Journal Club 2013年3月28日 8:30-8:55 ８階 医局 Umpierrez GE, Smiley D, Hermayer K, Khan A, Olson DE, Newton C, Jacobs S, Rizzo M, Peng L, Reyes D, Pinzon I, Fereira ME, Hunt V, Gore A, Toyoshima MT, Fonseca VA. Randomized Study Comparing a Basal Bolus With a Basal Plus Correction Insulin Regimen for the Hospital Management of Medical and Surgical patients With Type 2 Diabetes: Basal Plus Trial. Diabetes Care. 2013 Feb 22. [Epub ahead of print] 2013年3月28日　8:30-8:55 ８階　医局 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 栗原　郁実 Kurihara, Ikumi

Medical ICUでの高血糖と死亡率

Surgical ICUでのインスリン強化療法による 死亡率減少 周術期（主に術後）には、 血糖を200mg/dl程度にする治療に比較し100mg/dl前後にすると死亡率が半減する。

重症入院患者へのインスリン治療：死亡率 （無作為ランダム化研究のメタ解析） 周術期（主に術後）には、 血糖を200mg/dl程度にする治療に比較し100mg/dl前後にすると死亡率が半減する。 心筋梗塞ではそれほどの差はない。 35 publications, n=8478

最低血糖値と死亡 血糖スライディングをおこなっていた頃のデータ 0.18 0.16 0.14 0.12 死亡数 0.10 0.08 0.06 0.04 0.02 0.00 入院中最低血糖値 （mg/dL） <30（49） 30-39（76） >39（213） 米ブリガム・アンド・ウィメンズ病院（ボストン）などで、2003年1月から2004年8月に大学付属病院へ入院した糖尿病患者2, 582例（入院4, 368回）についてレトロスペクティブに検討。最低血糖値が10 mg/dL減少するごとに死亡リスクが3倍。 Diabetes Care 32: 1153–1157, 2009 5

低血糖は非常に危険 （病棟診療） 高血糖の場合には「補正量」を追加で使用 血糖スライディングスケールは「有効でなく使ってはいけない！」（米国糖尿病学会Clinical Practice Recommendation） 高血糖の場合には「補正量」を追加で使用

院内血糖管理ガイドライン VIII. DIABETES CARE IN SPECIFIC SETTINGS A. Diabetes care in the hospital Recommendations ● Scheduled prandial insulin doses should be appropriately timed in relation to meals and should be adjusted according to point-of-care glucose levels. The traditional sliding-scale insulin regimens are ineffective as monotherapy and are generally not recommended. (C) ● Using correction dose or "supplemental" insulin to correct premeal hyperglycemia in addition to scheduled prandial and basal insulin is recommended. (E) DIABETES CARE, VOLUME 32, SUPPLEMENT 1, JANUARY 2009 S13

院内血糖管理ガイドライン Diabetes care in the hospital Recommendations ● Scheduled subcutaneous insulin with basal, nutritional, and correction components is the preferred method for achieving and maintaining glucose control in noncritically ill patients. (C) . ● Using correction dose or "supplemental" insulin to correct premeal hyperglycemia in addition to scheduled prandial and basal insulin is recommended. (E) ● Prolonged therapy with sliding scale insulin (SSI) as the sole regimen is ineffective in the majority of patients, increases risk of both hypoglycemia and hyperglycemia, and has recently been shown to be associated with adverse outcomes in general surgery patients with type 2 diabetes . SSI is potentially dangerous in type 1 diabetes. DIABETES CARE, VOLUME 35, SUPPLEMENT 1, JANUARY 2012

周術期，急性期の血糖管理 VIII. DIABETES CARE IN SPECIFIC SETTINGS A. Diabetes care in the hospital Recommendations ● All patients with diabetes admitted to the hospital should have their diabetes clearly identified in the medical record. (E) ● Goals for blood glucose levels: Critically ill surgical patients’ blood glucose levels should be kept as close to 110 mg/dl (6.1 mmol/l) as possible and generally 140 mg/dl (7.8 mmol/l). (A) These patients require an intravenous insulin protocol that has demonstrated efficacy and safety in achieving the desired glucose Critically ill nonsurgical patients’ glycemic targets are less well defined. DIABETES CARE, VOLUME 32, SUPPLEMENT 1, JANUARY 2009 S13

周術期，急性期の血糖管理 VIII. DIABETES CARE IN SPECIFIC SETTINGS A. Diabetes care in the hospital Recommendations ● All patients with diabetes admitted to the hospital should have their diabetes clearly identified in the medical record. (E) Goals for blood glucose levels: ● Critically ill patients: Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold of no greater than 180 mg/dl (10 mmol/l). Once insulin therapy is started, a glucose range of 140 –180 mg/dl (7.8 to 10 mmol/l) is recommended for the majority of critically ill patients. (A) These patients require an intravenous insulin protocol that has demonstrated efficacy and safety in achieving the desired glucose range without increasing risk for severe hypoglycemia. (E) ● Non–critically ill patients: BG＜140mg/dl (7.8 mmol/l) with random blood glucose ＜180 mg/dl (10.0 mmol/l), DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010 S13

シリンジポンプを用いたインスリン注入 による血糖管理のポイント 依頼のやり取り：看護師さんへの配慮 インスリン注入液準備 　　　よく混和　49.5mlの生食 ブドウ糖[点滴、経管栄養]もポンプで注入 血糖管理はチームで交代で行う インスリン注入率指示はこちらから電話 記録を残す 点滴や食事の開始/変更時の連絡 検査や処置で点滴や経管栄養中断に注意 血糖低下で次回70mg/dl以下になりそうであれば0.4U/hrに注入率を落とす

血糖による持続インスリン注入率の調節 とりあえず 血糖値÷100　［単位/hr］　で開始 300mg/dl ボーラスは　上記÷６単位

血糖による持続インスリン注入率の調節 安定してきたらΔで調節！ 160mg/dl 210mg/dl

食事開始に伴うインスリン皮下注射による血糖管理のポイント インスリン追加分泌補充は超速効型で食直後に 食事量スライディングスケールを用いる 　　（３分割：0-3，3-7，7-10割） 血糖補正を行う 　　目標血糖(120mg/dl) 　　１単位のインスリンで50mg/dl低下 基礎インスリン補充は朝，夕 中間型かレベミル２回から開始(食事量が不明の場合) 点滴中でインスリン混注やシリンジポンプから注入中には基礎インスリン補充はしない ☆単位数が多い場合は４分割もある 　　（４分割：0-2，2-5，5-8，8-10割）　

0000000 　　　CASE 1 　　　男　　　 　　 インスリン指示（食事開始後）

A basal-bolus insulin regimen is preferred over SSI.

Diabetes Care. 2013 Feb 22. [Epub ahead of print] care.diabetesjournals.org the 1Department of Medicine, Division of Endocrinology, Emory University, Atlanta, Georgia; the 2Department of Medicine, Division of Endocrinology, Medical University of South Carolina, Charleston, South Carolina; the 3Department of Medicine, Division of Endocrinology, Tulane Medical Center, New Orleans, Louisiana; the 4Atlanta Veterans Affairs Medical Center, Decatur, Georgia; the 5Department of Surgery, Emory University, Atlanta, Georgia; and the 6Rollins School of Public Health, Emory University, Atlanta, Georgia. Diabetes Care. 2013 Feb 22. [Epub ahead of print]

OBJECTIVE Effective and easily implemented insulin regimens are needed to facilitate hospital glycemic control in general medical and surgical patients with type 2 diabetes (T2D).

RESEARCH DESIGN AND METHODS This multicenter trial randomized 375 patients with T2D treated with diet, oral antidiabetic agents, or low-dose insulin (≦0.4 units/kg/day) to receive a basal bolus regimenwith glargine once daily and glulisine before meals, a basal plus regimen with glargine once daily and supplemental doses of glulisine, and sliding scale regular insulin (SSI).

We excluded patients with an admission, patients with any BG ＞400 mg/dL before randomization or with a history of hyperglycemic crises, patients with hyperglycemia without a known history of diabetes, patients admitted to or expected to require ICU admission, patients undergoing cardiac surgery, patients receiving corticosteroid therapy, patients with clinically relevant hepatic disease or impaired renal function (serum creatinine ＞3.0 mg/dL), patients with a history of diabetic ketoacidosis, pregnant patients, and patients with any mental condition rendering them unable to give informed consent.

1. Basal Bolus Regimen 1.A. Insulin Orders  Discontinue oral antidiabetic drugs and non-insulin injected antidiabetic medication on admission.  Starting insulin total daily dose (TDD): 0.5 units per kg of body weight.  Reduce insulin TDD to 0.3 units per kg of body weight in patients ≥ 70 years of age and/or with a serum creatinine ≥ 2.0 mg/dL.  Give half of total daily dose as insulin glargine and half as insulin glulisine.  Give insulin glargine once daily, at the same time of the day.  Give insulin glulisine in three equally divided doses before each meal. Hold insulin glulisine if patient not able to eat. 1.B. Supplemental insulin  Give supplemental insulin glulisine following the “sliding scale” protocol (1E) for blood glucose > 140 mg/dl.  If a patient is able and expected to eat all, give supplemental glulisine insulin before each meal and at bedtime following the “usual” column.  If a patient is not able to eat, give supplemental glulisine insulin every 6 hours (6-12-6-12) following the “sensitive” column. 1.C. Insulin adjustment If the fasting and predinner BG is between 100 - 140 mg/dl in the absence of hypoglycemia the previous day: no change If the fasting and predinner BG is between 140 - 180 mg/dl in the absence of hypoglycemia the previous day: increase insulin TDD by 10% every day If the fasting and predinner BG is >180 mg/dl in the absence of hypoglycemia the previous day: increase insulin TDD dose by 20% every day If the fasting and predinner BG is between 70 - 99 mg/dl in the absence of hypoglycemia: decrease insulin TDD dose by 10% every day If a patient develops hypoglycemia (BG <70 mg/dL), the insulin TDD should be decreased by 20%. 1.D. Blood glucose monitoring. Blood glucose will be measured before each meal and at bedtime (or every 6 hours if a patient is not eating) using a glucose meter 1.E. Supplemental Insulin Scale Blood Glucose (mg/dL) Insulin Sensitive Usual Insulin Resistant 141-180 2 4 6 181-220 4 6 8 221-260 6 8 10 261-300 8 10 12 301-350 10 12 14 351-400 12 14 16 > 400 14 16 18 ** Check appropriate column below and cross out other columns The numbers in each column indicate the number of units of glulisine or regular insulin per dose. Supplemental” dose is to be added to the scheduled dose of glulisine or regular insulin.

2. Basal Plus Regimen 2.A. Insulin Orders  Discontinue oral antidiabetic drugs and non-insulin injected antidiabetic medication on admission.  Starting glargine insulin total daily dose (TDD): 0.25 units per kg of body weight.  Reduce insulin TDD to 0.15 units per kg of body weight in patients ≥ 70 years of age and/or with a serum creatinine ≥ 2.0 mg/dL.  Give insulin glargine once daily, at the same time of the day. 2.B. Supplemental insulin  Give supplemental insulin glulisine following the “sliding scale” protocol (1E) for blood glucose > 140 mg/dl.  If a patient is able and expected to eat all, give supplemental glulisine insulin before each meal and at bedtime following the “usual” column.  If a patient is not able to eat, give supplemental glulisine insulin every 6 hours (6-12-6-12) following the “sensitive” column. 2.C. Insulin adjustment If the fasting and predinner BG is between 100 - 140 mg/dl in the absence of hypoglycemia the previous day: no change If the fasting and predinner BG is between 140 - 180 mg/dl in the absence of hypoglycemia the previous day: increase glargine TDD by 10% every day If the fasting and predinner BG is >180 mg/dl in the absence of hypoglycemia the previous day: increase glargine TDD dose by 20% every day If the fasting and predinner BG is between 70 - 99 mg/dl in the absence of hypoglycemia: decrease glargine TDD dose by 10% every day If a patient develops hypoglycemia (BG <70 mg/dL), the glargine TDD should be decreased by 20%. 2.D. Blood glucose monitoring. Blood glucose will be measured before each meal and at bedtime (or every 6 hours if a patient is not eating) using a glucose meter 2.E. Supplemental Insulin Scale Blood Glucose (mg/dL) Insulin Sensitive Usual Insulin Resistant 141-180 2 4 6 181-220 4 6 8 221-260 6 8 10 261-300 8 10 12 301-350 10 12 14 351-400 12 14 16 > 400 14 16 18 ** Check appropriate column below and cross out other columns The numbers in each column indicate the number of units of glulisine insulin per dose. Supplemental” dose is to be added to the scheduled dose of glulisine or regular insulin.

3. Regular Insulin By Sliding Scale 3.A. Insulin Orders  Discontinue oral antidiabetic drugs and non-insulin injected antidiabetic medication on admission.  Patients who are not eating or with intermittent nutritional intake  If a patient is not able to eat or if the nutritional intake is uncertain/intermittent, regular insulin will be administered every 6 hours following the “insulin sensitive” recommended dose of the sliding scale protocol (2D).  Patients who are eating  If a patient is able and expected to eat most of his/her meals, regular insulin will be administered before each meal and at bedtime following the “usual” recommended dose of the sliding scale protocol. 3.B. Insulin adjustment  If the fasting and pre-meal plasma glucose are persistently >140 mg/dL in the absence of hypoglycemia, the insulin scale of regular insulin could be increased from sensitive to usual, or from the usual to resistant scale.  If a patient develops hypoglycemia (blood glucose <60mg/dL), the sliding scale of regular insulin should be decreased from insulin resistant to usual scale or from the usual to sensitive scale. 3.C. Blood glucose monitoring. Blood glucose will be measured before each meal and at bedtime (or every 6 hours if a patient is not eating) using a glucose meter. 3.D. Supplemental Insulin Scale Blood Glucose (mg/dL) Insulin Sensitive Usual Insulin Resistant 141-180 2 4 6 181-220 4 6 8 221-260 6 8 10 261-300 8 10 12 301-350 10 12 14 351-400 12 14 16 > 400 14 16 18 ** Check appropriate column below and cross out other columns The numbers in each column indicate the number of units of glulisine insulin per dose. Supplemental” dose is to be added to the scheduled dose of glulisine or regular insulin.

Figure 1 Differences in glycemic control in medical and surgical patients with T2D treated with basal bolus (C) and basal plus (○) regimens. A:Mean daily BG levels. B:Mean BG levels before meals and bedtime.

RESULTS Improvement in mean daily blood glucose (BG) after the first day of therapy was similar between basal bolus and basal plus groups (P = 0.16), and both regimens resulted in a lower mean daily BG than did SSI (P = 0.04). In addition, treatment with basal bolus and basal plus regimens resulted in less treatment failure (defined as ＞2 consecutive BG＞240 mg/dL or a mean daily BG＞240 mg/dL) than did treatment with SSI (0 vs. 2 vs. 19%, respectively; P＜0.001). A BG ＜ 70 mg/dL occurred in 16% of patients in the basal bolus group, 13% in the basal plus group, and 3% in the SSI group (P = 0.02). There was no difference among the groups in the frequency of severe hypoglycemia (＜ 40 mg/dL; P = 0.76).

CONCLUSIONS The use of a basal plus regimen with glargine once daily plus corrective doses with glulisine insulin before meals resulted in glycemic control similar to a standard basal bolus regimen. The basal plus approach is an effective alternative to the use of a basal bolus regimen in general medical and surgical patients with T2D.

Message 病院内での血糖管理について,グラルギンが入っていれば、食事の前の血糖で補正するのでOK? （SSI［血糖スライディングスケール］は話にならないが…というか血糖が下がっていない。／下げるほどやると低血糖になるので倫理委員会を通らないということかもしれないが。また、glargineベースというのもどうかと感じる。また眠前血糖測定でインスリンを打つのか？？？） 今回の補正量計算の表は現実とは異なる。また低血糖についても今後評価が必要であろう。日本人ではこうならないと感じる。また心臓手術後やステロイド使用者では？そもそも除外している。 また食直後打ちは有力で、glulisineであれば米国やヨーロッパでは薬剤の説明にあるはず。 サノフィ社と精度の悪いPOC器の会社が利益を得そう!?