed at this time is his plasma sodium (Na+) concentration (PNa). Because the patient had hyponatraemia and a low Posm, the water diuresis was appropriate, and primary polydipsia rather than central or nephrogenic diabetes insipidus (DI) was the likely reason for polyuria. Their confidence was strengthened when they learnt that he had schizophrenia and drank copious volumes of water over the past 7 days.
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Enter Professor McCance |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Professor McCance was asked to comment on their clinical analysis, and he agreed to do so. Always the consummate clinician, he first went to the bedside to examine the patient, and was immediately struck by evidence of severe bruising. He was told that the patient threw his body against the walls of his apartment repeatedly. Head injuries were also obvious—both eyes were bruised, and closed due to extensive swelling, but skull X-ray examinations did not reveal a fracture. Nevertheless, the soft tissue injuries raised concerns about the diagnosis proposed. Adding to our professor’s concern, the patient was struggling vigorously against the restraints used to keep him in bed. The laboratory data on admission were also alarming—his plasma urea concentration (Purea) was < 0.7 mmol/l, and the PNa was 100 mmol/l (Table 2). We ask the reader to pause and answer the following question: ‘What is the significance of the very low plasma urea concentration?’
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Question 2: What is the significance of the very low plasma urea concentration? |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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At first glance, said McCance, one might be tempted to ascribe the low Purea to the high urine flow rate which increases the fractional excretion (FE) of urea from its usual value of close to 50 %.3 However, he pointed out that one should never be satisfied with this qualitative evaluation, especially when the data are decidedly abnormal. With a simple quantitative analysis, our professor demonstrated to his faintly embarrassed team that a high FE of urea was not an adequate explanation for the degree of reduction in the Purea.
Assume that the polyuria causes all the filtered urea to be excreted (FE of 100 %), he began. Initially, the urea excretion rate would double, causing the Purea to decline. The fall in the Purea will now cause a fall in its filtered load until the rate of excretion of urea once again matches its rate of production in steady state. This happens when the Purea is half its initial value, i.e. with half the usual filtered load and twice the usual FE. If we assume, continued McCance, a normal Purea for this patient to be 5 mmol/l, then the increase in FE can only account for lowering it to 2.5 mmol/l. The Purea of < 0.7 mmol/l therefore implies that urea production must be extremely low (< 1/3 of its usual rate). In the absence of severe liver disease, and there was nothing to suggest this, McCance concluded that this patient must have an extremely poor dietary protein intake. This deduction will have serious implications when treatment of his hyponatraemia is considered later in this article. At this juncture, Professor McCance went on to deal with issues concerning the differential diagnosis of the water diuresis. We ask the reader to pause and consider the next question: ‘Should other diagnostic possibilities be considered?’
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Question 3: Should other diagnostic possibilities be considered? |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Primary polydipsia was a correct diagnosis, because the patient had polyuria, a very low Uosm, and hyponatraemia. What bothered Professor McCance was that a diagnosis of primary polydipsia did not rule out DI as a contributing cause for the polyuria. Two facts suggested that central DI should be considered. First, there was an obvious head injury. Second, non-osmotic stimuli should have led to an ongoing release of vasopressin, yet his Uosm was very low, suggesting an absence of vasopressin on admission. The patient’s PNa of 100 mmol/l was extremely low, and implied that there was a retention of approximately 12 l of water, due to both a large water intake and the actions of vasopressin over the past 6–7 days (see response to question 9 later in this article). Therefore, despite a clinical setting where vasopressin had been acting recently and should continue to be released now (his extreme agitation), the urine composition was not consistent with current actions of this hormone. Thus we ask the reader to pause and answer the following question: ‘What could explain the current lack of renal actions of vasopressin?’
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Question 4: What could explain the current lack of renal actions of vasopressin? |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Physiology principle 3: actions of vasopressin
Vasopressin is a polypeptide produced in the hypothalamus and released from the posterior pituitary (Figure 2). Its main actions are on the distal portion of the kidney, where it binds to its specific V2 receptor to cause the insertion of water channels (aquaporin 2, AQP2) into their luminal membranes (Figure 1). Thus water reabsorption causes the osmolalities in the urine and the interstitial compartment of the inner medulla to become equal.
Return to the bedside: Professor McCance said that nephrogenic DI would be ruled out by giving vasopressin and observing a fall in the urine flow rate and a rise in the Uosm—this, in fact, occurred. We ask the reader to pause and answer the following question: ‘What urine flow rate did Professor McCance anticipate when vasopressin was given?’
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Question 5: What urine flow rate did Professor McCance anticipate when vasopressin was given? |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Return to physiology principle 1: control of the urine volume
The urine volume will be very low when the Uosm rises with such a low osmole excretion rate (equation 1).
Return to the bedside: With muscle damage being very likely, as suggested by the extensive bruising (and a very high creatinine kinase (CK) level of >10 633 U/l), too low a urine volume might contribute to the development of an acute renal failure. In fact, the urine flow rate fell from 10 ml/min to 0.5 ml/min within 60 min after a very low dose of dDAVP (a synthetic vasopressin analogue) was given (the Uosm rose to 360 mOsm/kg H2O). These data reflect the very low solute excretion rate that Professor McCance had recognized. Moreover, there was a potential danger of acute brain cell swelling if this patient were to drink a large volume of water when using a long-acting preparation of vasopressin. He decided to return the focus to salt and water, leaving a full discussion of acute renal failure for another day.
The very large water diuresis in a patient with such a severe degree of hyponatraemia (100 mmol/l) suggested the absence of actions of vasopressin (central DI) on admission. If central DI were due to the head injuries, it had to develop very late in the past 7-days because of this profound degree of hyponatraemia (vasopressin was acting during most of this past week). A curious medical student then cleared her throat and asked, ‘Could this be anything other than central DI?’ We ask the reader to pause and consider this question.
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Question 6: Could this be anything other than central DI? |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Professor McCance asked for suggestions to answer this question because he could not think of another diagnostic entity. A junior member of the team made a decisive comment. He had been involved with the treatment of a woman who developed a unique form of transient DI shortly after the delivery of her baby. This was not central DI, because her large urine volume did not fall when typical doses of vasopressin were given. Neither was it nephrogenic DI, because her polyuria disappeared promptly when the vasopressin analogue dDAVP was administered. He recalled that the urine-concentrating defect was attributed to a circulating enzyme that destroyed circulating vasopressin (a peptidase called a vasopressinase released from the retained necrotic placenta).4
Picking up on this suggestion, Professor McCance drew attention to the patient’s extensive soft tissue injuries and the very high circulating level of the muscle-derived enzyme CK. If damaged tissues could release so much CK, they might also release an enzyme that digests circulating polypeptides. This might also explain a transient form of DI without requiring central DI to be its cause. Professor McCance asked, ‘Why might the kidney respond to dDAVP and not vasopressin?’ The team surmised that dDAVP might not be destroyed by vasopressinase if it either required a terminal amino group (aminopeptidase) or 
-arginine (arginine-dependent peptidase), both of which are present in vasopressin (one d of dDAVP stands for desamino and the other stands for 
and not -arginine).
Professor McCance was impressed. On reflection, however, he offered a new twist to this story. He asked, ‘What might have made this patient particularly susceptible to a circulating vasopressinase?’ We ask the reader to pause and consider what Professor McCance had in mind.
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Question 7: What might have made this patient particularly susceptible to vasopressinase ? |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Physiology principle 4: enzyme kinetics
The total removal of vasopressin from plasma should depend on both the activity of the enzyme that removes it (vasopressinase) and the concentration of its substrate, vasopressin, in plasma.
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Return to the bedside: Two factors could have contributed to the destruction of enough vasopressin in the circulation to cause the DI picture. First, tissue damage could cause the release of vasopressinase. Second, because this patient lacked the major stimulus for the release of vasopressin (hypernatraemia, Figure 2), the level of this hormone in plasma might not be that high. Hence, before the soft tissue injuries occurred, non-osmotic stimuli may have released just enough vasopressin to cause sufficient water permeability in the distal nephron to permit water retention. In the emergency department, however, DI might have developed with vasopressinase levels that were only modestly elevated.
Professor McCance, although impressed with the suggested vasopressinase hypothesis for DI, wondered whether an enzyme could cause a low enough hormone concentration to prevent the formation of enough hormone-receptor complexes, and thereby cause the degree of polyuria that was seen in this patient. He deduced that the concentration of vasopressin in plasma would need to be so low that it would no longer bind to its specific renal V2 receptor on the basolateral aspect of collecting duct cells (Figure 1). We ask the reader to pause and consider, ‘Could an enzyme do this?’
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Question 8: How could an enzyme cause such a low concentration of its substrate (the hormone vasopressin in plasma in this case)? |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Physiology principle 5: binding of hormones to their receptors
Binding of hormones to their receptors is very specific, and occurs at a very low concentration of hormone; enough hormone-receptor complex is formed to have the desired biological effect (equation 3). Receptors have two special properties—they have a very high affinity for their substrate (needs only a very small concentration of hormone for binding) and only a small number of receptors need to be occupied to exert the biological effect. Hence very low concentrations of hormones exist in plasma, minimizing their renal clearance.
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| (3) |
Return to the bedside: Professor McCance began with a deductive approach initially, because he did not have data. He was told that the major pathway for peptide hormone removal involved hormone binding to its receptor on the external surface of cell membranes, internalization of the hormone receptor complex, and dissociation of the hormone from its receptor because of H+ secretion within the endosome, followed by return of the unoccupied receptor to the cell membrane (Figure 3). In the cell, the aqueous solution containing the hormone is transferred to a compartment (lysosomes) where that hormone is hydrolysed. Professor McCance suggested that there could be virtually complete destruction of the hormone in lysosomes to eliminate its biological activity for two reasons. First, it is possible that these enzymes have a very high affinity for these hormones. Second, there may be a long duration of exposure of this hormone to peptidases in the lysosome.
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Professor McCance then asked whether other mechanisms might be involved in hormone destruction. He was told that the steroid hormone cortisol is destroyed by enzymes in cells, requiring mineralocorticoid actions. In this case, a pair of enzymes works in tandem. First, a high-capacity, low-affinity enzyme destroys most of the hormone, lowering its concentration sufficiently so that a second enzyme with a high affinity for cortisol, but a low capacity to hydrolyse it, can diminish the final intracellular cortisol level sufficiently to prevent binding of cortisol to the intracellular mineralocorticoid receptor.
Professor McCance wondered whether a third hypothesis might help answer this puzzling question. Perhaps an enzyme could modify a hormone such as vasopressin so that it became a competitive inhibitor of vasopressin for binding to its V2 receptor. Thus, the low circulating level of vasopressin could no longer exert its biological effect.
All in all, Professor McCance concluded that there was a form of DI present. On the one hand, the DI could be due to a lesion in the CNS. On the other hand, the vasopressinase hypothesis might possibly explain the apparent DI in our patient, but it probably would need some refinement. This illustrates the importance of not accepting everything at face value and that more in-depth analysis is often needed. A thought attributed to Albert Einstein is appropriate here—‘Everything should be as simple as possible, but not simpler!’
Data from later in the course of the patient’s illness were helpful to cast light on the basis for DI. If the central DI were a permanent defect, the patient should continue to excrete dilute urine and become hypernatraemic if he did not have access to water. This did not occur. On the other hand, the release of vasopressinase from the damaged soft tissues should subside over a matter of days. If this were the cause, the urine should not remain maximally dilute while the patient was still hyponatraemic and not being treated with dDAVP. In fact, these latter findings did occur, suggesting that central DI was transient or due to a vasopressinase. Direct measurement of vasopressinase in plasma was unfortunately not obtained, as the possibility of a vasopressinase was only recognized in retrospect. Therefore this diagnostic suggestion must remain an unproven speculation in this patient.
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Summary |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Before turning to therapy, the diagnostic issues can be summarized. Our patient had primary polydipsia. To develop such a severe degree of hyponatraemia, he needed actions of vasopressin for most of his presumed 7-day course of water retention. His psychiatric illness, anxiety, stress and possibly an intake of drugs could have caused the release of vasopressin for non-osmotic reasons (Figure 2). Nevertheless, on admission, despite even stronger non-osmotic stimuli, he appeared to have a total absence of vasopressin actions. Perhaps this was due to central DI (head injuries) or a circulating vasopressinase released from damaged tissues. His excellent renal response to dDAVP ruled out nephrogenic DI. Finally, the very low Purea suggested that he had a poor prior dietary intake of protein for at least many days. This interpretation is underscored by the fact that he had such a low rate of filtration and excretion of urea despite the obvious bruising.
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Issues for therapy |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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It is crucial to separate acute from chronic hyponatraemia, because the dangers for the patient differ.5 In acute hyponatraemia, the danger is brain swelling and hence the goal of therapy is to reduce the size of the brain promptly. In contrast, with chronic hyponatraemia, the danger occurs with overly aggressive therapy to raise the PNa. The following reasoning was used by our team to suggest that the bulk of the hyponatraemia was chronic (> 48 h duration). First, the degree of expansion of the brain is limited by the rigid confines of the skull. Second, the brain ICF volume is close to 80% of brain water. Third, because the PNa reflects ICF volume (Figure 4), the skull cannot accommodate acute brain cell swelling with a PNa < 120 mmol/l. Therefore, with a PNa of 100 mmol/l and no evidence of a large increase in intracranial pressure, brain cell volume regulation should have occurred in most brain cells.6
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While the patient’s urine flow rate could easily be reduced, they were asked by Professor McCance to consider two issues before launching into therapy. First, ‘What was the basis for his hyponatraemia, Na+ loss and/or water gain?’ Second, ‘How fast should his hyponatraemia be corrected?’
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Question 9: What was the basis for his hyponatraemia, Na+ loss and/or water gain? |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Physiology principle 6: basis for hyponatraemia
The PNa is a ratio of the total quantity of Na+ in the ECF compartment and the ECF volume. Therefore, hyponatraemia can be due to a Na+ deficit and/or electrolyte-free water gain. It is important to consider the possible deficit for Na+ and the gain of electrolyte-free water in quantitative terms because it highlights the goals for therapy.
Return to the bedside: As a first step, the magnitude of a deficit of Na+ was considered, assuming for the moment that it would be the sole defect. In his normal condition with PNa of 140 mmol/l, this thin 70 kg patient should have 45 l of total body water (TBW), of which 15 l would be in his ECF compartment. Hence 2100 mmol of Na+ (140 mmol/l x 15 l) is his normal ECF Na+ content. His current PNa was 100 mmol/l, and if the ECF volume was close to normal as was suggested at the bedside, the content of Na+ in his ECF compartment would be 1500 mmol, revealing a very large (600 mmol) deficit of Na+. The second step is to calculate his positive water balance (really his new ICF volume if his ECF is normal). The low PNa (100 mmol/l) implies that his ICF volume is expanded (Figure 4). Hence, his normal ICF volume of 30 l would have become increased by 140/100 to a volume close to 42 l. Thus he had to retain approximately 12 l of extra electrolyte-free water in his ICF compartment, irrespective of the cause of the PNa of 100 mmol/l and the Posm of 202 mOsm/kg H2O. These extremely large numbers also imply that his severe degree of hyponatremia was largely chronic in nature. Professor McCance was nodding in agreement as they moved on to the next question. We invite the reader to pause and consider, ‘How fast should this hyponatremia be corrected?’
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Question 10: How fast should this hyponatremia be corrected? |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Physiology principle 7: defence of the ICF volume
Two facts permit an understanding of the control of the ICF volume (Figure 4). First, cells have water channels that permit water to move very rapidly to achieve osmotic equilibrium between the ECF and ICF compartments. Second, there are solutes that cannot easily move across cell membranes (effective osmoles or tonomoles in McCance’s vocabulary) that determine the ICF and ECF volumes. These intracellular tonomoles are primarily potassium (K+) ions and organic solutes other than urea, whereas the extracellular tonomoles are Na+ plus its attendant anions, chloride and bicarbonate. The absolute quantities of these tonomoles determine compartment volumes. A fall in ECF tonicity causes water to move into cells, expanding the ICF volume.
Return to the bedside: For brain cells not to swell during the process of developing a fall in the PNa from 140 to 100 mmol/l, these cells must lose K+ ions plus an ICF anion or lower their content of soluble organic tonomoles. During recovery, these brain cells must re-accumulate the solutes that were lost. Usually, it takes time to restore these ICF tonomoles so correction of hyponatraemia should be slow enough to prevent brain cell shrinkage and the osmotic demyelination syndrome (ODS).
At this point, the smiling McCance once again asked for help from the attending physicians, who told him that it appears that some of these organic anions require an exogenous intake to be replaced. Therefore patients who do not eat an adequate diet require even more time to regenerate these solutes in brain cells. This reminded the team of the importance of considering the basis for the very low Purea of < 0.7 mmol/l. In that discussion, Professor McCance deduced that this patient likely had a very low dietary intake of protein. Moreover, his diet was even more restricted than revealed by his low urea excretion rate, because he could have generated some urea by oxidizing proteins derived from tissue destruction.
Returning to the design of goals of therapy, Professor McCance was told that some authors prefer to limit the rise in PNa to 12 mmol/l/day,7 while others recommend even slower rates of correction (8 mmol/l/day).8 The approach of Professor McCance was very simple. His view was that the rate of correction of hyponatraemia should be individualized and slow enough to minimize the danger of ODS in every patient. At this point, he was told of a relatively recent clinical observation. When there is a K+ deficit9 or a nutritional problem,10 the rate of rise in PNa should be even slower, perhaps < 4 mmol/l in 24 h. Given all this information, Professor McCance said he would not wish to see any rise from the current value of 100 mmol/l in the next 24 h, because the patient probably had had a very low intake of food containing protein for many days. Moreover, he did not know when the DI picture began, although he knew it was recent in origin. Perhaps there was already a rise in PNa from its nadir due to the large water diuresis that was evident on admission, and this would have raised the PNa of the patient by an unknown amount. Although our professor could not be certain, his clinical judgment was to put more emphasis on preventing ODS than on acute swelling of brain cells.
Two alternative treatment strategies were considered. First, water intake should be stopped, while continuing to give dDAVP. Enough NaCl in hypertonic form would be needed to permit a rise in his PNa of close to 4 mmol/l/day until the deficit of Na+ in his ECF compartment was repaired and the patient could eat a regular diet. The danger of this strategy was that if the patient gained access to water, he could develop a possibly lethal degree of acute hyponatraemia. The second option for therapy would be to let the patient drink enough water to match his urine output, thereby minimizing too rapid a rate of correction of hyponatraemia. The danger of this therapy would be that if he did not drink for several hours, the rate of correction of hyponatraemia could be too rapid. Professor McCance opted for the first strategy, but recommended that the dose of dDAVP to lower the urine output be as low as possible (dDAVP has a duration of action of 8–12 h).
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Summary of issues for therapy |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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This patient had chronic (probably 7 days or more) hyponatraemia (large water gain and a secondary Na+ loss) related to psychogenic polydipsia and non-osmotic vasopressin release. On this background, he developed a very recent and large water diuresis implying a current absence of renal vasopressin actions. This had the potential of rapidly raising his PNa with the attendant risk of ODS. Two factors dramatically increased this risk of ODS. First, the nadir for his PNa may have been even lower than the 100 mmol/l documented on admission. Second, the re-accumulation of brain osmoles could be impaired, because of a very poor dietary intake. A rate of correction of hyponatraemia much slower than the usual recommendations was therefore selected. The PNa could be kept constant by employing simple principles of mass balance—ensuring that the composition and volume of the input matched that of the urine output (a tonicity balance11). Using the minimum dose of dDAVP to reduce the urine flow rate and raise the Uosm as well as the electrolyte concentration in the urine, permitted our goal of having inputs more easily match the outputs using available fluid replacement solutions.
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Concluding remarks |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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Our patient had two clinical emergencies. First, there was a very large water diuresis secondary to a lack of vasopressin activity. Second, there was a profound degree of hyponatraemia due to psychogenic polydipsia. In this symptom complex, vasopressin activity stimulated by non-osmotic causes needed to be sufficiently high to permit the retention of at least 12 l of electrolyte-free water. Among the lessons learnt were that one should not ignore any abnormal finding. By fully evaluating the low Purea, it was possible to deduce that the prior dietary intake was particularly low in protein. This had major implications for the design of therapy. Moreover, it is important to know when to turn to the literature or to colleagues for advice, as Professor McCance did in this case. All the patient’s data could not be explained by one diagnosis, illustrating that even in a young patient, more than one pathophysiological mechanism may be needed to explain all the data. Analysing each element in a quantitative fashion, using integrative physiology, and anticipating the appropriate response to a perturbation, revealed the most likely basis of the major two abnormalities, water diuresis and hyponatraemia, and allowed the design of a reasonable strategy for therapy.
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Appendix I: Case synopsis |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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A 39-year-old male with long-standing schizophrenia stopped taking his medications at least one week prior to arrival in the emergency department. After neighbours reported a very disruptive commotion coming from his apartment, police were called. On entering, they found a very disturbed irrational person who was extensively bruised. On arrival in the emergency department, his most obvious problems were massive soft tissue injuries to his head, arms, legs, and shoulders. His face was swollen to the point that he was unable to open his eyes. The patient was very aggressive and psychotic. He had a very large urine output. The physical examination was limited due to non-cooperation. The most striking laboratory abnormalities included a severe degree of hyponatraemia, low Purea (< 0.7 mmol/l) and a very high level of CK in plasma (> 10 633 U/l) (Table 2). His haemoglobin, glucose, and creatinine levels in blood were normal. The hospital course depicting changes in his PNa is shown in Figure 5. His PNa remained in the 130–133 mmol/l range following his acute therapy. He was discharged with no clinical evidence of osmotic demyelination.
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Footnotes |
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Address correspondence to Professor M.L. Halperin, Professor of Medicine, University of Toronto, St. Michael’s Hospital Annex, Lab #1, Research Wing, 38 Shuter Street, Toronto, Ontario, M5B 1A6, Canada. e-mail: mitchell.halperin{at}utoronto.ca
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References |
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TopSummaryIntroductionThe consultationQuestion 1: What...Enter Professor McCanceQuestion 2: What is the...Question 3: Should other...Question 4: What could...Question 5: What urine flow...Question 6: Could this be...Question 7: What might have...Question 8: How could an...SummaryIssues for therapyQuestion 9: What was the...Question 10: How fast...Summary of issues for...Concluding remarksAppendix I: Case synopsisReferences |
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