Pharmacotherapy

Pharmacotherapy for Clinical Pharmacists in Hospital Settings

Overview

Hyperglycemia in hospitalized patients represents a unique challenge that requires nuanced pharmacotherapeutic strategies. Clinical pharmacists play a pivotal role in tailoring these strategies, emphasizing evidence-based approaches that optimize patient outcomes while minimizing adverse events. This in-depth section will delve into the various pharmacological agents used, their mechanisms of action, dosing protocols, monitoring parameters, and key clinical considerations.

Glycemic Targets

The optimal glycemic target in hospitalized patients has been extensively studied but remains controversial. Historically, intensive insulin therapy targeting near-normal blood glucose levels was advocated based on findings like those in the landmark 2001 trial by Van den Berghe et al. which found that tight glycemic control (80-110 mg/dL) reduced mortality in critically ill surgical ICU patients . However, subsequent studies yielded inconsistent results, with some showing no mortality benefit and increased hypoglycemia with intensive insulin therapy.

Current guidelines from the American Diabetes Association (ADA), American Association of Clinical Endocrinologists (AACE), and Society of Critical Care Medicine (SCCM) recommend a target glucose range of 140-180 mg/dL for most critically ill patients. Less stringent targets of 140-200 mg/dL may be appropriate in certain patients, such as those with severe comorbidities, limited life expectancy, known hypoglycemia unawareness, or high risk for hypoglycemia. Ultimately, glycemic targets should be individualized based on a patient’s clinical status.

Inpatient glycemic targets for non-critically ill adult patients     

• Inpatient hyperglycemia = BG >140 mg/dL
• Inpatient hypoglycemia = BG <54 mg/dL
  • Severe hypoglycemia = severe cognitive impairment
  • BG ≤70 mg/dL = alert value
• NICE-SUGAR Study: ↑severe hypoglycemia (BG<40) with tightly controlled BG
• Target BG 140-180 mg/dL
• Persistent BG ≥180 = Initiate insulin therapy
• A1c for all diabetics or hyperglycemic patients (if not performed within 3 months)

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Initial Management: Insulin Therapy

• Insulin: The mainstay of treatment, especially for critically ill patients. Types include:
  • Rapid-acting: Aspart, Lispro
  • Short-acting: Regular insulin
  • Intermediate-acting: NPH
  • Long-acting: Glargine, Detemir

	Prandial		Basal
Action	Rapid	Short	Intermediate	Long
Insulin	Insulin lispro (HumaLOG)	Regular/HRI (HumuLIN R)	NPH (HumuLIN N)	Insulin glargine (Lantus)
Onset	5 to 15 min	30 to 60 min	2 to 4 hr	2 to 4 hr
Peak	30 to 90 min	2 to 3 hr	4 to 10 hr	Peakless
Duration	3 to 5 hr	5 to 8 hr	10 to 16 hr	20 to 24 hr
Pros	Fast onset (can be given 15 mins prior to a meal) Short duration of action Lower hypoglycemia risk (vs RHI)	Can be mixed in the same syringe with NPH	Inexpensive Can be mixed in the same syringe with RHI Niche use in patients with gastroparesis or slowed gastric emptying Niche use in steroid-induced hyperglycemia	Peakless (mimics endogenous basal insulin secretion) Long (24 hr) duration (once daily dosing) Lower risk for hypoglycemia (vs NPH)
Cons		Slow to peak (must be administered at least 30 mins prior to meal) Long duration of action (insulin levels remain elevated after meals) Increased risk for hypoglycemia (vs Rapid)	Distinct peak (not a good substitute for endogenous basal insulin secretion) Requires multiple daily injections	Expensive (generics not yet commercially available)

	HRI/NPH	Analogues
Pros	Inexpensive Fewer injections (can be combined in the same syringe)	Closely mimics endogenous insulin secretion Better reproducibility and consistency between patients Reduced risk for hypoglycemia
Cons	Does not closely approximate physiologic insulin secretion Limited control of FPG and PPG Associated with high risk for hypoglycemia	Requires more frequent injections (generally 4x/day)

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Types of Insulin

Rapid-acting Insulins

• Aspart (NovoLog), Lispro (Humalog)
  • Mechanism: Mimics endogenous insulin with a rapid onset and shorter duration.
  • Clinical Application: Ideal for mealtime coverage and high glucose levels.
  • Dosing: Typically 0.1-0.2 units/kg, adjusted based on frequent blood glucose monitoring.
  • Monitoring: Blood glucose every 1-2 hours initially.

Short-acting Insulin

• Regular Insulin (Humulin R, Novolin R)
  • Mechanism: Slightly slower onset and longer duration compared to rapid-acting insulins.
  • Clinical Application: Useful for continuous intravenous (IV) infusion, particularly in ICU settings.
  • Dosing: IV infusion generally starts at 0.1 units/kg/hr or bolus at 0.1 unit/kg
  • Monitoring: Blood glucose and potassium levels every 1-2 hours initially.

Intermediate-acting Insulin

• NPH (Humulin N, Novolin N)
  • Mechanism: Has a more prolonged action due to its protein formulation.
  • Clinical Application: Used for basal coverage in some non-critical settings.
  • Dosing: Usually 0.2 units/kg as a single daily dose or divided into two doses.
  • Monitoring: Blood glucose every 4-6 hours.

Long-acting Insulins

• Glargine (Lantus), Detemir (Levemir)
  • Mechanism: Provides consistent basal coverage with no pronounced peak.
  • Clinical Application: Generally reserved for stable, non-critical patients.
  • Dosing: 0.1-0.2 units/kg/day, generally as a single daily dose.
  • Monitoring: Blood glucose 2-4 times daily.

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Insulin Adjustment Protocols

Sliding Scale Insulin (SSI) in Depth

Overview

Sliding Scale Insulin is one of the oldest yet most commonly employed strategies for managing hyperglycemia in hospitalized patients. Despite newer protocols gaining favor, SSI remains a component of inpatient glycemic management, often in conjunction with other strategies like basal or nutritional insulin.

Mechanism

• Reactive Approach: SSI is a reactive strategy that adjusts insulin doses based on current blood glucose levels.
• Types of Insulin Used: Rapid-acting or short-acting insulins are typically used.

Clinical Application

• Advantages: Simple, easy to implement, and requires less frequent blood glucose monitoring compared to other regimens.
• Disadvantages: Reactive rather than proactive; lacks the ability to prevent spikes in blood glucose, and may result in wide glycemic fluctuations.

Sample SSI Protocol

Here is a sample protocol to illustrate the typical structure of an SSI scale:

• Blood Glucose < 70 mg/dL: Treat hypoglycemia according to hospital protocol.
• Blood Glucose 70-150 mg/dL: No additional insulin.
• Blood Glucose 151-200 mg/dL: Administer 1 units of rapid-acting insulin.
• Blood Glucose 201-250 mg/dL: Administer 2 units of rapid-acting insulin.
• Blood Glucose 251-300 mg/dL: Administer 3 units of rapid-acting insulin.
• Blood Glucose > 300 mg/dL: Administer 4 units of rapid-acting insulin and notify healthcare provider.

It’s worth noting that these are general guidelines; individual patient needs may vary widely and should be addressed on a case-by-case basis. The SSI protocol should be customized based on factors like renal function, age, and risk for hypoglycemia.

Monitoring and Adjustments

• Frequency of Blood Glucose Monitoring: Typically every 4-6 hours, but can be more frequent in unstable patients.
• Adjustments: SSI scales can be adjusted based on patterns observed in blood glucose levels. For instance, if a patient consistently has elevated morning blood glucose levels, the evening dose can be adjusted accordingly.

Clinical Pearls for Pharmacists

1. Combination Therapy: SSI is best used as part of a broader regimen that includes basal and nutritional insulin.
2. High-Risk Patients: Be cautious when using SSI in older adults, those with renal impairment, or those at high risk for hypoglycemia.
3. Documentation: Always document insulin administration times and corresponding blood glucose levels to aid in future adjustments.

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Basal-Bolus Insulin Regimen

• Mechanism: Mimics physiological insulin secretion.
• Clinical Application: Preferred method for most hospitalized patients, including the critically ill.
• Components: Basal insulin, nutritional insulin, and correctional (supplemental) insulin.
• Monitoring: Blood glucose before meals and at bedtime; may require more frequent monitoring in unstable patients.

Calculation for Insulin naïve: TDD of 0.3-0.6 units/kg (lower for leaner and/or poor renal function  and higher for obese and/or on glucocorticoids). Take 50% TDD provided as basal and 50% TTD as bolus insulin per meal (3 meals) 

• 0.3 units/kg: Underweight, older age, HD pt 
• 0.4 units/kg: Normal weight  
• 0.5 units/kg: Overweight 
• 0.6 units/kg: Obese, insulin resistant, pt on glucocorticoids 

Example:

For a 70 kg patient, the TDD of insulin would be calculated based on their weight and clinical factors as follows:

• If underweight, older age, or on hemodialysis:
  • Use 0.3 units/kg
  • TDD = 0.3 units/kg x 70 kg = 21 units
• If normal weight:
  • Use 0.4 units/kg
  • TDD = 0.4 units/kg x 70 kg = 28 units
• If overweight:
  • Use 0.5 units/kg
  • TDD = 0.5 units/kg x 70 kg = 35 units
• If obese, insulin resistant, or on glucocorticoids:
  • Use 0.6 units/kg
  • TDD = 0.6 units/kg x 70 kg = 42 units

Once the TDD is calculated, it can be divided into basal and bolus insulin doses:

• 50% of TDD as basal insulin
• 50% of TDD divided equally among 3 meals as bolus insulin

For example, for a 70 kg overweight patient with a TDD of 35 units:

• Basal dose = 50% of 35 units = 17 units
• Bolus dose = 50% of 35 units divided by 3 meals = ~6 units with each meal

So this patient would take 17 units of basal insulin daily and 6 units of bolus insulin with each meal. The doses can then be titrated based on blood glucose response.

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Transitioning Insulin Therapy

An important consideration is transitioning between different routes of insulin administration. When converting from intravenous to subcutaneous insulin, there should be an overlap period of 2-4 hours to prevent hyperglycemia. Subcutaneous basal insulin should be administered 1-2 hours before stopping the intravenous infusion. Rapid-acting insulin should be given shortly before the meal that coincides with the discontinuation of intravenous therapy.

The subcutaneous doses can be calculated based on the intravenous infusion rate. About 80% of the total daily intravenous dose can be used as the starting total daily subcutaneous dose (50% as basal, 50% as prandial/correctional). Close glucose monitoring is key during the transition period. The subcutaneous doses should subsequently be adjusted based on blood glucose trends.

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Non-Insulin Agents

The role of noninsulin antihyperglycemics is limited in the inpatient setting. Reasons include modest efficacy, slow onset, inability to provide prandial coverage, and adverse effects like hypoglycemia and volume depletion. However, certain lower-risk agents may be used cautiously in stable non-critically ill patients.

Metformin

• Mechanism: Reduces hepatic glucose production and improves peripheral insulin sensitivity.
• Clinical Application: Limited to non-critical patients with stable renal function.
• Dosing: 500-1000 mg twice daily, adjusted based on renal function.
• Monitoring: Serum creatinine, eGFR, blood glucose, and lactic acid levels.

Sulfonylureas (Glipizide, Glyburide)

• Mechanism: Stimulates pancreatic beta cells to secrete insulin.
• Clinical Application: Rarely used in the hospital setting due to the risk of hypoglycemia.
• Monitoring: Blood glucose and signs of hypoglycemia.

DPP-4 Inhibitors (Sitagliptin, Linagliptin)

• Mechanism: Increases incretin levels, inhibiting glucagon release.
• Clinical Application: May be used in non-critical settings.
• Dosing: Varies by drug and renal function.
• Monitoring: Blood glucose levels, renal function.

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Monitoring Glycemic Control

All inpatients with diabetes require regular glucose monitoring, with frequency determined by clinical status and insulin regimen. Critically ill patients on intravenous insulin infusions generally require hourly glucose checks. With subcutaneous regimens, glucose is typically checked before meals, at bedtime, and every 4-6 hours. More frequent monitoring is prudent during transitions between insulin regimens.

Point-of-care glucose meters should be validated for accuracy. Capillary blood glucose is typically used, but arterial or venous samples may be preferred in certain situations like shock or peripheral edema. Continuous glucose monitoring systems can provide helpful glycemic trend data in the hospital setting but usually do not replace traditional glucose meters.

For critially ill patients, a daily morning glycemic target is recommended since this has the strongest association with clinical outcomes . POC glucose, lab glucose, and any continuous glucose data should be reviewed each morning to assess results and determine if insulin regimen adjustments are indicated.

Beyond glucose monitoring, markers like A1C, electrolytes, renal function, and osmolarity should be trended to identify hypoglycemia and hyperglycemic complications.

Emerging Technologies: Continuous Glucose Monitoring (CGM)

Continuous Glucose Monitoring (CGM) has shown promise in inpatient settings, particularly in enhancing the detection of hypoglycemic events. These devices provide estimated glucose values at 5-15 minute intervals, giving a more comprehensive view of glycemic control compared to traditional point-of-care testing. However, it’s important to note that the use of CGM in the hospital has not yet been approved by regulatory agencies and remains investigational. Caution is advised in cases of acute physiological disturbances like hypoxemia, as they can affect CGM accuracy.

Clinical Pearls for Pharmacists

When reviewing insulin regimens, pharmacists should consider several key points:

• Assess indications – Could hyperglycemia be attributed to corticosteroids, TPN, etc. rather than a true elevation in baseline?
• Review prior diabetes therapy and preadmission A1C for context.
• Ensure appropriate transition between IV and subcutaneous insulin.
• Reinforce avoiding “stacking” of rapid-acting insulin doses.
• Consider the trajectory – is the patient clinically improving or worsening?
• Titrate insulin doses based on glucose patterns, not single readings.
• Remember prevention is ideal – target glucose 140-180 mg/dL.
• Individualize glycemic targets based on patient factors.
• Encourage basal-bolus regimens over sliding scale insulin alone.
• Promote coordination of meal timing and insulin dosing.
• Be vigilant for signs and symptoms of hypoglycemia.
• Provide diabetes education for nurses – insulin storage, administration, dilution, etc.
• During discharge planning, coordinate follow-up diabetes care.

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Conclusion

Inpatient hyperglycemia necessitates a nuanced approach to pharmacotherapy. The foundation is insulin, with the specific regimen tailored to the clinical scenario. Noninsulin agents have a limited role but may be used judiciously in stable patients. Clinical pharmacists promote safe, effective glycemic management through therapeutic monitoring, regimen review, nursing education, and care coordination. A patient-centered approach considers risks, benefits, trajectory during hospitalization, transitions of care, and individual preferences. Using evidence-based strategies and clinical judgment, pharmacists can optimize inpatient glycemic control and improve patient outcomes.