ACP：临床常见难题的专家见解

新奥尔良(EGMN)——在新奥尔良Ernest N. Morial会展中心举行的美国医师协会(ACP)年会上，美国梅奥医院的John B. Bundrick博士受邀分享了他对临床实践的见解。 

干眼症？再见 

对于人工泪液不足以缓解症状的老年干眼症患者，最佳的循证辅助治疗是鱼油胶囊。 

近期一项小型随机、双盲临床试验证实了鱼油补充剂对轻中度干眼症的益处。经过90天的治疗，与安慰剂对照组相比，鱼油组患者的泪液量明显增多，而且70%不再有症状，远高于对照组的37%(Cornea 2011;30:308-14)。研究者采用的是Thera泪液——一种具有专利权的鱼油产品，每日剂量中包含450 mg二十碳五烯酸、300 mg二十二碳六烯酸(DHA)和1000 mg亚麻油。这项临床试验是在数项流行病学研究的基础上开展的，这些流行病学研究提示干眼症与欧米伽-3脂肪酸膳食摄入量减少有关。据推测，该产品奏效的机制涉及鱼油对睑板腺油的有益影响。 

在年龄超过50岁的人群中，多达30%报告有干眼症。这通常涉及2种机制：泪液生成减少和蒸发损失增加，二者均与年龄相关性外层泪膜脂质含量改变有关。多数患者并不存在相关的潜在全身性疾病。一线对症治疗始终是人工泪液。 

固定难治性神经病变 

1例年龄69岁、血糖控制良好的男性2型糖尿病患者有3年的双足痛性糖尿病神经病变病史，尽管使用了较大剂量的加巴喷丁(2100 mg/d)，但晚上还是应疼痛而难以入睡。为了改善其神经病变相关性生活质量，最佳的干预措施是什么？答案是加用去甲替林。

近期一项双盲、随机、交叉试验显示，联合使用加巴喷丁和去甲替林这两种一线药物，可以比二者单药治疗更有效地缓解痛性糖尿病神经病变。基线时最大每日疼痛评分平均约为6分(评分范围为1~10分)，单药治疗后降至4分，而二联治疗后降至3分。虽然额外降低1分并不算多，但却具有统计学意义。更令人印象深刻的是，二联治疗可以大幅度改善睡眠和生活质量指标(Lancet 2009;374:1252-61)。

至于其他选择，多项临床试验显示，电磁场疗法和低强度激光对于痛性糖尿病神经病变均无效。由于存在滥用的潜在风险，加用吗啡是值得商榷的。加巴喷丁和普瑞巴林均被视为一线治疗，但目前还没有“头对头”研究表明普瑞巴林更有效，尽管该药价格远远高于加巴喷丁。

其他公认的痛性糖尿病神经病变一线治疗包括三环类抗抑郁药、文拉法辛、度洛西汀和局部利多卡因。大约半数患者对上述药物单药治疗有应答，有应答者的疼痛减轻程度通常不到60%，这种不太理想的结果促进了人们对联合治疗的研究。

恶化性夜尿症 

1例年龄69岁的1+良性前列腺增生男性患者备受夜尿症困扰，而且夜尿症在过去数年间逐步恶化，目前他每晚需要起床3次。他的体重指数为34 kg/m²，在过去1年内体重增加了10磅(约合4.54 kg)。据他妻子说，他多年来鼾声如雷。 

多达50%的阻塞性睡眠呼吸暂停患者有夜尿症。临床试验表明，持续气道正压通气(CPAP)可改善夜尿症。在一项研究中，CPAP使平均每晚夜尿次数从2.5次减少到0.7次，接受治疗的患者中70%以上报告称改善程度为良好或极好(Urology 2006;67:974-7)。 

 “这将成为说服睡眠呼吸暂停患者尝试CPAP的一个新理由，而且可能比降低心血管风险之类的理由更能打动患者。” 

可疑腕管综合征的确认——忘掉Tinel’s征和Phalen’s征

 “Tinel和Phalen这两种传统体征我们都学过，但已有多项研究证明其不具有诊断价值，无论有无这些体征，似然比均接近1.0。它们对诊断没有帮助，我甚至已经不再做相应检查了。”

与此相反，在以神经传导和肌电图为金标准的研究中，如果存在正中神经支配区痛觉减退，则患有腕管综合征的似然比约为3。

痛觉减退的测试方法是，嘱患者用手指做Texas Longhorn动作(一种模仿德克萨斯大学吉祥物——长角牛——头和角形状的手势)，然后用1枚锐利的针触碰食指和小指的掌侧(见下图)。如果食指对触碰的感觉明显不及小指敏锐，就提示正中神经支配区痛觉减退，这是诊断腕管综合征的好办法(JAMA 2000;283:3110-7)。


Texas Longhorn动作测试
 

普通感冒的非正统治疗选择

鼻内给予异丙托溴铵和羟甲唑啉当然不能治愈感冒，但的确能显著缓解鼻部症状。一篇纳入7项随机试验、2,144例急性病毒性上呼吸道感染患者的Cochrane综述显示，鼻内给予异丙托溴铵在缓解感冒流涕症状方面非常有效(Cochrane Database Syst. Rev. 2011;7:CD008231)。

例如，在一项招募了943例患者的代表性研究中，鼻漏评分从基线时的6.5分(评分范围为1~10分)降至治疗后的3.4分。典型剂量为双侧鼻孔各喷2下0.06%溶液，每日用药4次。

异丙托溴胺并不能改善普通感冒的鼻塞症状。一篇基于临床试验的综述显示，鼻内给予赛洛唑啉与羟甲唑啉的疗效相当，不论单用还是与异丙托溴胺联用，均可显示减少普通感冒患者的鼻塞评分(Curr. Med. Res. Opin. 2010;26:889-99)。

 “我自己每次感冒时都使用异丙托溴铵和羟甲唑啉，用过之后鼻子几乎跟没感冒时一样。在给患者看病时不怕流鼻涕、不必擦鼻子的感觉真是太好了。”

Bundrick博士报告称无相关利益冲突。


 

NEW ORLEANS (EGMN) – How do you fit as many internists as possible into the largest auditorium at the Ernest N. Morial Convention Center in New Orleans?

Invite Dr. John B. Bundrick of the Mayo Clinic in Rochester, Minnesota, to start sharing clinical pearls. To a packed auditorium, the general internist shared the following practical clinical insights:

• Dry eye? Bye-bye. For the aging patient troubled by dry eyes who doesn’t obtain adequate relief with artificial tears, the best evidence-based adjunctive therapy is fish oil capsules.

That’s right, fish oil supplements proved beneficial in patients with mild to moderate dry eyes syndrome in a recent small, randomized, double-blind clinical trial, Dr. Bundrick said at the annual meeting of the American College of Physicians.

After 90 days of treatment, patients in the fish oil group had significantly greater tear volume, compared with placebo-treated controls. Moreover, 70% of them had become asymptomatic, compared with 37% of controls (Cornea 2011;30:308-14).

The investigators utilized Thera Tears, a proprietary fish oil product with a daily dose that contains 450 mg of eicosapentaenoic acid, 300 mg of docosahexaenoic acid, and 1,000 mg of flaxseed oil.

“I figured it would be superexpensive, but it turns out to cost about $13 on the Internet for a 90-day supply,” he said.

The clinical trial was prompted by several prior epidemiologic studies documenting an association between dry eyes syndrome and reduced dietary intake of omega-3 fatty acids. The proposed mechanism of benefit involves fish oil’s salutary effects on meibomian gland oils.

Dry eyes are reported by up to 30% of individuals older than age 50. Two mechanisms are typically involved: decreased tear production and increased evaporative loss due to age-related alterations in the lipid content of the outermost layer of the tear film. In the vast majority of cases, there is no related underlying systemic disease. First-line symptomatic therapy is always artificial tears.

•Fixing refractory neuropathy. A 69-year-old man with well-controlled type 2 diabetes presents with a 3-year history of painful diabetic neuropathy in both feet, despite being on gabapentin at a robust dosage of 2,100 mg/day. The pain is such that he’s having trouble sleeping at night.

What’s the best intervention aimed at improving his quality of life related to the neuropathy? Add nortriptyline.

A recent double-blind, randomized, crossover trial showed that the combination of gabapentin and nortriptyline provided more effective relief of painful diabetic neuropathy than did either of these first-line agents alone. Baseline maximum daily pain scores averaged about 6 on a 1-10 scale, dropping to 4 with either monotherapy and to 3 with dual therapy. Although that extra 1-point drop with combination therapy was modest, it was statistically significant. More impressive were the substantial improvements in sleep and quality of life measurements with dual therapy (Lancet 2009;374:1252-61).

As for other options, clinical trials have shown neither electromagnetic field therapy nor low-intensity lasers to be effective for painful diabetic neuropathy. Adding morphine is problematic because of the misuse potential. And although both gabapentin and pregabalin are both considered first-line therapies, there have been no head-to-head studies to demonstrate that pregabalin – a far costlier drug – is more effective.

Other accepted first-line therapies for painful diabetic neuropathy are the tricyclic antidepressants, venlafaxine, duloxetine, and topical lidocaine. About half of patients will respond to any of these agents when they are used as monotherapy, and the responders typically experience less than a 60% reduction in their pain. Those less than stellar results have been the impetus for study of combination therapies.

•Worsening nocturia. A 69-year-old man with 1+ benign prostatic hyperplasia is troubled by nocturia that has gotten progressively worse during the past several years. He needs to get up three times a night. His body mass index is 34 kg/m², he has gained 10 pounds during the past year, and his wife has mentioned that he has snored loudly for many years.

Nocturia occurs in up to half of patients with obstructive sleep apnea. And clinical trials have shown CPAP (continuous positive airway pressure) improves nocturia. In one study, CPAP reduced the mean number of episodes from 2.5 to 0.7 per night, and more than 70% of treated patients reported good-to-excellent relief (Urology 2006;67:974-7).

“It’s one more way to persuade your patients with sleep apnea to try CPAP. The cardiovascular morbidity and all that sometimes doesn’t get their attention, but if you can help their nocturia, maybe they’ll go for it,” the internist observed.

•Confirming suspected carpal tunnel syndrome. Forget about Tinel’s sign and Phalen’s maneuver.

“The traditional signs of Tinel and Phalen that we all learned have been shown in multiple studies to have no diagnostic value, with a likelihood ratio close to 1.0 whether they’re present or absent. They’re not helpful. I don’t even do them anymore,” Dr. Bundrick said.

In contrast, hypalgesia in the median nerve territory, when present, has a likelihood ratio of about 3 for carpal tunnel syndrome in studies in which nerve conduction and electromyography are the gold standard.

The test for hypalgesia is done by having the patient make the Texas Longhorn sign with his fingers. (This is a gesture that mimics the shape of the head and horns of the University of Texas mascot, a longhorn steer.) A sharp pin is then touched to the palmar aspect of the index and little fingers. If the index finger is noticeably less sensitive to the pin, that’s indicative of hypalgesia in the median nerve territory, a finding that’s good for ruling in the diagnosis of carpal tunnel syndrome (JAMA 2000;283:3110-7).

•An unorthodox option for the common cold. There is no cure, of course, but the nasal symptoms are substantially improved with the use of intranasal ipratropium and oxymetazoline. A Cochrane review of intranasal ipratropium involving seven randomized trials and 2,144 patients with acute viral upper respiratory tract infections concluded that the topical agent was highly effective at improving the runny nose aspect of the colds (Cochrane Database Syst. Rev. 2011;7:CD008231).

For example, in one representative study of 943 patients, rhinorrhea scores dropped from a baseline of 6.5 on a 1-10 scale to 3.4 with treatment. The typical dose was two squirts of the 0.06% solution in each nostril four times daily.

Ipratropium doesn’t improve the nasal congestion element of the common cold. But a review of clinical trials of intranasal xylometazoline, which is equivalent to the oxymetazoline available over the counter in the United States, showed substantial reduction in nasal congestion scores in patients with the common cold, regardless of whether the medication was used alone or in combination with intranasal ipratropium (Curr. Med. Res. Opin. 2010;26:889-99).

“I’ll add a personal testimonial: I use this stuff myself every time I have a cold, and it’s almost as if you don’t have a cold at all from the nasal perspective. It’s great when you’re seeing patients, so you’re not dribbling and reaching for [a facial tissue] all the time,” Dr. Bundrick said. “Ipratropium is now available generically; a 15-mL bottle, which is usually good for a couple years, costs about $35. And oxymetazoline is $3-$4.”

Dr. Bundrick reported having no financial conflicts.