Overview of sweating in palliative care

INTRODUCTION — Sweating is the body’s normal mechanism to maintain optimal physiologic temperature. When the body’s internal temperature rises beyond the normal range, sweating occurs to allow the body to cool and return to normal physiologic temperature. Hyperhidrosis is defined as inappropriately excessive sweating beyond what is required for thermoregulatory needs and environmental conditions. It is often described as night sweats or nocturnal diaphoresis when it occurs at night (see "Evaluation of the patient with night sweats or generalized hyperhidrosis", section on 'Definitions'). This topic will review the clinical presentation, assessment and management of sweating in the palliative care population.

CLASSIFICATION — Hyperhidrosis can be categorized as primary or secondary. Primary, or idiopathic, hyperhidrosis affects approximately 3 percent of the population, usually begins around puberty or earlier, and has a strong genetic predisposition. It is usually localized to areas with high eccrine sweat glands, such as the axilla, palms, and soles of the feet (and, less commonly, the head and face). (See "Primary focal hyperhidrosis".)

By contrast, secondary hyperhidrosis can accompany a variety of conditions that fall under the categories of endocrine, metabolic, or neurologic disorders; tumors; infections and other febrile illnesses; or medication use. It is usually generalized (rather than focal), and may be present exclusively at night (see 'Generalized' below and 'Focal' below). It is more difficult to treat than localized primary hyperhidrosis. The main causes of secondary hyperhidrosis in palliative care populations are outlined in the table (table 1).

Hyperhidrosis can also be classified as generalized or focal. (See 'Generalized' below and 'Focal' below.)

PREVALENCE — Hyperhidrosis generally affects about 3 to 4 percent of people in the United States [1,2]. However, the prevalence in palliative care populations, including those with advanced cancer, ranges from 5 to 28 percent [3,4]. For example, night sweats are especially common in patients with Hodgkin lymphoma, manifesting in 25 percent of patients as an early symptom; night sweats are one of the “B” symptoms used for staging classification. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'B symptoms'.)

PATHOPHYSIOLOGY — The majority of sweat glands in the body are eccrine glands. These are distributed throughout the body surface, predominantly in the palmar, plantar, axillary, and craniofacial regions, and they are innervated by the sympathetic nervous system. The main neurotransmitter of the neuroglandular junction of the sympathetic fibers is acetylcholine, unlike in most other sympathetic nerve terminals, whose neurotransmitter is noradrenaline. Acetylcholine normally binds to muscarinic receptors in eccrine sweat glands to induce sweating as a physiologic response to core body temperature control during times of physical or psychological stress [5]. In hyperhidrosis, there is hyperactivity of the sympathetic nervous system which results in excessive release of acetylcholine from the nerve ending and an impairment of the negative feedback mechanism to the hypothalamus. This causes the body to sweat more than what is required to cool down the body's temperature [6,7].

It is also believed that, specifically in axillary hyperhidrosis, there is an abnormal regeneration of sympathetic nerves or an increase in the number and/or distribution of eccrine glands due to hyperstimulation [8]. This finding is not identified in palmar hyperhidrosis.

ETIOLOGY — The etiology of primary hyperhidrosis appears unclear but genetic factors are believed to play a role [8]. The causes of secondary hyperhidrosis are relatively easier to characterize because they usually accompany a variety of conditions that fall under the general categories of endocrine, metabolic, neurologic, or psychiatric disorders; tumors; febrile illnesses (including infection); or medication use. The main causes of secondary hyperhidrosis in palliative care populations are outlined in the table (table 1). A more comprehensive discussion of the differential diagnosis of night sweats is available elsewhere. (See "Evaluation of the patient with night sweats or generalized hyperhidrosis".)

Generalized

Cancer patients — Among palliative care patients with cancer, generalized sweating may be tumor or treatment related. However, hyperhidrosis in palliative care patients can be multifactorial (eg, both liver metastases and withdrawal from opioids).

●Sweating may be commonly experienced by patients with breast and prostate cancer, but this is more commonly attributed to treatment rather than the disease itself (eg, vasomotor symptoms associated with treatments that result in estrogen or androgen deficiency [selective estrogen receptor modulators, aromatase inhibitors, and androgen deprivation therapy]). (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Side effects' and "Side effects of androgen deprivation therapy", section on 'Vasomotor symptoms' and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Side effects'.)

●Patients with Hodgkin lymphoma and non-Hodgkin lymphoma may report fever and/or night sweats as early constitutional symptoms. In either case, the pathophysiology underlying the development of night sweats is not known. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Systemic "B" symptoms'.)

●Less commonly, leukemia and multiple myeloma may be associated with fever and night sweats.

●Patients with nonhematologic malignancies may also experience night sweats, sometimes attributed to tumor-related fever or flushing. Malignancy is one of the most common causes of fever of unknown origin. (See "Fever of unknown origin in adults: Etiologies", section on 'Malignancies'.)

●Reports exist of night sweats among patients with most types of solid tumors, but this is most common with renal cell cancer and primary liver cancers such as cholangiocarcinoma. Other solid tumors metastatic to the liver can also cause fever and night sweats, but this is uncommon overall and typically associated with a bulky, treatment-refractory tumor [9]. The pathophysiology is unclear. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma", section on 'Fever' and "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts", section on 'Metastatic tumors' and "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Other clinical presentations'.)

●Advanced medullary carcinoma of the thyroid may cause flushing due to calcitonin secretion. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Clinical presentation'.)

●Insulinomas may cause night sweats because of nocturnal hypoglycemia. (See "Insulinoma", section on 'Clinical features'.)

●Vasoactive intestinal polypeptide (VIP)-secreting tumors can also cause sweats. (See "VIPoma: Clinical manifestations, diagnosis, and management", section on 'Clinical manifestations'.)

Other causes — Infectious, neurologic, endocrine, and medication-related etiologies for generalized night sweats are discussed in detail elsewhere. A list of medications associated with sweating is provided in the table (table 2). (See "Evaluation of the patient with night sweats or generalized hyperhidrosis".)

Focal — Secondary focal hyperhidrosis can be associated with peripheral neuropathies, such as with diabetic neuropathy or complex regional pain syndrome (CRPS) [10,11]. In the former, sweating may disappear with progression of neuropathy secondary to nerve damage. In CRPS, pain is usually severe and predominant, and it can be debilitating. Post-stroke unilateral hyperhidrosis has been observed following lesions to the cerebrum, hypothalamus and midbrain, and spinal cord [12-22], which is partly due to the disruption of inhibitory neural signals that regulate sweating contralateral to the lesion.

CLINICAL PRESENTATION AND ASSESSMENT — Most advanced cancer patients with hyperhidrosis describe symptoms as nocturnal (night sweats) and of moderate to severe intensity [23-25]. Night sweats may be associated with the need to change clothes or sheets (drenching sweats).

Initial assessment should include a detailed history, medication review, symptom assessment, and physical examination, which all help reveal the location and severity of hyperhidrosis and provide clues to the possible underlying etiology.

●Patients who are younger, have a family history of the disorder, present with a chronic onset of more than six months, and have bilateral involvement usually have primary hyperhidrosis. Symptoms that present later in life are more likely of a secondary cause [6].

●Specific symptoms that should be sought include pain, weight loss, anxiety, jitteriness, flushing, sleep disruption, signs and symptoms of autonomic neuropathy, and fever and other symptoms/signs suggestive of infection.

The severity of hyperhidrosis may be assessed by the impact on functioning, social interactions, sleep, and the need to change clothes and bed linens. A number of objective hyperhidrosis assessment scales [26] are available and are mainly used for focal hyperhidrosis; they are generally not relevant in the palliative care setting.

Further diagnostic workup (ie, laboratory evaluation and diagnostic radiographic imaging), especially if fever is found, depends on the clinical context and goals of care.

MANAGEMENT

General principles and nonpharmacologic measures — Hyperhidrosis in palliative care patients is predominantly secondary in nature and its treatment can be challenging for both the patient and the clinician. The first steps in management should involve treatment of the underlying etiology, if clinically appropriate, such as infections or hyperthyroidism. A medication review is appropriate (table 2), and if a patient is taking a medication known to cause flushing or excessive sweating, the medication should be withdrawn, if possible, as a diagnostic trial. If this is not possible, changing to a lower dose, an extended-release formulation of the medication, or a drug less likely to cause sweating is another potential strategy.

Nonpharmacologic treatment approaches to symptom management include use of fans to keep the skin cool, wearing loose cotton clothing, use of cotton bed linens, and maintaining adequate hydration, along with emotional support and reassurance. In one study among men with prostate cancer, cognitive-behavioral therapy reduced hot flashes with paced breathing and relaxation, among other measures [27].

Pharmacologic measures

Generalized symptoms by etiology

●Infection – If infection is suspected due to fever, and the goals of care are not consistent with a formal diagnostic workup, an empiric seven-day course of antibiotics such as levofloxacin 500 mg daily, or, in the case of suspected severe infection, standard broad-spectrum agents such as ceftazidime 2 g intravenous (IV) every eight hours or imipenem 500 mg IV every six hours may be reasonable. If more aggressive care is indicated, basic infectious workup including a complete blood count, urinalysis, blood cultures, and chest radiograph may be initiated. More detailed infectious workup is discussed elsewhere. (See "Evaluation of the patient with night sweats or generalized hyperhidrosis".)

●Tumor-associated – If tumor-associated fever is suspected, acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs) are initially used. A randomized trial of three oral NSAIDs in 48 patients with tumor-related fever showed comparable efficacy for naproxen, diclofenac sodium, and indomethacin, although naproxen provided the most rapid response [28]. Although less effective than NSAIDs, a trial of glucocorticoid such as prednisone 40 to 150 mg daily for two or more days may be considered in refractory cases, if it is not contraindicated [29].

●Other causes – For all other causes, NSAIDs are usually first-line treatment, followed by glucocorticoids for refractory symptoms as described above. Other options reported to be potentially effective may include cimetidine 400 to 800 mg once daily [26], olanzapine 5 mg twice daily [30], oxybutynin 5 mg at bedtime [31], and gabapentin at a starting dose of 100 mg three times daily [32]. Night sweats have also been shown to improve with use of thalidomide given at 100 mg daily; however, its use is limited by side effects including painful, sometimes irreversible peripheral neuropathy, teratogenicity, and somnolence [33-35].

●Vasomotor symptoms – Hyperhidrosis because of vasomotor symptoms (ie, hot flashes) typically presents as intermittent episodes of sudden heat sensation beginning on the upper chest and face that rapidly becomes generalized with profuse sweating. It is sometimes associated with palpitations, chills, shivering, and a feeling of anxiety. Among palliative care patients, it may either occur in postmenopausal women or in women who experience a “premature menopause” as a result of surgery and/or chemotherapy, or among hormone-related cancer patients such as breast, prostate, and endometrial cancer populations. Treatment approaches are discussed separately. (See "Menopausal hot flashes".)

Focal symptoms — Most of the treatments described below are used for primary and localized hyperhidrosis and may therefore be rarely useful in palliative care patients, since the etiology in this patient population is predominantly secondary and generalized in nature. Oral anticholinergic agents may be of relatively more value and relevance in the palliative care patient population due to their generalized effects [36,37].

●Topical agents – Over-the-counter aluminum chloride hexahydrate has been used. It is best applied at night and washed off in the morning. Mild skin irritation can occur from its use [7]. Glycopyrronium tosylate topical cloth is also approved to treat excessive sweating [6]. Other topical agents include topical glycopyrrolate, topical oxybutynin, tannic acid, and potassium permanganate.

●Oral anticholinergic agents – For patients who do not respond to topical treatment or who have more generalized symptoms, oral anticholinergic agents such as oral oxybutynin, glycopyrrolate, benztropine, or propantheline bromide (where available) may be considered. Adverse effects such as dry eyes, dry mouth, urinary retention, and constipation can occur.

●Iontophoresis – This consists of passing a direct current across the skin with agents such as tap water or anticholinergics [38]. The mechanism of action is unclear. Tap water iontophoresis has a lower adherence rate because it is more time-consuming and less effective than anticholinergic iontophoresis, but it has a relatively safe side effect profile.

●Botulinum toxin – Botulinum toxin A injection can be used for treatment of localized or regional hyperhidrosis in patients who do not respond to topical and oral medication therapy [39]. These injections are more expensive compared with topical and systemic medications.

●Laser therapy – This is a relatively more recent treatment option for primary hyperhidrosis, especially in patients with unsuccessful results from topical and/or systemic treatments [40]. It functions by delivering energy to the tissue to damage the sweat glands, thereby reducing sweating. It is known to have a limited side effect profile which includes burns [41].

●Surgical treatments – Surgical procedures such as sympathectomy, radiofrequency ablation, subcutaneous liposuction, and surgical excision of affected areas are used in refractory cases.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care".)

SUMMARY AND RECOMMENDATIONS

●Causes – Secondary hyperhidrosis can accompany a variety of conditions, including endocrine, metabolic, neurologic, or psychiatric disorders; tumors; febrile illnesses (including infection); or medication use. The main causes of secondary hyperhidrosis in palliative care populations are outlined in the table (table 1).

●Assessment – Initial assessment should include a history, medication review, symptom assessment and physical examination geared toward identifying possible etiologies and the severity of the hyperhidrosis. Further diagnostic workup, especially if fever is found, depends on the clinical scenario and goals of care. (See 'Clinical presentation and assessment' above.)

●General treatment principles – The first steps in management should involve treatment of the underlying etiology, if clinically appropriate and consistent with the goals of care, as well as elimination of any potential aggravating factors (eg, hyperthyroidism). If a patient is taking a medication known to cause flushing or excessive sweating, the medication should be withdrawn, if possible, as a diagnostic trial (table 2). (See 'General principles and nonpharmacologic measures' above.)

●Specific treatments

•Nonpharmacologic treatment approaches to management include the use of fans to keep the skin cool, wearing loose cotton clothing, the use of cotton bed linens, and maintaining adequate hydration. (See 'General principles and nonpharmacologic measures' above.)

•If infection is suspected and the goals of care are not consistent with a formal infectious workup, an empiric course of antibiotics is reasonable. (See 'Generalized symptoms by etiology' above.)

•For patients with suspected tumor-related fever and for those without fever, empiric treatment with acetaminophen or a nonsteroidal antiinflammatory drug (NSAID) is reasonable, followed by a glucocorticoid for refractory symptoms. (See 'Generalized symptoms by etiology' above.)

•If sweating is a component of vasomotor symptoms (ie, hot flashes), treatment approaches may include megestrol, gabapentin, or antidepressants. (See 'Generalized symptoms by etiology' above and "Menopausal hot flashes".)

•Focal symptoms can be treated with topical agents (eg, aluminum chloride hexahydrate), oral anticholinergics (eg, oxybutynin, glycopyrrolate, benztropine), botulinum toxin, and procedures such as iontophoresis and sympathectomy. (See 'Focal symptoms' above.)