主要治疗目标:
必须强调的是,成功的治疗需要频繁监测临床和实验室指标以达到治愈标准。应该保存治疗方案以及记录治疗阶段和实验室数据的流程图。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
[51]Fasanmade OA, Odeniyi IA, Ogbera AO. Diabetic ketoacidosis: diagnosis and management. Afr J Med Med Sci. 2008 Jun;37(2):99-105.
http://www.ncbi.nlm.nih.gov/pubmed/18939392?tool=bestpractice.com
[52]Andrade OV, Ihara FO, Troster EJ. Metabolic acidosis in childhood: why, when and how to treat. J Pediatr (Rio J). 2007 May;83(2 Suppl):S11-21.
http://www.ncbi.nlm.nih.gov/pubmed/17508091?tool=bestpractice.com
[53]Piva JP, Czepielewskii M, Garcia PC, et al. Current perspectives for treating children with diabetic ketoacidosis. J Pediatr (Rio J). 2007 Nov;83(5 Suppl):S119-27.
http://www.ncbi.nlm.nih.gov/pubmed/17973055?tool=bestpractice.com
初始治疗和支持疗法
大部分患者被送到急诊科,应在此进行初始治疗。早期管理应遵循以下几个重要的的步骤:
收入重症监护病房 (ICU) 的指征为血液动力学不稳定或心源性休克、意识状态改变、呼吸功能不全、重度酸中毒以及伴有昏迷的高渗状态。
应根据观察到的低血压和组织灌注较差的临床体征(包括少尿、发绀、四肢冰冷、精神状态改变)做出血流动力学不稳的诊断。进入 ICU 病房后,需使用中央静脉和动脉导管,并同时持续经皮血氧测量。氧合作用和气道保护至关重要。通常需要插管和机械通气,同时持续监测呼吸参数。因为有频繁出现肠梗阻和误吸的风险,因此经常需要鼻胃管吸引。
血流动力学不稳定患者的最初管理包括:通过补液来纠正低血容量和低血压、密切监测、以及升压药疗法(多巴胺疗法)。多巴胺是首选升压药,可根据血压和其他血流动力学的参数来调整其静脉输注的速度。如果患者输入中等剂量的多巴胺后,仍为低血压状态,应开始给予直接血管收缩剂(如去甲肾上腺素),并逐渐调整剂量以维持平均动脉压在 60 mmHg。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
[57]Hillman K. Fluid resuscitation in diabetic emergencies - a reappraisal. Intensive Care Med. 1987;13(1):4-8.
http://www.ncbi.nlm.nih.gov/pubmed/3104431?tool=bestpractice.com
液体疗法
液体缺乏量平均为 6 L。[58]Gosmanov AR, Gosmanova EO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes. 2014 Jun 30;7:255-64.
http://www.ncbi.nlm.nih.gov/pubmed/25061324?tool=bestpractice.com
初始治疗后,应该开始持续液体疗法。目标是恢复丢失的液体。应在 12-24 小时内逐步纠正液体缺乏,因为纠正过快可导致患者出现脑水肿。[59]Hom J, Sinert R. Evidence-based emergency medicine/critically appraised topic. Is fluid therapy associated with cerebral edema in children with diabetic ketoacidosis? Ann Emerg Med. 2008 Jul;52(1):69-75.e1.
http://www.ncbi.nlm.nih.gov/pubmed/18387706?tool=bestpractice.com
[60]Levin DL. Cerebral edema in diabetic ketoacidosis. Pediatr Crit Care Med. 2008 May;9(3):320-9.
http://www.ncbi.nlm.nih.gov/pubmed/18446108?tool=bestpractice.com
所有患者在入院后的第一个小时内接受 1.0-1.5 L 等渗溶液(0.9%氯化钠)的初始治疗后,应该进行水合状态的临床评价。直立性低血压或仰卧位低血压伴随黏膜干燥和皮肤弹性差提示严重容量不足,应以 1.0 L/小时的速度输入 0.9% 氯化钠溶液,直到严重容量不足的症状得以解决。由于轻度容量不足,这些患者仍要根据校正的血清钠水平继续接受液体疗法。
轻度容量不足的患者(特征是没有低血压),应该评估校正后的血清钠水平。国际标准单位公式:校正后钠水平 (mmol/L) = 钠水平检测值 (mmol/L) + 0.016 ([葡萄糖水平 (mmol/L) x 18] - 100)。常用单位公式:校正钠 (mEq/L) = 血钠检测值 (mEq/L) + 0.016 [血糖(mg/dL) - 100]。
对于低钠血症患者:开始应该以 250-500 mL/小时的速率静脉输注 0.9% 氯化钠,当血糖达到 11.1 mmol/L(200 mg/dL)时,输液疗法应改为以 150-250 mL/小时的速率输注 5% 葡萄糖和 0.45% 氯化钠。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
[57]Hillman K. Fluid resuscitation in diabetic emergencies - a reappraisal. Intensive Care Med. 1987;13(1):4-8.
http://www.ncbi.nlm.nih.gov/pubmed/3104431?tool=bestpractice.com
高钠血症或血钠正常的患者,建议以 250-500 mL/小时的速率静脉输注 0.45% 氯化钠,当血糖达到 11.1 mmol/L(200 mg/dL)时,改为以 150-250 mL/小时的速率静脉输注 5% 葡萄糖和 0.45% 氯化钠。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
[45]Joint British Diabetes Societies Inpatient Care Group. The management of diabetic ketoacidosis in adults. September 2013 [internet publication].
https://www.diabetes.org.uk/resources-s3/2017-09/Management-of-DKA-241013.pdf
[57]Hillman K. Fluid resuscitation in diabetic emergencies - a reappraisal. Intensive Care Med. 1987;13(1):4-8.
http://www.ncbi.nlm.nih.gov/pubmed/3104431?tool=bestpractice.com
[61]British Society for Paediatric Endocrinology and Diabetes. BSPED interim guideline for the management of children and young people under the age of 18 years with diabetic ketoacidosis. January 2020 [internet publication].
https://www.bsped.org.uk/media/1712/new-dka-guideline-v6-final.pdf
胰岛素治疗
目标是通过低剂量胰岛素治疗,使血糖和血浆渗透压稳定且逐渐降低,以减少治疗并发症包括低血糖和低钾血症发生的风险。
在排除低钾血症后(即:在开始胰岛素治疗前,血钾水平应>3.3 mmol/L [>3.3mEq/L]),患者应当接受普通胰岛素持续静脉输注治疗。现行指南推荐了两种低剂量治疗替代方案。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
[62]American Diabetes Association. Standards of medical care in diabetes - 2019. Diabetes Care. 2019 Jan;42(suppl 1):S1-S193.
https://care.diabetesjournals.org/content/42/Supplement_1
第一种方案是持续静脉输注普通胰岛素,剂量为 0.14 单位/kg/h(对于体重为 70 kg 的患者,约为 10 单位/h),开始时无需给予冲击量静脉推注。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
这是因为多项研究发现,如果剂量高于 0.1 单位/kg/h,通过静脉输注给予低剂量普通胰岛素足以治疗 DKA。另一种治疗方案是初始采用 0.1 单位/kg 冲击量静脉推注,然后以 0.1 单位/kg/h 的剂量持续输注。[58]Gosmanov AR, Gosmanova EO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes. 2014 Jun 30;7:255-64.
http://www.ncbi.nlm.nih.gov/pubmed/25061324?tool=bestpractice.com
这些低剂量胰岛素治疗方案能够使血糖浓度以 2.8-4.2 mmol/L/小时(50-75 mg/dL/小时)的速度降低。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
如果在第一个小时的胰岛素输注期间,血糖没有下降至少 10% 或 2.8 mmol/L (50 mg/dL),应该以 0.14 单位/kg 的冲击量静脉推注一次普通胰岛素,并且应当继续采取原来的胰岛素持续输注速度进行输注(0.1 单位/kg/小时或 0.14 单位/kg/小时,取决于所选择的给药方案)。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
[58]Gosmanov AR, Gosmanova EO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes. 2014 Jun 30;7:255-64.
http://www.ncbi.nlm.nih.gov/pubmed/25061324?tool=bestpractice.com
不再推荐滑动胰岛素注射法(sliding scale)。如果血清葡萄糖<11.1 mmol/L(200 mg/dL),则应当将输注速度减至 0.02-0.05 单位/kg/小时,此时可以将右旋葡萄糖添加到静脉输注的液体中。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
[58]Gosmanov AR, Gosmanova EO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes. 2014 Jun 30;7:255-64.
http://www.ncbi.nlm.nih.gov/pubmed/25061324?tool=bestpractice.com
然后,应当调节胰岛素输注速度(或右旋葡萄糖浓度),将血糖水平维持在 8.3-11.1 mmol/L(150-200 mg/dL)之间。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
患有严重 DKA(血糖 >13.9 mmol/L [>250 mg/dL]、动脉血 pH 值 <7.00、血清碳酸氢盐<10 mmol/L [<10 mEq/L])、低血压、全身性水肿(重度全身性水肿)的患者或存在其他相关严重疾病的患者,应在 ICU 采用上述普通胰岛素静脉输注的方案进行治疗。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
[63]Fisher JN, Shahshahani MN, Kitabchi AE. Diabetic ketoacidosis: low-dose insulin therapy by various routes. N Engl J Med. 1977 Aug 4;297(5):238-41.
http://www.ncbi.nlm.nih.gov/pubmed/406561?tool=bestpractice.com
[64]Umpierrez GE, Cuervo R, Karabell A, et al. Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. Diabetes Care. 2004 Aug;27(8):1873-8.
https://care.diabetesjournals.org/content/27/8/1873.full
http://www.ncbi.nlm.nih.gov/pubmed/15277410?tool=bestpractice.com
[65]Umpierrez GE, Latif K, Stoever J, et al. Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis. Am J Med. 2004 Sep 1;117(5):291-6.
http://www.ncbi.nlm.nih.gov/pubmed/15336577?tool=bestpractice.com
轻度至中度 DKA 患者(血浆葡萄糖>13.9mmol/L [>250 mg/dL]、动脉血 pH 值 7.00-7.30、血清碳酸氢根 10-18 mmol/L [10-18 mEq/L])在未合并急性心肌梗死、充血性心力衰竭、终末期肾衰竭或肝衰竭、使用类固醇或妊娠时,可接受速效胰岛素皮下注射,以作为静脉输注胰岛素的一种替代治疗。[66]Ludvigsson J, Samuelsson U. Continuous insulin infusion (CSII) or modern type of multiple daily injections (MDI) in diabetic children and adolescents: a critical review on a controversial issue. Pediatr Endocrinol Rev. 2007 Dec;5(2):666-78.
http://www.ncbi.nlm.nih.gov/pubmed/18084161?tool=bestpractice.com
[67]Mukhopadhyay A, Farrell T, Fraser RB, et al. Continuous subcutaneous insulin infusion vs intensive conventional insulin therapy in pregnant diabetic women: a systematic review and metaanalysis of randomized, controlled trials. Am J Obstet Gynecol. 2007 Nov;197(5):447-56.
http://www.ncbi.nlm.nih.gov/pubmed/17678864?tool=bestpractice.com
[68]Andrade-Castellanos CA, Colunga-Lozano LE, Delgado-Figueroa N, et al. Subcutaneous rapid-acting insulin analogues for diabetic ketoacidosis. Cochrane Database Syst Rev. 2016 Jan 21;(1):CD011281.
https://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011281.pub2/abstract
http://www.ncbi.nlm.nih.gov/pubmed/26798030?tool=bestpractice.com
[ ]
How do subcutaneous rapid-acting insulin analogs compare with regular insulin in people with diabetic ketoacidosis?/cca.html?targetUrl=https://cochranelibrary.com/cca/doi/10.1002/cca.1713/full展示答案 在一个中心的成人研究中,已经证明这是安全有效的。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
建议方案是以 0.3 单位/kg 的剂量皮下注射速效胰岛素,1 小时后给予另一次 0.2 单位/kg 的皮下注射。此后,应每 2 小时接受 0.2 单位/kg,直到血糖<13.9 mmol/L (<250 mg/dL)。达到此数值后,胰岛素剂量应减半至每 2 小时 0.1 单位/kg,直到 DKA 消退。[64]Umpierrez GE, Cuervo R, Karabell A, et al. Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. Diabetes Care. 2004 Aug;27(8):1873-8.
https://care.diabetesjournals.org/content/27/8/1873.full
http://www.ncbi.nlm.nih.gov/pubmed/15277410?tool=bestpractice.com
这些研究的结果在多中心试验中得到验证之前,持续静脉输注普通胰岛素应仍是首选给药途径,因为其半衰期短并易于调整剂量。这是与皮下注射胰岛素起效时间延迟以及半衰期延长相比较的结果。但在 ICU 入院等待时间增长或医疗资源有限的地方,可考虑在门诊病房、普通病房或急诊科中使用胰岛素类似物治疗轻度单纯性 DKA 发作。
[Figure caption and citation for the preceding image starts]: 成人 DKA 管理。缩略语:血糖 (BG);糖尿病酮症酸中毒 (DKA);小时 (h);静脉注射 (IV);皮下 (SC)图片由 BMJ 知识中心制作,参考自:Gosmanov AR, Gosmanova EO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. [Citation ends].
钾疗
胰岛素治疗以及对于酸中毒和高渗血症的纠正将促使钾进入细胞,这可能会导致严重低钾血症。因此,我们的目标是纠正实际钾的缺乏,从而防止呼吸麻痹、心律失常等低钾血症的致命并发症。
在血钾水平达到 3.3mmol/L(<3.3 mEq/L)之前不应开始胰岛素治疗。同样,如果在治疗过程中的任何时候血钾低于 3.3 mmol/L(<3.3mEq/),应停止胰岛素治疗并给予静脉补钾。所有血钾 <5.3 mmol/L(<5.3 mEq/L)并且尿排出量足够(>50 mL/h)的患者,都应该在每升输入的液体中增加 20-30 mmol(20-30 U [mEq])钾,以防止因胰岛素治疗而造成的低血钾。如果钾水平 >5.3 mmol/L(>5.3mEq/L),不需要补钾治疗,但应每 2 小时检测一次血钾水平。mEq/L)。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
碳酸氢盐治疗
患 DKA 时是否应用碳酸氢盐仍存在争议。动脉血 pH 值>7.0 时,胰岛素治疗即可阻止脂类分解,消除酮症酸中毒,而不需要加用碳酸氢钠。如果这些患者使用碳酸氢盐治疗,可能会增加低钾血症、组织摄氧量减少以及脑水肿的风险。
尽管资料有限,但成人 DKA 患者动脉血液pH值<7 时可使用碳酸氢盐治疗。[69]Chua HR, Schneider A, Bellomo R. Bicarbonate in diabetic ketoacidosis - a systematic review. Ann Intensive Care. 2011 Jul 6;1(1):23.
http://www.annalsofintensivecare.com/content/1/1/23
http://www.ncbi.nlm.nih.gov/pubmed/21906367?tool=bestpractice.com
基于对动脉血 pH 值为 6.9-7.0 的成人患者的研究,可将 50 mmol 碳酸氢钠溶于 200 mL 灭菌水,并加入 10 mmol (10 mEq) 氯化钾,于 1 小时内经静脉注入,直至 pH 值>7.0。
成人患者的 pH 值<6.9时,建议将 100 mmol 碳酸氢钠溶于 400 mL 灭菌水(等渗溶液),加入 20 mmol (20 mEq) 氯化钾,以 200 mL/小时的速度静脉滴注 2 小时,直至 pH 值>7.0。对于监测治疗过程来说,静脉 pH 值已经足够,应该至少每小时进行检测。应每 2 个小时重复一次治疗,直至 pH 值>7.0。
碳酸氢盐治疗和胰岛素治疗一样,能降低血钾;因此,在等渗碳酸氢盐输注时应加入氯化钾。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
[70]Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med. 1986 Dec;105(6):836-40.
http://www.ncbi.nlm.nih.gov/pubmed/3096181?tool=bestpractice.com
[Figure caption and citation for the preceding image starts]: 碳酸氢盐和钾的管理流程改编自:Kitabchi AE, Umpierrez GE, Miles JM, et al.Diabetes Care.2009,32:1335-43 [Citation ends].
磷酸盐治疗
在 DKA 患者中,尽管机体总磷酸盐缺乏(平均缺乏 1.0 mmol/kg 体重),但血清磷酸盐水平在就诊时经常为正常或升高,不过随着胰岛素治疗,会出现下降。既往研究没有发现给予 DKA 患者磷酸盐补充治疗有任何益处。因此,不推荐常规磷酸盐补充治疗。
然而,为了避免心脏、呼吸和骨骼肌功能障碍,对于存在心脏功能障碍(例如,有左心室功能障碍的体征)、症状性贫血或呼吸抑制(例如,血氧饱和度下降)的患者以及确诊为低磷血症(血清磷酸盐浓度<1.0 mg/dL)的患者,可能需谨慎给予磷酸盐治疗。[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com
治疗监测
监测呼吸参数和血流动力学状态对血流动力学不稳定的患者尤为重要。
初始实验室评估后,血糖和电解质至少每小时检测一次;钙、镁、和磷酸盐每 2 小时检查一次,然后根据患者的临床情况和对治疗的反应,每 2-6 小时进行一次尿素、肌酐、酮体检查。
β-羟丁酸 (BOHB) 的连续测定可能有助于监测对 DKA 治疗的反应。但是,不推荐在缺少 BOHB 测定能力的情况下对酮体进行测量。BOHB 转化为乙酰乙酸,后者在 DKA 的治疗过程中用硝普盐方法检测。因此,DKA 治疗过程中乙酰乙酸的增加可能错误地提示酮血症恶化。
当前证据表明,监测碳酸氢盐、阴离子间隙和 pH 能够体现机体对治疗的反应。用流程图对这些检查发现以及精神状态、生命体征、胰岛素用量、液体和电解质治疗以及尿量等进行分类记录,能够帮助判断机体对治疗的反应和对危险情况的解决。在 DKA 治疗期间进行代谢检查可提供肾功能和钠水平变化的动态信息。
在治愈糖尿病酮症酸中毒之前,应持续进行管理和监测。治愈标准为:[1]Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43.
http://care.diabetesjournals.org/content/32/7/1335.full
http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com