Evidence for the use of demeclocycline in the treatment of hyponatraemia secondary to SIADH: a systematic review

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Summary

Aims

Hyponatraemia ( HN) is the most common electrolyte balance disorder in clinical practice. Since the 1970s, demeclocycline has been used in some countries to treat chronic HN secondary to syndrome of inappropriate antidiuretic hormone secretion ( SIADH). The precise mechanism of action of demeclocycline is unclear, but has been linked to the induction of nephrogenic diabetes insipidus. Furthermore, the safety profile of demeclocycline is variable with an inconsistent time to onset, and a potential for complications. There has been no systematic evaluation of the use of demeclocycline for the treatment of HN secondary to SIADH to date. A systematic literature review was performed to obtain an insight into the clinical safety and efficacy of demeclocycline for this condition.

Methods

Embase ^™, MEDLINE ^®, MEDLINE ^® In‐Process, and The Cochrane Library were searched on two occasions using Me SH terms combined with free‐text terms. References were screened by two independent reviewers. Relevant publications were then extracted by two independent reviewers, with a third reviewer collating and finalising extractions.

Results

The searches returned a total of 705 hits. 632 abstracts were screened after the removal of duplicates. Following screening, 35 full‐length publications were reviewed. Of these, 17 were excluded, resulting in 18 studies deemed relevant for data extraction. Two were randomised controlled trials ( RCTs), 16 were non‐ RCTs, and 10 were case reports.

Discussion

Although most reports suggest that demeclocycline can address serum sodium levels in specific patients with HN, efficacy is variable, and may depend upon the underlying aetiology. Demeclocycline dose adjustments can be complex, and as its use in clinical practice is not well defined, it can differ between healthcare professionals.

Conclusion

There is a lack of clinical and economic evidence supporting the use of demeclocycline for HN secondary to SIADH. Patients receiving demeclocycline for HN secondary to SIADH must be closely monitored.

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Most cited references 32

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Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.

Benoit Renneboog, Wim Musch, Xavier Vandemergel … (2006)

The study objective was to determine the eventual consequences (falls, unsteadiness, and cognitive impairment) of mild chronic hyponatremia, which is generally considered as asymptomatic. In a case-control study, we focused on the incidence of falls among 122 patients (mean age 72+/-13 years) with asymptomatic chronic hyponatremia (mean serum sodium concentration [SNa] 126+/-5 mEq/L), who were admitted to the medical emergency department, compared with 244 matched controls. To explore the mechanisms of the excess of falls, we prospectively asked 16 comparable patients (mean age 63+/-15 years; SNa+/-2 mEq/L) to perform 8 attention tests and a gait test consisting of 3 steps "in tandem," in which we measured the "total traveled way" by the center of pressure or total traveled way. Thereafter, the patients were treated and tested again (50% of the patients were tested first with normal SNa to avoid learning biases). Epidemiology of falls: Twenty-six patients (21.3%) of 122 were admitted for falls, compared with only 5.3% of the control patients (adjusted odds ratio: 67; 95% confidence: 7.5-607; P <.001). The frequency of falls was the same regardless of the level of hyponatremia. Gait: The total traveled way by the center of pressure significantly increased in hyponatremia (1336+/-320 mm vs 1047+/-172 mm with normal SNa; P=.003). Attention tests: The mean response time was 673+/-182 milliseconds in hyponatremia and 615+/-184 milliseconds in patients with normal SNa (difference: 58 milliseconds, P <.001). The total error number in hyponatremia increased 1.2-fold (P=.001). These modifications were comparable to those observed after alcohol intake in 10 volunteers. Mild chronic hyponatremia induces a high incidence of falls possibly as the result of marked gait and attention impairments. Treating these patients might prevent a considerable number of hospitalizations.

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The syndrome of inappropriate secretion of antidiuretic hormone.

Frederic C. Bartter, William Schwartz (1967)

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Diagnosis and management of hyponatremia in cancer patients.

Jorge J Castillo, Marc Vincent, Eric Justice (2012)

Hyponatremia, a common electrolyte abnormality in oncology practice, may be a negative prognostic factor in cancer patients based on a systematic analysis of published studies. The largest body of evidence comes from small-cell lung cancer (SCLC), for which hyponatremia was identified as an independent risk factor for poor outcome in six of 13 studies. Hyponatremia in the cancer patient is usually caused by the syndrome of inappropriate antidiuretic hormone (SIADH), which develops more frequently with SCLC than with other malignancies. SIADH may be driven by ectopic production of arginine vasopressin (AVP) by tumors or by effects of anticancer and palliative medications on AVP production or action. Other factors may cause hypovolemic hyponatremia, including diarrhea and vomiting caused by cancer therapy. Hyponatremia may be detected on routine laboratory testing before or during cancer treatment or may be suggested by the presence of mostly neurological symptoms. Treatment depends on several factors, including symptom severity, onset timing, and extracellular volume status. Appropriate diagnosis is important because treatment differs by etiology, and choosing the wrong approach can worsen the electrolyte abnormality. When hyponatremia is caused by SIADH, hypertonic saline is indicated for acute, symptomatic cases, whereas fluid restriction is recommended to achieve a slower rate of correction for chronic asymptomatic hyponatremia. Pharmacological therapy may be necessary when fluid restriction is insufficient. The orally active, selective AVP receptor 2 (V(2))-receptor antagonist tolvaptan provides a mechanism-based option for correcting hyponatremia caused by SIADH or other conditions with inappropriate AVP elevations. By blocking AVP effects in the renal collecting duct, tolvaptan promotes aquaresis, leading to a controlled increase in serum sodium levels.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Clin Pract

Journal ID (iso-abbrev): Int. J. Clin. Pract

Journal ID (doi): 10.1111/(ISSN)1742-1241

Journal ID (publisher-id): IJCP

Title: International Journal of Clinical Practice

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1368-5031

ISSN (Electronic): 1742-1241

Publication date (Print): December 2015

Publication date (Electronic): 19 August 2015

Volume: 69

Issue: 12 ( doiID: 10.1111/ijcp.2015.69.issue-12 )

Pages: 1396-1417

Affiliations

[ ¹ ] Department of EndocrinologyUniversity Hospital Lewisham LondonUK

[ ² ]Otsuka Pharmaceutical UK Limited WexhamUK

[ ³ ]Otsuka Pharmaceutical Europe Limited WexhamUK

Author notes

[*] [* ] Correspondence to:

Penny Dhanjal, Otsuka Pharmaceutical UK Limited, Gallions, Wexham Springs, Framewood Road, Wexham SL3 6PJ, UK

Tel.: + 44 (0) 79 1932 5210

Fax: + 44 (0) 20 8848 0529

Email: pdhanjal@ 123456otsuka.co.uk

Article

Publisher ID: IJCP12713

DOI: 10.1111/ijcp.12713

PMC ID: 5042094

PubMed ID: 26289137

SO-VID: 101196a7-47af-4b15-ae5a-25a09b604b20

License:

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date received : April 2015

Date accepted : July 2015

Page count

Pages: 22

Funding

Funded by: Otsuka Pharmaceutical Europe Ltd.

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component-id ijcp12713

cover-date December 2015

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:29.09.2016

Evidence for the use of demeclocycline in the treatment of hyponatraemia secondary to SIADH: a systematic review

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Most cited references 32

Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.

The syndrome of inappropriate secretion of antidiuretic hormone.

Diagnosis and management of hyponatremia in cancer patients.

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