Introduction

Optimal nutrition in the hospital setting has been shown to improve outcomes in adult patients, and there is a growing body of evidence that the same is true for pediatric patients. Malnutrition refers to any disorder of nutritional status resulting from a deficiency or excess of nutrient intake, imbalance of essential nutrients, or impaired nutrient metabolism. Malnutrition occurs in up to half of hospitalized children in the United States, but varies considerably by age and disease state. An understanding of the fundamental nutritional requirements of pediatric patients is essential to providing optimal care for hospitalized children. Pediatric hospitalists should be experts in making objective nutritional assessments and managing frequently encountered nutritional problems. Pediatric hospitalists should lead, coordinate, or participate in multidisciplinary efforts to screen for malnutrition and improve the nutritional status of hospitalized pediatric patients.

Knowledge

Pediatric hospitalists should be able to:

• Describe the normal growth patterns for children at various ages and the potential effect of malnutrition on growth.

• List the anthropometric measurements commonly used to assess acute and chronic nutritional status.

• Describe the basic nutritional requirements for hospitalized pediatric patients, based on gestational age, chronologic age, weight, activity level, and other characteristics.

• Compare and contrast the composition of human milk versus commonly used commercial formulas, and explain why human milk is superior nutrition for infants.

• Describe the differences in composition of commonly used commercial formulas, as well as protein hydrosylate and other special formulas, and list the clinical indications for each type of formula.

• Compare and contrast the benefits and costs of blended foods versus commonly used enteral formulas as complete nutritional sources for children receiving gastric, duodenal, or jejunal tube feedings.

• List the indications for specific vitamin and mineral supplementation, including exclusive breastfeeding, chronic anti‐epileptic therapy, food allergies resulting in extreme dietary restrictions, and others.

• List the factors that place hospitalized pediatric patients at risk for poor nutrition.

• Compare and contrast marasmus and kwashiorkor.

• Define the term protein‐energy malnutrition.

• List the signs and symptoms of common vitamin and mineral deficiencies.

• List the indications and contraindications for both enteral and parenteral nutrition, and describe the complications associated with each type of supplemental nutrition.

• Discuss the monitoring needs for pediatric patients on chronic enteral or parenteral nutrition attending to electrolyte and mineral disturbances, growth, and other parameters.

• Describe the refeeding syndrome and list the risk factors associated with its development.

• Explain the importance of nutrition screening, as well as the indications for consultation with a nutritionist, gastroenterologist, or other subspecialist.

Skills

Pediatric hospitalists should be able to:

• Use anthropometric data to determine the presence, degree, and chronicity of malnutrition.

• Conduct a focused history and physical examination, attending to details that may indicate a particular nutrient, vitamin, or mineral deficiency.

• Conduct a directed laboratory evaluation to obtain information about nutritional status and vitamin or mineral deficiencies, as indicated.

• Calculate the basic caloric, protein, fat, and fluid requirements for hospitalized pediatric patients, for both daily needs and catch up growth.

• Provide lactation support to all mothers, especially those who are experiencing difficulty with initiating or maintaining breastfeeding or milk supply or those who have a complication from breastfeeding, including plugged ducts or mastitis.

• Choose an appropriate formula, delivery device, and method of administration when enteral nutrition is required.

• Initiate and advance parenteral nutrition using the appropriate initial composition of parenteral nutrition solution, delivery device, and method of administration when parenteral nutrition is required.

• Appropriately monitor laboratory values to ensure the efficacy of supplemental nutrition support and to screen for complications.

• Recognize and treat complications of both enteral and parenteral nutrition, such as metabolic derangements, infection, and delivery device malfunction.

• Recognize and treat the refeeding syndrome.

• Consult a nutritionist, gastroenterologist, or other subspecialists when indicated.

Attitudes

Pediatric hospitalists should be able to:

• Recognize the importance of screening for malnutrition and optimizing nutritional status for hospitalized pediatric patients.

• Communicate effectively with patients, the family/caregiver, and healthcare providers regarding findings and care plans.

• Collaborate with a nutritionist or subspecialists to devise and implement a nutrition care plan.

• Collaborate with the primary care provider and subspecialists to ensure coordinated, longitudinal care for children requiring specialized nutrition support.

• Arrange for an effective and safe transition of care from the inpatient to outpatient providers, preserving the multidisciplinary nature of the nutrition care team when appropriate.

Systems organization and Improvement

In order to improve efficiency and quality within their organizations, pediatric hospitalists should:

• Lead, coordinate, or participate in efforts to develop systems that support the initiation and maintenance of breastfeeding for infants

• Work with hospital administration, hospital staff, subspecialists, and other services/consultants to promote prompt nutritional screening for all hospitalized patients and multidisciplinary team care to address nutritional problems when indicated.

• Lead, coordinate or participate in the development and implementation of cost‐effective, evidence‐based care pathways to standardize the evaluation and management for hospitalized children with nutritional needs

Introduction

Optimal nutrition in the hospital setting has been shown to improve outcomes in adult patients, and there is a growing body of evidence that the same is true for pediatric patients. Malnutrition refers to any disorder of nutritional status resulting from a deficiency or excess of nutrient intake, imbalance of essential nutrients, or impaired nutrient metabolism. Malnutrition occurs in up to half of hospitalized children in the United States, but varies considerably by age and disease state. An understanding of the fundamental nutritional requirements of pediatric patients is essential to providing optimal care for hospitalized children. Pediatric hospitalists should be experts in making objective nutritional assessments and managing frequently encountered nutritional problems. Pediatric hospitalists should lead, coordinate, or participate in multidisciplinary efforts to screen for malnutrition and improve the nutritional status of hospitalized pediatric patients.

Knowledge

Pediatric hospitalists should be able to:

• Describe the normal growth patterns for children at various ages and the potential effect of malnutrition on growth.

• List the anthropometric measurements commonly used to assess acute and chronic nutritional status.

• Describe the basic nutritional requirements for hospitalized pediatric patients, based on gestational age, chronologic age, weight, activity level, and other characteristics.

• Compare and contrast the composition of human milk versus commonly used commercial formulas, and explain why human milk is superior nutrition for infants.

• Describe the differences in composition of commonly used commercial formulas, as well as protein hydrosylate and other special formulas, and list the clinical indications for each type of formula.

• Compare and contrast the benefits and costs of blended foods versus commonly used enteral formulas as complete nutritional sources for children receiving gastric, duodenal, or jejunal tube feedings.

• List the indications for specific vitamin and mineral supplementation, including exclusive breastfeeding, chronic anti‐epileptic therapy, food allergies resulting in extreme dietary restrictions, and others.

• List the factors that place hospitalized pediatric patients at risk for poor nutrition.

• Compare and contrast marasmus and kwashiorkor.

• Define the term protein‐energy malnutrition.

• List the signs and symptoms of common vitamin and mineral deficiencies.

• List the indications and contraindications for both enteral and parenteral nutrition, and describe the complications associated with each type of supplemental nutrition.

• Discuss the monitoring needs for pediatric patients on chronic enteral or parenteral nutrition attending to electrolyte and mineral disturbances, growth, and other parameters.

• Describe the refeeding syndrome and list the risk factors associated with its development.

• Explain the importance of nutrition screening, as well as the indications for consultation with a nutritionist, gastroenterologist, or other subspecialist.

Skills

Pediatric hospitalists should be able to:

• Use anthropometric data to determine the presence, degree, and chronicity of malnutrition.

• Conduct a focused history and physical examination, attending to details that may indicate a particular nutrient, vitamin, or mineral deficiency.

• Conduct a directed laboratory evaluation to obtain information about nutritional status and vitamin or mineral deficiencies, as indicated.

• Calculate the basic caloric, protein, fat, and fluid requirements for hospitalized pediatric patients, for both daily needs and catch up growth.

• Provide lactation support to all mothers, especially those who are experiencing difficulty with initiating or maintaining breastfeeding or milk supply or those who have a complication from breastfeeding, including plugged ducts or mastitis.

• Choose an appropriate formula, delivery device, and method of administration when enteral nutrition is required.

• Initiate and advance parenteral nutrition using the appropriate initial composition of parenteral nutrition solution, delivery device, and method of administration when parenteral nutrition is required.

• Appropriately monitor laboratory values to ensure the efficacy of supplemental nutrition support and to screen for complications.

• Recognize and treat complications of both enteral and parenteral nutrition, such as metabolic derangements, infection, and delivery device malfunction.

• Recognize and treat the refeeding syndrome.

• Consult a nutritionist, gastroenterologist, or other subspecialists when indicated.

Attitudes

Pediatric hospitalists should be able to:

• Recognize the importance of screening for malnutrition and optimizing nutritional status for hospitalized pediatric patients.

• Communicate effectively with patients, the family/caregiver, and healthcare providers regarding findings and care plans.

• Collaborate with a nutritionist or subspecialists to devise and implement a nutrition care plan.

• Collaborate with the primary care provider and subspecialists to ensure coordinated, longitudinal care for children requiring specialized nutrition support.

• Arrange for an effective and safe transition of care from the inpatient to outpatient providers, preserving the multidisciplinary nature of the nutrition care team when appropriate.

Systems organization and Improvement

In order to improve efficiency and quality within their organizations, pediatric hospitalists should:

• Lead, coordinate, or participate in efforts to develop systems that support the initiation and maintenance of breastfeeding for infants

• Work with hospital administration, hospital staff, subspecialists, and other services/consultants to promote prompt nutritional screening for all hospitalized patients and multidisciplinary team care to address nutritional problems when indicated.

• Lead, coordinate or participate in the development and implementation of cost‐effective, evidence‐based care pathways to standardize the evaluation and management for hospitalized children with nutritional needs

Introduction

Optimal nutrition in the hospital setting has been shown to improve outcomes in adult patients, and there is a growing body of evidence that the same is true for pediatric patients. Malnutrition refers to any disorder of nutritional status resulting from a deficiency or excess of nutrient intake, imbalance of essential nutrients, or impaired nutrient metabolism. Malnutrition occurs in up to half of hospitalized children in the United States, but varies considerably by age and disease state. An understanding of the fundamental nutritional requirements of pediatric patients is essential to providing optimal care for hospitalized children. Pediatric hospitalists should be experts in making objective nutritional assessments and managing frequently encountered nutritional problems. Pediatric hospitalists should lead, coordinate, or participate in multidisciplinary efforts to screen for malnutrition and improve the nutritional status of hospitalized pediatric patients.

Knowledge

Pediatric hospitalists should be able to:

• Describe the normal growth patterns for children at various ages and the potential effect of malnutrition on growth.

• List the anthropometric measurements commonly used to assess acute and chronic nutritional status.

• Describe the basic nutritional requirements for hospitalized pediatric patients, based on gestational age, chronologic age, weight, activity level, and other characteristics.

• Compare and contrast the composition of human milk versus commonly used commercial formulas, and explain why human milk is superior nutrition for infants.

• Describe the differences in composition of commonly used commercial formulas, as well as protein hydrosylate and other special formulas, and list the clinical indications for each type of formula.

• Compare and contrast the benefits and costs of blended foods versus commonly used enteral formulas as complete nutritional sources for children receiving gastric, duodenal, or jejunal tube feedings.

• List the indications for specific vitamin and mineral supplementation, including exclusive breastfeeding, chronic anti‐epileptic therapy, food allergies resulting in extreme dietary restrictions, and others.

• List the factors that place hospitalized pediatric patients at risk for poor nutrition.

• Compare and contrast marasmus and kwashiorkor.

• Define the term protein‐energy malnutrition.

• List the signs and symptoms of common vitamin and mineral deficiencies.

• List the indications and contraindications for both enteral and parenteral nutrition, and describe the complications associated with each type of supplemental nutrition.

• Discuss the monitoring needs for pediatric patients on chronic enteral or parenteral nutrition attending to electrolyte and mineral disturbances, growth, and other parameters.

• Describe the refeeding syndrome and list the risk factors associated with its development.

• Explain the importance of nutrition screening, as well as the indications for consultation with a nutritionist, gastroenterologist, or other subspecialist.

Skills

Pediatric hospitalists should be able to:

• Use anthropometric data to determine the presence, degree, and chronicity of malnutrition.

• Conduct a focused history and physical examination, attending to details that may indicate a particular nutrient, vitamin, or mineral deficiency.

• Conduct a directed laboratory evaluation to obtain information about nutritional status and vitamin or mineral deficiencies, as indicated.

• Calculate the basic caloric, protein, fat, and fluid requirements for hospitalized pediatric patients, for both daily needs and catch up growth.

• Provide lactation support to all mothers, especially those who are experiencing difficulty with initiating or maintaining breastfeeding or milk supply or those who have a complication from breastfeeding, including plugged ducts or mastitis.

• Choose an appropriate formula, delivery device, and method of administration when enteral nutrition is required.

• Initiate and advance parenteral nutrition using the appropriate initial composition of parenteral nutrition solution, delivery device, and method of administration when parenteral nutrition is required.

• Appropriately monitor laboratory values to ensure the efficacy of supplemental nutrition support and to screen for complications.

• Recognize and treat complications of both enteral and parenteral nutrition, such as metabolic derangements, infection, and delivery device malfunction.

• Recognize and treat the refeeding syndrome.

• Consult a nutritionist, gastroenterologist, or other subspecialists when indicated.

Attitudes

Pediatric hospitalists should be able to:

• Recognize the importance of screening for malnutrition and optimizing nutritional status for hospitalized pediatric patients.

• Communicate effectively with patients, the family/caregiver, and healthcare providers regarding findings and care plans.

• Collaborate with a nutritionist or subspecialists to devise and implement a nutrition care plan.

• Collaborate with the primary care provider and subspecialists to ensure coordinated, longitudinal care for children requiring specialized nutrition support.

• Arrange for an effective and safe transition of care from the inpatient to outpatient providers, preserving the multidisciplinary nature of the nutrition care team when appropriate.

Systems organization and Improvement

In order to improve efficiency and quality within their organizations, pediatric hospitalists should:

• Lead, coordinate, or participate in efforts to develop systems that support the initiation and maintenance of breastfeeding for infants

• Work with hospital administration, hospital staff, subspecialists, and other services/consultants to promote prompt nutritional screening for all hospitalized patients and multidisciplinary team care to address nutritional problems when indicated.

• Lead, coordinate or participate in the development and implementation of cost‐effective, evidence‐based care pathways to standardize the evaluation and management for hospitalized children with nutritional needs

Introduction

Many infants and children are hospitalized in the United States each year for fluid and electrolyte disorders. Dehydration from gastroenteritis alone accounts for more than 200,000 pediatric hospitalizations each year. An understanding of pediatric fluid therapy is one of the most important advances of pediatric medicine and a cornerstone of current inpatient pediatric practice. Although the majority of previously healthy hospitalized children can compensate for errors in calculations of fluid therapy, mistakes, even in healthy children admitted for minor illnesses, can have devastating outcomes. Patients with underlying disease processes are at even greater risk for adverse outcomes if fluids and electrolytes are not meticulously managed. Pediatric hospitalists should be experts at managing frequently encountered fluid and electrolyte abnormalities.

Knowledge

Pediatric hospitalists should be able to:

• Discuss the physiology of fluid and electrolyte homeostasis and the changes that occur with growth and development.

• Discuss how maintenance fluid calculations are based upon water and electrolyte homeostasis using various methods such as the body surface area or Holliday Segar methods. Describe the methods used for calculation of excessive fluid losses due to causes such as diarrhea, increased ostomy output, burns, and vomiting; identify the best fluid replacement type for each.

• Describe common errors in clinical estimations of dehydration and fluid and electrolyte requirements.

• Explain the rationale, indications and contraindications for oral rehydration, including the correct glucose and electrolyte composition and technique for administration.

• Discuss the benefits of and barriers to use of nasogastric tubes for administering enteral fluids.

• Discuss the options and indications for different methods of parenteral fluid administration, including intravenous, intraosseous, and subcutaneous.

• Review the indications for administering a parenteral fluid bolus for resuscitation and explain the rationale for the use of isotonic fluids for rehydration.

• Discuss the benefits and risks of repeated lab testing and intravenous access placement, including cost, pain, effect on clinical management, family/caregiver perceptions, staff time, and others.

• Compare and contrast true hyponatremia with pseudohyponatremia and give examples of conditions in which these exist.

• List differential diagnoses for hyponatremia and hypernatremia.

• Summarize the management of hypo‐ and hypernatremia, attending to duration of corrective therapy and potential complications during correction.

• Distinguish between hyperkalemia and pseudohyperkalemia and give examples of the conditions in which these exist.

• List differential diagnoses for hypokalemia and hyperkalemia.

• Distinguish hypocalcemia from pseudohypocalcemia and give examples of the conditions in which these exist.

• Discuss the interaction of fluid and electrolytes with acid/base balance.

• Describe common acid/base disturbances that accompany the most frequently encountered causes of fluid deficit and give examples of exacerbating issues such as underlying co‐morbidity and use of over‐the‐counter medications.

Skills

Pediatric hospitalists should be able to:

• Accurately calculate maintenance fluid and electrolyte requirements for hospitalized infants and children.

• Promptly adjust maintenance fluids for increased insensible losses and ongoing fluid and electrolyte needs.

• Estimate the degree of dehydration for children of various ages based upon clinical symptoms and signs.

• Recognize common presenting signs and symptoms in infants and children that are associated with an excess or deficit of each common electrolyte and glucose.

• Correctly estimate osmolar disturbance by interpreting electrolyte, glucose and blood urea nitrogen results.

• Calculate and administer an isotonic fluid bolus correctly when indicated.

• Obtain intravenous or intraosseous access in moderate to severely dehydrated patients.

• Assess the success of fluid resuscitation by interpreting clinical change and laboratory values.

• Calculate and administer maintenance and deficit fluid replacement for isotonic, hypertonic, and hypotonic dehydration.

• Interpret urine and serum electrolytes and osmolality, as well as fluid status (hypo, hyper or isovolemic), to determine the etiology for hyponatremia or hypernatremia.

• Correct hyponatremia using appropriate replacement or restriction of fluids, sodium chloride, and medications depending upon the diagnosis.

• Correct hypernatremia using an appropriate electrolyte composition and rate of fluid replacement, as well as medications depending upon the diagnosis.

• Correct hypoglycemia using an appropriate replacement solution.

• Interpret EKG findings in the context of specific electrolyte abnormalities.

• Safely prescribe electrolyte replacement therapy and institute proper monitoring for arrhythmias.

• Correct symptomatic hyperkalemia using a combination of therapies to stabilize cardiac conduction, redistribute potassium to the intracellular space and remove it from the body.

Attitudes

Pediatric hospitalists should be able to:

• Consult pediatric subspecialists appropriately to expedite the diagnosis and management of serious electrolyte disorders.

• Recognize the benefits of oral rehydration and advocate for its use when indicated and clinically appropriate.

• Coordinate subspecialty and primary care follow up for patients with persistent disturbances at discharge as appropriate.

• Consider cost‐effectiveness, pain, and patient safety when creating plans for the treatment of fluid deficits.

Systems Organization and Improvement

In order to improve efficiency and quality within their organizations, pediatric hospitalists should:

• Lead, coordinate or participate in plans to develop institutional policies to safely monitor and administer fluids and electrolytes.

• Work collaboratively with others such as surgeons, intensivists, and advanced practice nurses to establish venous access when needed.

• Lead, coordinate or participate in developing guidelines for the treatment of fluid and electrolyte abnormalities in the hospital and community.

Introduction

Many infants and children are hospitalized in the United States each year for fluid and electrolyte disorders. Dehydration from gastroenteritis alone accounts for more than 200,000 pediatric hospitalizations each year. An understanding of pediatric fluid therapy is one of the most important advances of pediatric medicine and a cornerstone of current inpatient pediatric practice. Although the majority of previously healthy hospitalized children can compensate for errors in calculations of fluid therapy, mistakes, even in healthy children admitted for minor illnesses, can have devastating outcomes. Patients with underlying disease processes are at even greater risk for adverse outcomes if fluids and electrolytes are not meticulously managed. Pediatric hospitalists should be experts at managing frequently encountered fluid and electrolyte abnormalities.

Knowledge

Pediatric hospitalists should be able to:

• Discuss the physiology of fluid and electrolyte homeostasis and the changes that occur with growth and development.

• Discuss how maintenance fluid calculations are based upon water and electrolyte homeostasis using various methods such as the body surface area or Holliday Segar methods. Describe the methods used for calculation of excessive fluid losses due to causes such as diarrhea, increased ostomy output, burns, and vomiting; identify the best fluid replacement type for each.

• Describe common errors in clinical estimations of dehydration and fluid and electrolyte requirements.

• Explain the rationale, indications and contraindications for oral rehydration, including the correct glucose and electrolyte composition and technique for administration.

• Discuss the benefits of and barriers to use of nasogastric tubes for administering enteral fluids.

• Discuss the options and indications for different methods of parenteral fluid administration, including intravenous, intraosseous, and subcutaneous.

• Review the indications for administering a parenteral fluid bolus for resuscitation and explain the rationale for the use of isotonic fluids for rehydration.

• Discuss the benefits and risks of repeated lab testing and intravenous access placement, including cost, pain, effect on clinical management, family/caregiver perceptions, staff time, and others.

• Compare and contrast true hyponatremia with pseudohyponatremia and give examples of conditions in which these exist.

• List differential diagnoses for hyponatremia and hypernatremia.

• Summarize the management of hypo‐ and hypernatremia, attending to duration of corrective therapy and potential complications during correction.

• Distinguish between hyperkalemia and pseudohyperkalemia and give examples of the conditions in which these exist.

• List differential diagnoses for hypokalemia and hyperkalemia.

• Distinguish hypocalcemia from pseudohypocalcemia and give examples of the conditions in which these exist.

• Discuss the interaction of fluid and electrolytes with acid/base balance.

• Describe common acid/base disturbances that accompany the most frequently encountered causes of fluid deficit and give examples of exacerbating issues such as underlying co‐morbidity and use of over‐the‐counter medications.

Skills

Pediatric hospitalists should be able to:

• Accurately calculate maintenance fluid and electrolyte requirements for hospitalized infants and children.

• Promptly adjust maintenance fluids for increased insensible losses and ongoing fluid and electrolyte needs.

• Estimate the degree of dehydration for children of various ages based upon clinical symptoms and signs.

• Recognize common presenting signs and symptoms in infants and children that are associated with an excess or deficit of each common electrolyte and glucose.

• Correctly estimate osmolar disturbance by interpreting electrolyte, glucose and blood urea nitrogen results.

• Calculate and administer an isotonic fluid bolus correctly when indicated.

• Obtain intravenous or intraosseous access in moderate to severely dehydrated patients.

• Assess the success of fluid resuscitation by interpreting clinical change and laboratory values.

• Calculate and administer maintenance and deficit fluid replacement for isotonic, hypertonic, and hypotonic dehydration.

• Interpret urine and serum electrolytes and osmolality, as well as fluid status (hypo, hyper or isovolemic), to determine the etiology for hyponatremia or hypernatremia.

• Correct hyponatremia using appropriate replacement or restriction of fluids, sodium chloride, and medications depending upon the diagnosis.

• Correct hypernatremia using an appropriate electrolyte composition and rate of fluid replacement, as well as medications depending upon the diagnosis.

• Correct hypoglycemia using an appropriate replacement solution.

• Interpret EKG findings in the context of specific electrolyte abnormalities.

• Safely prescribe electrolyte replacement therapy and institute proper monitoring for arrhythmias.

• Correct symptomatic hyperkalemia using a combination of therapies to stabilize cardiac conduction, redistribute potassium to the intracellular space and remove it from the body.

Attitudes

Pediatric hospitalists should be able to:

• Consult pediatric subspecialists appropriately to expedite the diagnosis and management of serious electrolyte disorders.

• Recognize the benefits of oral rehydration and advocate for its use when indicated and clinically appropriate.

• Coordinate subspecialty and primary care follow up for patients with persistent disturbances at discharge as appropriate.

• Consider cost‐effectiveness, pain, and patient safety when creating plans for the treatment of fluid deficits.

Systems Organization and Improvement

In order to improve efficiency and quality within their organizations, pediatric hospitalists should:

• Lead, coordinate or participate in plans to develop institutional policies to safely monitor and administer fluids and electrolytes.

• Work collaboratively with others such as surgeons, intensivists, and advanced practice nurses to establish venous access when needed.

• Lead, coordinate or participate in developing guidelines for the treatment of fluid and electrolyte abnormalities in the hospital and community.

Introduction

Many infants and children are hospitalized in the United States each year for fluid and electrolyte disorders. Dehydration from gastroenteritis alone accounts for more than 200,000 pediatric hospitalizations each year. An understanding of pediatric fluid therapy is one of the most important advances of pediatric medicine and a cornerstone of current inpatient pediatric practice. Although the majority of previously healthy hospitalized children can compensate for errors in calculations of fluid therapy, mistakes, even in healthy children admitted for minor illnesses, can have devastating outcomes. Patients with underlying disease processes are at even greater risk for adverse outcomes if fluids and electrolytes are not meticulously managed. Pediatric hospitalists should be experts at managing frequently encountered fluid and electrolyte abnormalities.

Knowledge

Pediatric hospitalists should be able to:

• Discuss the physiology of fluid and electrolyte homeostasis and the changes that occur with growth and development.

• Discuss how maintenance fluid calculations are based upon water and electrolyte homeostasis using various methods such as the body surface area or Holliday Segar methods. Describe the methods used for calculation of excessive fluid losses due to causes such as diarrhea, increased ostomy output, burns, and vomiting; identify the best fluid replacement type for each.

• Describe common errors in clinical estimations of dehydration and fluid and electrolyte requirements.

• Explain the rationale, indications and contraindications for oral rehydration, including the correct glucose and electrolyte composition and technique for administration.

• Discuss the benefits of and barriers to use of nasogastric tubes for administering enteral fluids.

• Discuss the options and indications for different methods of parenteral fluid administration, including intravenous, intraosseous, and subcutaneous.

• Review the indications for administering a parenteral fluid bolus for resuscitation and explain the rationale for the use of isotonic fluids for rehydration.

• Discuss the benefits and risks of repeated lab testing and intravenous access placement, including cost, pain, effect on clinical management, family/caregiver perceptions, staff time, and others.

• Compare and contrast true hyponatremia with pseudohyponatremia and give examples of conditions in which these exist.

• List differential diagnoses for hyponatremia and hypernatremia.

• Summarize the management of hypo‐ and hypernatremia, attending to duration of corrective therapy and potential complications during correction.

• Distinguish between hyperkalemia and pseudohyperkalemia and give examples of the conditions in which these exist.

• List differential diagnoses for hypokalemia and hyperkalemia.

• Distinguish hypocalcemia from pseudohypocalcemia and give examples of the conditions in which these exist.

• Discuss the interaction of fluid and electrolytes with acid/base balance.

• Describe common acid/base disturbances that accompany the most frequently encountered causes of fluid deficit and give examples of exacerbating issues such as underlying co‐morbidity and use of over‐the‐counter medications.

Skills

Pediatric hospitalists should be able to:

• Accurately calculate maintenance fluid and electrolyte requirements for hospitalized infants and children.

• Promptly adjust maintenance fluids for increased insensible losses and ongoing fluid and electrolyte needs.

• Estimate the degree of dehydration for children of various ages based upon clinical symptoms and signs.

• Recognize common presenting signs and symptoms in infants and children that are associated with an excess or deficit of each common electrolyte and glucose.

• Correctly estimate osmolar disturbance by interpreting electrolyte, glucose and blood urea nitrogen results.

• Calculate and administer an isotonic fluid bolus correctly when indicated.

• Obtain intravenous or intraosseous access in moderate to severely dehydrated patients.

• Assess the success of fluid resuscitation by interpreting clinical change and laboratory values.

• Calculate and administer maintenance and deficit fluid replacement for isotonic, hypertonic, and hypotonic dehydration.

• Interpret urine and serum electrolytes and osmolality, as well as fluid status (hypo, hyper or isovolemic), to determine the etiology for hyponatremia or hypernatremia.

• Correct hyponatremia using appropriate replacement or restriction of fluids, sodium chloride, and medications depending upon the diagnosis.

• Correct hypernatremia using an appropriate electrolyte composition and rate of fluid replacement, as well as medications depending upon the diagnosis.

• Correct hypoglycemia using an appropriate replacement solution.

• Interpret EKG findings in the context of specific electrolyte abnormalities.

• Safely prescribe electrolyte replacement therapy and institute proper monitoring for arrhythmias.

• Correct symptomatic hyperkalemia using a combination of therapies to stabilize cardiac conduction, redistribute potassium to the intracellular space and remove it from the body.

Attitudes

Pediatric hospitalists should be able to:

• Consult pediatric subspecialists appropriately to expedite the diagnosis and management of serious electrolyte disorders.

• Recognize the benefits of oral rehydration and advocate for its use when indicated and clinically appropriate.

• Coordinate subspecialty and primary care follow up for patients with persistent disturbances at discharge as appropriate.

• Consider cost‐effectiveness, pain, and patient safety when creating plans for the treatment of fluid deficits.

Systems Organization and Improvement

In order to improve efficiency and quality within their organizations, pediatric hospitalists should:

• Lead, coordinate or participate in plans to develop institutional policies to safely monitor and administer fluids and electrolytes.

• Work collaboratively with others such as surgeons, intensivists, and advanced practice nurses to establish venous access when needed.

• Lead, coordinate or participate in developing guidelines for the treatment of fluid and electrolyte abnormalities in the hospital and community.

Increasing evidence suggests that in hospitalized adult patients with and without diabetes, hyperglycemia is associated with increased risk of complications, prolonged length of hospitalization, and death.15 Past studies have shown that intensive glucose control in the intensive care unit (ICU) with continuous insulin infusion (CII) improves clinical outcomes by reducing the risk of multiorgan failure, systemic infection, and mortality. Effective management of hyperglycemia, an independent marker of poor outcome,1, 3, 6 is also associated with a decreased length of ICU and hospital stay79 and decreased total hospitalization cost.10 Based on several observational and interventional studies, improved control of blood glucose (BG) has been recommended for most adult patients with critical illness.2, 6, 11

Detrimental effects of hyperglycemia on outcome are not limited to patients in the ICU setting and CII has increasingly been used in non‐ICU settings. In such patients, the presence of hyperglycemia has been associated with prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 6 In general medicine and surgery services, however, hyperglycemia is frequently overlooked and inadequately addressed. Numerous reports have shown that sliding scale regular insulin (SSRI) continues to be the most common insulin prescribed regimen in the non‐ICU setting.12 This regimen is challenged by limited and variable efficacy and continued concern for hypoglycemia13; thus, a more structured, target‐driven protocol such as scheduled SC insulin or a CII protocol could facilitate glycemic control in the non‐ICU setting. Recently, we reported that a scheduled regimen using basal‐bolus insulin subcutaneously was safe, effective, and superior to SSRI in controlling BG levels in hospitalized subjects with type 2 diabetes. As in many institutions in the United States, we have used CII protocols as an alternative to subcutaneous (SC) insulin for the management of persistent hyperglycemia in non‐ICU areas during the past 10 years, particularly during the postoperative period, transplant recipients, or patients transferred from the ICU. There is, however, no clinical evidence regarding the safety, efficacy, or outcomes with the use of CII in the non‐ICU setting. Accordingly, we analyzed our experience on the efficacy and safety of CII in the management of hyperglycemia in general medicine and surgical services.

Research Design and Methods

This retrospective chart analysis was conducted in adult patients >18 years of age who were consecutively admitted to the general medical and surgical wards between July 1, 2004 and June 30, 2005 at Emory University Hospital, a 579‐bed tertiary care facility staffed exclusively by Emory University School of Medicine faculty members and residents. The CII protocol, employing regular insulin (Novolin‐R Novo Nordisk Pharmaceuticals, Princeton, NJ) with a very short half‐life, in this study is a dynamic protocol14 that has been available at all nursing stations at Emory Hospital for the past decade (Table 1). The insulin rate is calculated using the formula (BG 60) (multiplier) = units of insulin per hour. The multiplier is a value used to denote the degree of insulin sensitivity based on glucose pattern and response to insulin. The multiplier typically starts at a value of 0.02 and is adjusted by the nurse as needed to achieve target BG levels based on bedside capillary glucose measurements. Blood glucose levels were checked every 1 to 2 hours by the nursing staff (nurse:patient ratio = 1:5) according to the protocol.

Of 1404 patients treated with CII during the hospital stay, 1191 patients received CII in the ICU and 213 patients received CII in non‐ICU areas. The final analysis included a total of 200 non‐ICU patient records after excluding 13 patients with diabetic ketoacidosis, incomplete documentation of glycemic records, or with duration of CII for less than 3 hours. Data collected included demographics, medical history, admission diagnoses, inpatient medications, inpatient laboratory values, bedside BG measurements, insulin doses used, nutrition status during CII, length of stay, disposition at discharge, and mortality rate. Nutrition status was defined in 3 ways: (1) nil per os or nothing by mouth (NPO); (2) oral nutrition (PO‐regular or PO‐liquid); and (3) tube feeds or total parenteral nutrition (TF/TPN). Data collection was limited to the first 10 days of CII use. This study was approved by the Institutional Review Board at Emory University.

The primary aim of the study was to determine the efficacy (mean daily BG levels) and safety (number of hyperglycemic [200 mg/dL] and hypoglycemic [60 mg/dL] events) during CII. We also determined the presence of potential risk factors associated with hypoglycemic and hyperglycemic events (age, body mass index [BMI], nutrition status, renal function, corticosteroid therapy, and use of enteral and parenteral nutrition) during CII.

Results

The cohort of 200 patients consisted of 54% males and 46% females, 53% Caucasian, 37% Black, with a mean age of 52 16 years (Table 2). Forty‐five percent of patients were admitted to the general medicine service and the remaining 55% were admitted to the surgical service for admission diagnoses that included cardiovascular disorders, trauma/surgery gastrointestinal disorders, renal disorders, and infection.

The primary indication for CII was poor glycemic control in 93.4% of patients. Forty‐one percent of subjects were receiving corticosteroids and 16% were continued on the insulin drip after transferring from an ICU. Nearly 90% of subjects had a history of diabetes and 11% were diagnosed with new‐onset diabetes. The mean admission BG concentration was 325 235 mg/dL (mean SD) and the mean A1c in 121 subjects in whom it was measured was 9.1 3%. The mean BG prior to the initiation of CII (323 184) was similar to the admission BG.

Of the 173 subjects that had well‐documented glycemic goals, the BG targeted during CII was 150 mg/dL in 85% of patients while the remaining subjects had a target BG goal that ranged from 70 to 250 mg/dL. The most commonly prescribed BG target goals were 80 to 110 mg/dL (41.6%), 80 to 120 mg/dL (13.9%), and 100 to 150 mg/dL (5.8%).

BG improved rapidly after the initiation of CII. BG on the first day of CII was 182 71 mg/dL; day 2: 142 42 mg/dL; day 3: 131 38 mg/dL; and day 4: 132 43 in response to receiving an average of 84 66 units/day, 71 61 units/day, 70 61 units/day, and 64 29 units/day, respectively (Table 3). Irrespective of the target BG goal, 67% of patients reached BG levels of 150 mg/dL by 48 hours of CII initiation. The duration of CII ranged between 4 and 240 hours, with an average of 41.6 hours and a median of 28 hours. The average insulin infusion rate during CII was 4.29 2.99 units/hour and the mean amount of insulin required to attain glycemic goals was 1.96 1.88 units/kg/day.

During CII, 48% and 35% of patients had at least 1 episode of hyperglycemia (BG >200 mg/dL) on the second and third day of CII, respectively. Hypoglycemia (BG <60 mg/dL) was noted at least once in 22% of the cohort (day 1: 11%; day 2: 16%; and day 3: 14%); however, severe hypoglycemia (BG <40 mg/dL) only occurred in 5% of subjects. During the CII, 37% of patients experienced a BG <70 mg/dL. When BG targets were stratified (<120 mg/dL vs. 120‐180 mg/dL vs. >180 mg/dL), we found no significant association between the target BG goal and the frequency of hypoglycemic or hyperglycemic events during CII. None of the episodes of hypoglycemia were associated with significant or permanent complications.

The analysis of collected variables for influence on glycemic control (ie, BMI, age, corticosteroid use, renal function, and nutrition status) revealed that subjects with a creatinine level >1.5 mg/dL may have an increased risk of hyperglycemia (BG >200 mg/dL) (P = 0.047) but not hypoglycemia. The analysis also found that younger patients (51 16 years) were more likely to have episodes of hyperglycemia than older patients (57 13 years) (P = 0.027). Hospital length of stay and mortality rate (3%) were not associated with the rate of hyperglycemic or hypoglycemic events.

Eighty‐two percent of patients received nutrition support at some point while on the CII: 48% PO‐regular diet; 14% PO‐liquid diet; and 20% TF/TPN. Due to the titration of nutrition from NPO at CII initiation to PO, NPO status was analyzed in a time‐dependent fashion. Thus, among patients on CII on day 1, day 2, day 3, day 4, and days 510; 34.0%, 26.3%, 11.3%, 12.5%, and 10.5%, respectively, were NPO.

As compared to subjects maintained NPO, subjects that received oral nutrition while on CII had an increased rate of hyperglycemic events (BG >200 mg/dL: 86% vs. 76%, P = 0.19; >300 mg/dL: 57% vs. 53%, P = 0.69; >400 mg/dL: 32% vs. 21%, P = 0.22) and a decreased rate of hypoglycemic events (BG <70 mg/dL: 33% vs. 41%, P = 0.39; BG <60 mg/dL: 20% vs. 26%, P = 0.49; and BG <40 mg/dL: 4% vs. 6%, P = 0.65). The multivariate regression analyses, however, which considered age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests, showed that nutrition status during CII was associated with increased frequency of hyperglycemic (P = 0.042) and hypoglycemic events (P = 0.086). As compared to NPO, oral intake (PO‐regular or PO‐liquid) was associated with a significantly increased frequency of hyperglycemic (P = 0.012) and hypoglycemic events (P = 0.035). Patients treated with TPN had lower BG values than those not on TPN. Although we observed no increased number of hypoglycemic events, TPN‐treated subjects had higher mortality than non‐TPN treated subjects (P < 0.001).

Discussion

Our study aimed to determine the safety and efficacy of CII in non‐critically‐ill patients with persistent hyperglycemia in general medicine and surgical services. We observed that the use of CII was effective in controlling hyperglycemia, with two‐thirds of patients achieving their target BG 150 mg/dL by 48 hours of insulin infusion. The rate of hypoglycemic events with the use of CII in non‐ICU patients was similar to that reported in recent ICU trials with intensive glycemic control7, 8, 15, 16 and is comparable to that reported in studies using SC insulin therapy in non‐ICU settings.17, 18 The number of hypoglycemic and hyperglycemic events was significantly higher in patients allowed to eat compared to those patients kept NPO during CII. There is substantial observational evidence linking hyperglycemia in hospitalized patients (with and without diabetes) to poor outcomes. There is ongoing debate, however, about the optimal level of BG in hospitalized patients. Early cohort studies as well as randomized controlled trials (RCTs) suggest that intensive treatment of hyperglycemia reduces length of hospital and ICU stay, multiorgan failure and systemic infections, and mortality.7, 9 These positive reports led the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) to recommend tight glycemic control (target of 80‐110 mg/dL) in critical care units. Recent multicenter controlled trials, however, have not been able to reproduce these results and in fact, have reported an increased risk of severe hypoglycemia and mortality in ICU patients in association with tight glycemic control.15, 16, 19 New glycemic targets call for more reasonable, achievable, and safer glycemic targets20, 21 in patients receiving CII in the ICU setting. The recent ADA/AACE Inpatient Task Force now recommends against aggressive BG targets of <110 mg/dL for patients in the ICU, and suggests maintaining glucose levels between 140 and 180 mg/dL during insulin therapy. However, lower targets between 110 and 140 mg/dL, while not evidence‐based, may be acceptable in a subset of patients as long as these levels can be achieved safely by a well‐trained staff.

There are no RCTs examining the effect of intensive glycemic control on outcomes or the optimal glycemic target in hospitalized patients outside the ICU setting. However, several observational studies point to a strong association between hyperglycemia and poor clinical outcomes, including prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 5 Despite the paucity of randomized controlled trials on general medical‐surgical floors, a premeal BG target of <140 mg/dL with random BG <180 mg/dL are recommended as long as this target can be safely achieved.21

Our study indicates that the use of CII in the non‐ICU setting is effective in improving glycemic control. After the first day of CII, the mean glucose level was within the recommended BG target of <180 mg/dL for patients treated with CII in the ICU. Moreover, the mean daily BG level during CII was lower than those recently reported with the use of SC basal‐bolus and insulin neutral protamine hagedorn (NPH) and regular insulin combinations in non‐ICU settings.17, 18 In the Randomized Study of Basal Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes (RABBIT 2) trial, a study that compared the efficacy and safety of an SC basal‐bolus to a sliding scale insulin regimen, showed that 66% and 38% of patients, respectively, reached a target BG of <140 mg/dL.17 The Comparison of Inpatient Insulin Regimens: DEtemir plus Aspart vs. NPH plus regular in Medical Patients with Type 2 Diabetes (DEAN Trial) trial reported daily mean BG levels after the first day of 160 38 mg/dL and 158 51 mg/dL in the detemir/aspart and NPH/regular group, respectively with an achieved BG target of <140 mg/dL in 45% of patients in the detemir/aspart and in 48% in the NPH/regular18; whereas in this study we observed that most patients reached the target BG goal by 48 hours of the CII regimen.

Increasing evidence indicates that inpatient hypoglycemia is associated with short‐term and long‐term adverse outcomes.22, 23 The incidence of severe hypoglycemia (<40 mg/dL) with intensified glycemic control has ranged between 9.8% and 19%7, 15 vs. <5% in conventional treatment. In the present study, 35% of patients experienced a BG <70 mg/dL, 22% had a BG <60 mg/dL, and 5% of patients had a BG <40 mg/dL. The lower rate of hypoglycemic events with the use of CII in the non‐ICU setting observed in this study is likely the result of a more relaxed glycemic target of 80 to 150 mg/dL for the majority of subjects, as well as fewer severe comorbidities compared to patients in the ICU, where the presence of sepsis or hepatic, adrenal, or renal failure increase the risk of hypoglycemia.2224

Multivariate analyses adjusted for age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests showed that nutrition status during CII was an important factor associated with increased frequency of hyperglycemic and hypoglycemic events. Compared to subjects maintained NPO, subjects who received oral intake while on CII had a significantly increased rate of hyperglycemic and hypoglycemic events. The increased risk of hypoglycemia for those allowed to eat is expected as the protocol would mandate an increase in the CII rate in response to the prandial BG increase but does not make provisions for BG assessments or CII adjustments in relationship to the meal. These results indicate that in stable patients who are ready to start eating, CII should be stopped and transitioned to SC insulin regimen. In patients who may benefit from the continued use of CII (eg, patients requiring multistep procedures/surgeries), treatment with CII could be continued with supplemental mealtime insulin (intravenous [IV] or SC).

CII may be useful in cases of patients with persistent hyperglycemia despite scheduled SC insulin regimen; in patients where rapid glycemic control may be warranted in order to decrease the risk of increased inflammation and vascular dysfunction in acute coronary syndromes; and to enhance wound healing status post surgical procedures. Other clinical scenarios in which CII may be preferred and no ICU bed is required include cases of new‐onset diabetes with significant hyperglycemia (BG >300 mg/dL), type 1 diabetes poorly controlled with SC insulin, uncontrolled gestational diabetes, parenteral nutrition use, perioperative states, or the use of high‐dose steroids or chemotherapy.

Our findings are limited by the retrospective nature of our study and the evaluation of patients in a single university medical center. Selection bias should be considered in the interpretation of the results since each index case was selected by the attending physician to be treated with CII as opposed to another regimen for inpatient glycemic control. The selection bias, however, may be limited by the fact that the subjects in this study placed on CII seemed to be similar to those in the general hospital population. A previous pilot study from a different academic institution, however, reported that implementing CII protocols in non‐ICU patients is safe and improved glycemic control without increasing hypoglycemia.25 In addition, because most subjects in this study had a history of diabetes prior to admission, these results may not be generalizable to populations with stress‐induced hyperglycemia.

In summary, our study indicates that a CII regimen is an effective option for the management of patients with persistent hyperglycemia in the non‐critical care setting. Most patients achieved and remained within targeted BG levels during CII. The overall rate of hypoglycemic events was similar to that reported in recent randomized clinical trials in the ICU and with SC insulin therapy. The frequency of hypoglycemic and hyperglycemic events was significantly increased in patients allowed to eat during CII suggesting that CII should be stopped and patients should be transitioned to an SC insulin regimen once oral intake is initiated. Future prospective, randomized studies are needed to compare the efficacy and safety of CII protocols to SC insulin protocols in the management of patients with persistent hyperglycemia in the non‐ICU setting.

Increasing evidence suggests that in hospitalized adult patients with and without diabetes, hyperglycemia is associated with increased risk of complications, prolonged length of hospitalization, and death.15 Past studies have shown that intensive glucose control in the intensive care unit (ICU) with continuous insulin infusion (CII) improves clinical outcomes by reducing the risk of multiorgan failure, systemic infection, and mortality. Effective management of hyperglycemia, an independent marker of poor outcome,1, 3, 6 is also associated with a decreased length of ICU and hospital stay79 and decreased total hospitalization cost.10 Based on several observational and interventional studies, improved control of blood glucose (BG) has been recommended for most adult patients with critical illness.2, 6, 11

Detrimental effects of hyperglycemia on outcome are not limited to patients in the ICU setting and CII has increasingly been used in non‐ICU settings. In such patients, the presence of hyperglycemia has been associated with prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 6 In general medicine and surgery services, however, hyperglycemia is frequently overlooked and inadequately addressed. Numerous reports have shown that sliding scale regular insulin (SSRI) continues to be the most common insulin prescribed regimen in the non‐ICU setting.12 This regimen is challenged by limited and variable efficacy and continued concern for hypoglycemia13; thus, a more structured, target‐driven protocol such as scheduled SC insulin or a CII protocol could facilitate glycemic control in the non‐ICU setting. Recently, we reported that a scheduled regimen using basal‐bolus insulin subcutaneously was safe, effective, and superior to SSRI in controlling BG levels in hospitalized subjects with type 2 diabetes. As in many institutions in the United States, we have used CII protocols as an alternative to subcutaneous (SC) insulin for the management of persistent hyperglycemia in non‐ICU areas during the past 10 years, particularly during the postoperative period, transplant recipients, or patients transferred from the ICU. There is, however, no clinical evidence regarding the safety, efficacy, or outcomes with the use of CII in the non‐ICU setting. Accordingly, we analyzed our experience on the efficacy and safety of CII in the management of hyperglycemia in general medicine and surgical services.

Research Design and Methods

This retrospective chart analysis was conducted in adult patients >18 years of age who were consecutively admitted to the general medical and surgical wards between July 1, 2004 and June 30, 2005 at Emory University Hospital, a 579‐bed tertiary care facility staffed exclusively by Emory University School of Medicine faculty members and residents. The CII protocol, employing regular insulin (Novolin‐R Novo Nordisk Pharmaceuticals, Princeton, NJ) with a very short half‐life, in this study is a dynamic protocol14 that has been available at all nursing stations at Emory Hospital for the past decade (Table 1). The insulin rate is calculated using the formula (BG 60) (multiplier) = units of insulin per hour. The multiplier is a value used to denote the degree of insulin sensitivity based on glucose pattern and response to insulin. The multiplier typically starts at a value of 0.02 and is adjusted by the nurse as needed to achieve target BG levels based on bedside capillary glucose measurements. Blood glucose levels were checked every 1 to 2 hours by the nursing staff (nurse:patient ratio = 1:5) according to the protocol.

Of 1404 patients treated with CII during the hospital stay, 1191 patients received CII in the ICU and 213 patients received CII in non‐ICU areas. The final analysis included a total of 200 non‐ICU patient records after excluding 13 patients with diabetic ketoacidosis, incomplete documentation of glycemic records, or with duration of CII for less than 3 hours. Data collected included demographics, medical history, admission diagnoses, inpatient medications, inpatient laboratory values, bedside BG measurements, insulin doses used, nutrition status during CII, length of stay, disposition at discharge, and mortality rate. Nutrition status was defined in 3 ways: (1) nil per os or nothing by mouth (NPO); (2) oral nutrition (PO‐regular or PO‐liquid); and (3) tube feeds or total parenteral nutrition (TF/TPN). Data collection was limited to the first 10 days of CII use. This study was approved by the Institutional Review Board at Emory University.

The primary aim of the study was to determine the efficacy (mean daily BG levels) and safety (number of hyperglycemic [200 mg/dL] and hypoglycemic [60 mg/dL] events) during CII. We also determined the presence of potential risk factors associated with hypoglycemic and hyperglycemic events (age, body mass index [BMI], nutrition status, renal function, corticosteroid therapy, and use of enteral and parenteral nutrition) during CII.

Results

The cohort of 200 patients consisted of 54% males and 46% females, 53% Caucasian, 37% Black, with a mean age of 52 16 years (Table 2). Forty‐five percent of patients were admitted to the general medicine service and the remaining 55% were admitted to the surgical service for admission diagnoses that included cardiovascular disorders, trauma/surgery gastrointestinal disorders, renal disorders, and infection.

The primary indication for CII was poor glycemic control in 93.4% of patients. Forty‐one percent of subjects were receiving corticosteroids and 16% were continued on the insulin drip after transferring from an ICU. Nearly 90% of subjects had a history of diabetes and 11% were diagnosed with new‐onset diabetes. The mean admission BG concentration was 325 235 mg/dL (mean SD) and the mean A1c in 121 subjects in whom it was measured was 9.1 3%. The mean BG prior to the initiation of CII (323 184) was similar to the admission BG.

Of the 173 subjects that had well‐documented glycemic goals, the BG targeted during CII was 150 mg/dL in 85% of patients while the remaining subjects had a target BG goal that ranged from 70 to 250 mg/dL. The most commonly prescribed BG target goals were 80 to 110 mg/dL (41.6%), 80 to 120 mg/dL (13.9%), and 100 to 150 mg/dL (5.8%).

BG improved rapidly after the initiation of CII. BG on the first day of CII was 182 71 mg/dL; day 2: 142 42 mg/dL; day 3: 131 38 mg/dL; and day 4: 132 43 in response to receiving an average of 84 66 units/day, 71 61 units/day, 70 61 units/day, and 64 29 units/day, respectively (Table 3). Irrespective of the target BG goal, 67% of patients reached BG levels of 150 mg/dL by 48 hours of CII initiation. The duration of CII ranged between 4 and 240 hours, with an average of 41.6 hours and a median of 28 hours. The average insulin infusion rate during CII was 4.29 2.99 units/hour and the mean amount of insulin required to attain glycemic goals was 1.96 1.88 units/kg/day.

During CII, 48% and 35% of patients had at least 1 episode of hyperglycemia (BG >200 mg/dL) on the second and third day of CII, respectively. Hypoglycemia (BG <60 mg/dL) was noted at least once in 22% of the cohort (day 1: 11%; day 2: 16%; and day 3: 14%); however, severe hypoglycemia (BG <40 mg/dL) only occurred in 5% of subjects. During the CII, 37% of patients experienced a BG <70 mg/dL. When BG targets were stratified (<120 mg/dL vs. 120‐180 mg/dL vs. >180 mg/dL), we found no significant association between the target BG goal and the frequency of hypoglycemic or hyperglycemic events during CII. None of the episodes of hypoglycemia were associated with significant or permanent complications.

The analysis of collected variables for influence on glycemic control (ie, BMI, age, corticosteroid use, renal function, and nutrition status) revealed that subjects with a creatinine level >1.5 mg/dL may have an increased risk of hyperglycemia (BG >200 mg/dL) (P = 0.047) but not hypoglycemia. The analysis also found that younger patients (51 16 years) were more likely to have episodes of hyperglycemia than older patients (57 13 years) (P = 0.027). Hospital length of stay and mortality rate (3%) were not associated with the rate of hyperglycemic or hypoglycemic events.

Eighty‐two percent of patients received nutrition support at some point while on the CII: 48% PO‐regular diet; 14% PO‐liquid diet; and 20% TF/TPN. Due to the titration of nutrition from NPO at CII initiation to PO, NPO status was analyzed in a time‐dependent fashion. Thus, among patients on CII on day 1, day 2, day 3, day 4, and days 510; 34.0%, 26.3%, 11.3%, 12.5%, and 10.5%, respectively, were NPO.

As compared to subjects maintained NPO, subjects that received oral nutrition while on CII had an increased rate of hyperglycemic events (BG >200 mg/dL: 86% vs. 76%, P = 0.19; >300 mg/dL: 57% vs. 53%, P = 0.69; >400 mg/dL: 32% vs. 21%, P = 0.22) and a decreased rate of hypoglycemic events (BG <70 mg/dL: 33% vs. 41%, P = 0.39; BG <60 mg/dL: 20% vs. 26%, P = 0.49; and BG <40 mg/dL: 4% vs. 6%, P = 0.65). The multivariate regression analyses, however, which considered age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests, showed that nutrition status during CII was associated with increased frequency of hyperglycemic (P = 0.042) and hypoglycemic events (P = 0.086). As compared to NPO, oral intake (PO‐regular or PO‐liquid) was associated with a significantly increased frequency of hyperglycemic (P = 0.012) and hypoglycemic events (P = 0.035). Patients treated with TPN had lower BG values than those not on TPN. Although we observed no increased number of hypoglycemic events, TPN‐treated subjects had higher mortality than non‐TPN treated subjects (P < 0.001).

Discussion

Our study aimed to determine the safety and efficacy of CII in non‐critically‐ill patients with persistent hyperglycemia in general medicine and surgical services. We observed that the use of CII was effective in controlling hyperglycemia, with two‐thirds of patients achieving their target BG 150 mg/dL by 48 hours of insulin infusion. The rate of hypoglycemic events with the use of CII in non‐ICU patients was similar to that reported in recent ICU trials with intensive glycemic control7, 8, 15, 16 and is comparable to that reported in studies using SC insulin therapy in non‐ICU settings.17, 18 The number of hypoglycemic and hyperglycemic events was significantly higher in patients allowed to eat compared to those patients kept NPO during CII. There is substantial observational evidence linking hyperglycemia in hospitalized patients (with and without diabetes) to poor outcomes. There is ongoing debate, however, about the optimal level of BG in hospitalized patients. Early cohort studies as well as randomized controlled trials (RCTs) suggest that intensive treatment of hyperglycemia reduces length of hospital and ICU stay, multiorgan failure and systemic infections, and mortality.7, 9 These positive reports led the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) to recommend tight glycemic control (target of 80‐110 mg/dL) in critical care units. Recent multicenter controlled trials, however, have not been able to reproduce these results and in fact, have reported an increased risk of severe hypoglycemia and mortality in ICU patients in association with tight glycemic control.15, 16, 19 New glycemic targets call for more reasonable, achievable, and safer glycemic targets20, 21 in patients receiving CII in the ICU setting. The recent ADA/AACE Inpatient Task Force now recommends against aggressive BG targets of <110 mg/dL for patients in the ICU, and suggests maintaining glucose levels between 140 and 180 mg/dL during insulin therapy. However, lower targets between 110 and 140 mg/dL, while not evidence‐based, may be acceptable in a subset of patients as long as these levels can be achieved safely by a well‐trained staff.

There are no RCTs examining the effect of intensive glycemic control on outcomes or the optimal glycemic target in hospitalized patients outside the ICU setting. However, several observational studies point to a strong association between hyperglycemia and poor clinical outcomes, including prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 5 Despite the paucity of randomized controlled trials on general medical‐surgical floors, a premeal BG target of <140 mg/dL with random BG <180 mg/dL are recommended as long as this target can be safely achieved.21

Our study indicates that the use of CII in the non‐ICU setting is effective in improving glycemic control. After the first day of CII, the mean glucose level was within the recommended BG target of <180 mg/dL for patients treated with CII in the ICU. Moreover, the mean daily BG level during CII was lower than those recently reported with the use of SC basal‐bolus and insulin neutral protamine hagedorn (NPH) and regular insulin combinations in non‐ICU settings.17, 18 In the Randomized Study of Basal Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes (RABBIT 2) trial, a study that compared the efficacy and safety of an SC basal‐bolus to a sliding scale insulin regimen, showed that 66% and 38% of patients, respectively, reached a target BG of <140 mg/dL.17 The Comparison of Inpatient Insulin Regimens: DEtemir plus Aspart vs. NPH plus regular in Medical Patients with Type 2 Diabetes (DEAN Trial) trial reported daily mean BG levels after the first day of 160 38 mg/dL and 158 51 mg/dL in the detemir/aspart and NPH/regular group, respectively with an achieved BG target of <140 mg/dL in 45% of patients in the detemir/aspart and in 48% in the NPH/regular18; whereas in this study we observed that most patients reached the target BG goal by 48 hours of the CII regimen.

Increasing evidence indicates that inpatient hypoglycemia is associated with short‐term and long‐term adverse outcomes.22, 23 The incidence of severe hypoglycemia (<40 mg/dL) with intensified glycemic control has ranged between 9.8% and 19%7, 15 vs. <5% in conventional treatment. In the present study, 35% of patients experienced a BG <70 mg/dL, 22% had a BG <60 mg/dL, and 5% of patients had a BG <40 mg/dL. The lower rate of hypoglycemic events with the use of CII in the non‐ICU setting observed in this study is likely the result of a more relaxed glycemic target of 80 to 150 mg/dL for the majority of subjects, as well as fewer severe comorbidities compared to patients in the ICU, where the presence of sepsis or hepatic, adrenal, or renal failure increase the risk of hypoglycemia.2224

Multivariate analyses adjusted for age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests showed that nutrition status during CII was an important factor associated with increased frequency of hyperglycemic and hypoglycemic events. Compared to subjects maintained NPO, subjects who received oral intake while on CII had a significantly increased rate of hyperglycemic and hypoglycemic events. The increased risk of hypoglycemia for those allowed to eat is expected as the protocol would mandate an increase in the CII rate in response to the prandial BG increase but does not make provisions for BG assessments or CII adjustments in relationship to the meal. These results indicate that in stable patients who are ready to start eating, CII should be stopped and transitioned to SC insulin regimen. In patients who may benefit from the continued use of CII (eg, patients requiring multistep procedures/surgeries), treatment with CII could be continued with supplemental mealtime insulin (intravenous [IV] or SC).

CII may be useful in cases of patients with persistent hyperglycemia despite scheduled SC insulin regimen; in patients where rapid glycemic control may be warranted in order to decrease the risk of increased inflammation and vascular dysfunction in acute coronary syndromes; and to enhance wound healing status post surgical procedures. Other clinical scenarios in which CII may be preferred and no ICU bed is required include cases of new‐onset diabetes with significant hyperglycemia (BG >300 mg/dL), type 1 diabetes poorly controlled with SC insulin, uncontrolled gestational diabetes, parenteral nutrition use, perioperative states, or the use of high‐dose steroids or chemotherapy.

Our findings are limited by the retrospective nature of our study and the evaluation of patients in a single university medical center. Selection bias should be considered in the interpretation of the results since each index case was selected by the attending physician to be treated with CII as opposed to another regimen for inpatient glycemic control. The selection bias, however, may be limited by the fact that the subjects in this study placed on CII seemed to be similar to those in the general hospital population. A previous pilot study from a different academic institution, however, reported that implementing CII protocols in non‐ICU patients is safe and improved glycemic control without increasing hypoglycemia.25 In addition, because most subjects in this study had a history of diabetes prior to admission, these results may not be generalizable to populations with stress‐induced hyperglycemia.

In summary, our study indicates that a CII regimen is an effective option for the management of patients with persistent hyperglycemia in the non‐critical care setting. Most patients achieved and remained within targeted BG levels during CII. The overall rate of hypoglycemic events was similar to that reported in recent randomized clinical trials in the ICU and with SC insulin therapy. The frequency of hypoglycemic and hyperglycemic events was significantly increased in patients allowed to eat during CII suggesting that CII should be stopped and patients should be transitioned to an SC insulin regimen once oral intake is initiated. Future prospective, randomized studies are needed to compare the efficacy and safety of CII protocols to SC insulin protocols in the management of patients with persistent hyperglycemia in the non‐ICU setting.

Increasing evidence suggests that in hospitalized adult patients with and without diabetes, hyperglycemia is associated with increased risk of complications, prolonged length of hospitalization, and death.15 Past studies have shown that intensive glucose control in the intensive care unit (ICU) with continuous insulin infusion (CII) improves clinical outcomes by reducing the risk of multiorgan failure, systemic infection, and mortality. Effective management of hyperglycemia, an independent marker of poor outcome,1, 3, 6 is also associated with a decreased length of ICU and hospital stay79 and decreased total hospitalization cost.10 Based on several observational and interventional studies, improved control of blood glucose (BG) has been recommended for most adult patients with critical illness.2, 6, 11

Detrimental effects of hyperglycemia on outcome are not limited to patients in the ICU setting and CII has increasingly been used in non‐ICU settings. In such patients, the presence of hyperglycemia has been associated with prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 6 In general medicine and surgery services, however, hyperglycemia is frequently overlooked and inadequately addressed. Numerous reports have shown that sliding scale regular insulin (SSRI) continues to be the most common insulin prescribed regimen in the non‐ICU setting.12 This regimen is challenged by limited and variable efficacy and continued concern for hypoglycemia13; thus, a more structured, target‐driven protocol such as scheduled SC insulin or a CII protocol could facilitate glycemic control in the non‐ICU setting. Recently, we reported that a scheduled regimen using basal‐bolus insulin subcutaneously was safe, effective, and superior to SSRI in controlling BG levels in hospitalized subjects with type 2 diabetes. As in many institutions in the United States, we have used CII protocols as an alternative to subcutaneous (SC) insulin for the management of persistent hyperglycemia in non‐ICU areas during the past 10 years, particularly during the postoperative period, transplant recipients, or patients transferred from the ICU. There is, however, no clinical evidence regarding the safety, efficacy, or outcomes with the use of CII in the non‐ICU setting. Accordingly, we analyzed our experience on the efficacy and safety of CII in the management of hyperglycemia in general medicine and surgical services.

Research Design and Methods

This retrospective chart analysis was conducted in adult patients >18 years of age who were consecutively admitted to the general medical and surgical wards between July 1, 2004 and June 30, 2005 at Emory University Hospital, a 579‐bed tertiary care facility staffed exclusively by Emory University School of Medicine faculty members and residents. The CII protocol, employing regular insulin (Novolin‐R Novo Nordisk Pharmaceuticals, Princeton, NJ) with a very short half‐life, in this study is a dynamic protocol14 that has been available at all nursing stations at Emory Hospital for the past decade (Table 1). The insulin rate is calculated using the formula (BG 60) (multiplier) = units of insulin per hour. The multiplier is a value used to denote the degree of insulin sensitivity based on glucose pattern and response to insulin. The multiplier typically starts at a value of 0.02 and is adjusted by the nurse as needed to achieve target BG levels based on bedside capillary glucose measurements. Blood glucose levels were checked every 1 to 2 hours by the nursing staff (nurse:patient ratio = 1:5) according to the protocol.

Of 1404 patients treated with CII during the hospital stay, 1191 patients received CII in the ICU and 213 patients received CII in non‐ICU areas. The final analysis included a total of 200 non‐ICU patient records after excluding 13 patients with diabetic ketoacidosis, incomplete documentation of glycemic records, or with duration of CII for less than 3 hours. Data collected included demographics, medical history, admission diagnoses, inpatient medications, inpatient laboratory values, bedside BG measurements, insulin doses used, nutrition status during CII, length of stay, disposition at discharge, and mortality rate. Nutrition status was defined in 3 ways: (1) nil per os or nothing by mouth (NPO); (2) oral nutrition (PO‐regular or PO‐liquid); and (3) tube feeds or total parenteral nutrition (TF/TPN). Data collection was limited to the first 10 days of CII use. This study was approved by the Institutional Review Board at Emory University.

The primary aim of the study was to determine the efficacy (mean daily BG levels) and safety (number of hyperglycemic [200 mg/dL] and hypoglycemic [60 mg/dL] events) during CII. We also determined the presence of potential risk factors associated with hypoglycemic and hyperglycemic events (age, body mass index [BMI], nutrition status, renal function, corticosteroid therapy, and use of enteral and parenteral nutrition) during CII.

Results

The cohort of 200 patients consisted of 54% males and 46% females, 53% Caucasian, 37% Black, with a mean age of 52 16 years (Table 2). Forty‐five percent of patients were admitted to the general medicine service and the remaining 55% were admitted to the surgical service for admission diagnoses that included cardiovascular disorders, trauma/surgery gastrointestinal disorders, renal disorders, and infection.

The primary indication for CII was poor glycemic control in 93.4% of patients. Forty‐one percent of subjects were receiving corticosteroids and 16% were continued on the insulin drip after transferring from an ICU. Nearly 90% of subjects had a history of diabetes and 11% were diagnosed with new‐onset diabetes. The mean admission BG concentration was 325 235 mg/dL (mean SD) and the mean A1c in 121 subjects in whom it was measured was 9.1 3%. The mean BG prior to the initiation of CII (323 184) was similar to the admission BG.

Of the 173 subjects that had well‐documented glycemic goals, the BG targeted during CII was 150 mg/dL in 85% of patients while the remaining subjects had a target BG goal that ranged from 70 to 250 mg/dL. The most commonly prescribed BG target goals were 80 to 110 mg/dL (41.6%), 80 to 120 mg/dL (13.9%), and 100 to 150 mg/dL (5.8%).

BG improved rapidly after the initiation of CII. BG on the first day of CII was 182 71 mg/dL; day 2: 142 42 mg/dL; day 3: 131 38 mg/dL; and day 4: 132 43 in response to receiving an average of 84 66 units/day, 71 61 units/day, 70 61 units/day, and 64 29 units/day, respectively (Table 3). Irrespective of the target BG goal, 67% of patients reached BG levels of 150 mg/dL by 48 hours of CII initiation. The duration of CII ranged between 4 and 240 hours, with an average of 41.6 hours and a median of 28 hours. The average insulin infusion rate during CII was 4.29 2.99 units/hour and the mean amount of insulin required to attain glycemic goals was 1.96 1.88 units/kg/day.

During CII, 48% and 35% of patients had at least 1 episode of hyperglycemia (BG >200 mg/dL) on the second and third day of CII, respectively. Hypoglycemia (BG <60 mg/dL) was noted at least once in 22% of the cohort (day 1: 11%; day 2: 16%; and day 3: 14%); however, severe hypoglycemia (BG <40 mg/dL) only occurred in 5% of subjects. During the CII, 37% of patients experienced a BG <70 mg/dL. When BG targets were stratified (<120 mg/dL vs. 120‐180 mg/dL vs. >180 mg/dL), we found no significant association between the target BG goal and the frequency of hypoglycemic or hyperglycemic events during CII. None of the episodes of hypoglycemia were associated with significant or permanent complications.

The analysis of collected variables for influence on glycemic control (ie, BMI, age, corticosteroid use, renal function, and nutrition status) revealed that subjects with a creatinine level >1.5 mg/dL may have an increased risk of hyperglycemia (BG >200 mg/dL) (P = 0.047) but not hypoglycemia. The analysis also found that younger patients (51 16 years) were more likely to have episodes of hyperglycemia than older patients (57 13 years) (P = 0.027). Hospital length of stay and mortality rate (3%) were not associated with the rate of hyperglycemic or hypoglycemic events.

Eighty‐two percent of patients received nutrition support at some point while on the CII: 48% PO‐regular diet; 14% PO‐liquid diet; and 20% TF/TPN. Due to the titration of nutrition from NPO at CII initiation to PO, NPO status was analyzed in a time‐dependent fashion. Thus, among patients on CII on day 1, day 2, day 3, day 4, and days 510; 34.0%, 26.3%, 11.3%, 12.5%, and 10.5%, respectively, were NPO.

As compared to subjects maintained NPO, subjects that received oral nutrition while on CII had an increased rate of hyperglycemic events (BG >200 mg/dL: 86% vs. 76%, P = 0.19; >300 mg/dL: 57% vs. 53%, P = 0.69; >400 mg/dL: 32% vs. 21%, P = 0.22) and a decreased rate of hypoglycemic events (BG <70 mg/dL: 33% vs. 41%, P = 0.39; BG <60 mg/dL: 20% vs. 26%, P = 0.49; and BG <40 mg/dL: 4% vs. 6%, P = 0.65). The multivariate regression analyses, however, which considered age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests, showed that nutrition status during CII was associated with increased frequency of hyperglycemic (P = 0.042) and hypoglycemic events (P = 0.086). As compared to NPO, oral intake (PO‐regular or PO‐liquid) was associated with a significantly increased frequency of hyperglycemic (P = 0.012) and hypoglycemic events (P = 0.035). Patients treated with TPN had lower BG values than those not on TPN. Although we observed no increased number of hypoglycemic events, TPN‐treated subjects had higher mortality than non‐TPN treated subjects (P < 0.001).

Discussion

Our study aimed to determine the safety and efficacy of CII in non‐critically‐ill patients with persistent hyperglycemia in general medicine and surgical services. We observed that the use of CII was effective in controlling hyperglycemia, with two‐thirds of patients achieving their target BG 150 mg/dL by 48 hours of insulin infusion. The rate of hypoglycemic events with the use of CII in non‐ICU patients was similar to that reported in recent ICU trials with intensive glycemic control7, 8, 15, 16 and is comparable to that reported in studies using SC insulin therapy in non‐ICU settings.17, 18 The number of hypoglycemic and hyperglycemic events was significantly higher in patients allowed to eat compared to those patients kept NPO during CII. There is substantial observational evidence linking hyperglycemia in hospitalized patients (with and without diabetes) to poor outcomes. There is ongoing debate, however, about the optimal level of BG in hospitalized patients. Early cohort studies as well as randomized controlled trials (RCTs) suggest that intensive treatment of hyperglycemia reduces length of hospital and ICU stay, multiorgan failure and systemic infections, and mortality.7, 9 These positive reports led the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) to recommend tight glycemic control (target of 80‐110 mg/dL) in critical care units. Recent multicenter controlled trials, however, have not been able to reproduce these results and in fact, have reported an increased risk of severe hypoglycemia and mortality in ICU patients in association with tight glycemic control.15, 16, 19 New glycemic targets call for more reasonable, achievable, and safer glycemic targets20, 21 in patients receiving CII in the ICU setting. The recent ADA/AACE Inpatient Task Force now recommends against aggressive BG targets of <110 mg/dL for patients in the ICU, and suggests maintaining glucose levels between 140 and 180 mg/dL during insulin therapy. However, lower targets between 110 and 140 mg/dL, while not evidence‐based, may be acceptable in a subset of patients as long as these levels can be achieved safely by a well‐trained staff.

There are no RCTs examining the effect of intensive glycemic control on outcomes or the optimal glycemic target in hospitalized patients outside the ICU setting. However, several observational studies point to a strong association between hyperglycemia and poor clinical outcomes, including prolonged hospital stay, infection, disability after hospital discharge, and death.1, 3, 5 Despite the paucity of randomized controlled trials on general medical‐surgical floors, a premeal BG target of <140 mg/dL with random BG <180 mg/dL are recommended as long as this target can be safely achieved.21

Our study indicates that the use of CII in the non‐ICU setting is effective in improving glycemic control. After the first day of CII, the mean glucose level was within the recommended BG target of <180 mg/dL for patients treated with CII in the ICU. Moreover, the mean daily BG level during CII was lower than those recently reported with the use of SC basal‐bolus and insulin neutral protamine hagedorn (NPH) and regular insulin combinations in non‐ICU settings.17, 18 In the Randomized Study of Basal Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes (RABBIT 2) trial, a study that compared the efficacy and safety of an SC basal‐bolus to a sliding scale insulin regimen, showed that 66% and 38% of patients, respectively, reached a target BG of <140 mg/dL.17 The Comparison of Inpatient Insulin Regimens: DEtemir plus Aspart vs. NPH plus regular in Medical Patients with Type 2 Diabetes (DEAN Trial) trial reported daily mean BG levels after the first day of 160 38 mg/dL and 158 51 mg/dL in the detemir/aspart and NPH/regular group, respectively with an achieved BG target of <140 mg/dL in 45% of patients in the detemir/aspart and in 48% in the NPH/regular18; whereas in this study we observed that most patients reached the target BG goal by 48 hours of the CII regimen.

Increasing evidence indicates that inpatient hypoglycemia is associated with short‐term and long‐term adverse outcomes.22, 23 The incidence of severe hypoglycemia (<40 mg/dL) with intensified glycemic control has ranged between 9.8% and 19%7, 15 vs. <5% in conventional treatment. In the present study, 35% of patients experienced a BG <70 mg/dL, 22% had a BG <60 mg/dL, and 5% of patients had a BG <40 mg/dL. The lower rate of hypoglycemic events with the use of CII in the non‐ICU setting observed in this study is likely the result of a more relaxed glycemic target of 80 to 150 mg/dL for the majority of subjects, as well as fewer severe comorbidities compared to patients in the ICU, where the presence of sepsis or hepatic, adrenal, or renal failure increase the risk of hypoglycemia.2224

Multivariate analyses adjusted for age, gender, race, BMI, renal function, steroid use, history of diabetes, and number of BG tests showed that nutrition status during CII was an important factor associated with increased frequency of hyperglycemic and hypoglycemic events. Compared to subjects maintained NPO, subjects who received oral intake while on CII had a significantly increased rate of hyperglycemic and hypoglycemic events. The increased risk of hypoglycemia for those allowed to eat is expected as the protocol would mandate an increase in the CII rate in response to the prandial BG increase but does not make provisions for BG assessments or CII adjustments in relationship to the meal. These results indicate that in stable patients who are ready to start eating, CII should be stopped and transitioned to SC insulin regimen. In patients who may benefit from the continued use of CII (eg, patients requiring multistep procedures/surgeries), treatment with CII could be continued with supplemental mealtime insulin (intravenous [IV] or SC).

CII may be useful in cases of patients with persistent hyperglycemia despite scheduled SC insulin regimen; in patients where rapid glycemic control may be warranted in order to decrease the risk of increased inflammation and vascular dysfunction in acute coronary syndromes; and to enhance wound healing status post surgical procedures. Other clinical scenarios in which CII may be preferred and no ICU bed is required include cases of new‐onset diabetes with significant hyperglycemia (BG >300 mg/dL), type 1 diabetes poorly controlled with SC insulin, uncontrolled gestational diabetes, parenteral nutrition use, perioperative states, or the use of high‐dose steroids or chemotherapy.

Our findings are limited by the retrospective nature of our study and the evaluation of patients in a single university medical center. Selection bias should be considered in the interpretation of the results since each index case was selected by the attending physician to be treated with CII as opposed to another regimen for inpatient glycemic control. The selection bias, however, may be limited by the fact that the subjects in this study placed on CII seemed to be similar to those in the general hospital population. A previous pilot study from a different academic institution, however, reported that implementing CII protocols in non‐ICU patients is safe and improved glycemic control without increasing hypoglycemia.25 In addition, because most subjects in this study had a history of diabetes prior to admission, these results may not be generalizable to populations with stress‐induced hyperglycemia.

In summary, our study indicates that a CII regimen is an effective option for the management of patients with persistent hyperglycemia in the non‐critical care setting. Most patients achieved and remained within targeted BG levels during CII. The overall rate of hypoglycemic events was similar to that reported in recent randomized clinical trials in the ICU and with SC insulin therapy. The frequency of hypoglycemic and hyperglycemic events was significantly increased in patients allowed to eat during CII suggesting that CII should be stopped and patients should be transitioned to an SC insulin regimen once oral intake is initiated. Future prospective, randomized studies are needed to compare the efficacy and safety of CII protocols to SC insulin protocols in the management of patients with persistent hyperglycemia in the non‐ICU setting.

Vascular surgery is the most morbid of the noncardiac surgeries, with a 30‐day mortality estimated to be 3% to 10% and 6‐month mortality estimated to be 10% to 30%.14 Adverse outcomes are highly correlated with the presence of perioperative ischemia and infarction. Perioperative ischemia is associated with a 9‐fold increase in the odds of unstable angina, nonfatal myocardial infarction, and cardiac death, while a perioperative myocardial infarction increases the odds of death 20‐fold up to 2 years after surgery.57 Prior research has centered on the single or combination use of perioperative beta‐blockers and statins, which has been associated with decreased short‐term and long‐term mortality after vascular surgery,814 with the exceptions of the Metoprolol After Vascular Surgery (MAVS)15 and the Perioperative Beta‐Blockade (POBBLE) studies,16 which were negative beta‐blocker randomized controlled trials exclusively in vascular surgery patients, and the Perioperative Ischemic Evaluation (POISE) study,17 which was the largest perioperative beta‐blocker trial to date in noncardiac surgery, with 41% of the patients undergoing vascular surgery.

There have been few studies assessing clinical outcomes in patients taking multiple concurrent cardioprotective medications. Clinicians are challenged to apply research results to their patients, who generally take multiple drugs. A retrospective cohort study of acute coronary syndrome patients did assess the use of evidence‐based, combination therapies, including aspirin, ACE inhibitors, beta‐blockers, and statins, compared to the use of none of these agents and found an association with decreased 6‐month mortality.18 There are no prior noncardiac surgery studies assessing the concurrent use of multiple possibly cardioprotective drugs. There is 1 cohort study of coronary artery bypass graft surgery patients that assessed aspirin, ACE inhibitor, beta‐blocker, and statin use and found associations with decreased mortality.19 As preoperative coronary revascularization has not been found to produce improved survival after vascular surgery, clarifying which perioperative medicines alone or in combination may improve outcomes becomes even more important.20 We sought to ascertain if the use of concurrent combination aspirin, ACE inhibitors, beta‐blockers, and statins compared to nonuse was associated with a decrease in 6‐month mortality after vascular surgery.

Patients and Methods

Results

Patient Characteristics

There were 3020 patients with a median age of 67 years, and interquartile range of 59 to 75 years. Ninety‐nine percent were male, and all patients were assessed for death at 6 months after surgery (Table 1). Ten percent (304) had combination all‐4‐drug exposure, 22% (652) had 3‐drug exposure, 24% (736) had 2‐drug exposure, 26% (783) had 1‐drug exposure, and 18% (545) had no study drug exposures. Eight percent (229) of surgeries were aortic, 28% (861) were carotid, 28% (852) were lower extremity amputation, and 36% (1078) were lower extremity bypass. Twenty‐two percent (665) of patients were low risk, with a RCRI of 0, 60% (1822) were moderate risk with a RCRI of 1 to 2, and 18% (553) were high risk with a RCRI of 3. Overall the 6‐month mortality was 9.7% (294). The 6‐month mortality for carotid endarterectomy was 5.0% (43/861), for lower extremity bypass 7.6% (82/1078), for aorta repair 9.2% (21/229), and for lower extremity amputation 17.4% (148/852).

Table 1.Patient Demographics and Unadjusted Relative Risk of 6‐month Mortality

Variable	Level	N (%) Overall N = 3020	Relative Risk (95% CI)	Chi Square P‐Value
NOTE: Overall 6 month mortality: 9.7% (294). Abbreviations: Ace, angiotensin‐converting enzyme; CA, cancer; CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVA, cerebral vascular disease; DM, diabetes mellitus; HTN, hypertension; IQR, interquartile range; Lipid, hyperlipidemia; RCRI, Revised cardiac risk index; TIA, transient ischemic attack. * Age was continuous. P for linear trend. Chi‐square for overall group effect.
Age: year, median (IQR)		67 (59, 75)	1.04 (1.031.06)	<0.001*
Sex	Female	44 (1.5)	1	0.490
	Male	2976 (98.5)	1.48 (0.464.81)
Preoperative medical conditions	HTN	2388 (79.1)	1.40 (0.011.93)	0.036
	DM	1455 (48.2)	1.45 (1.131.84)	0.003
COPD	912 (30.2)	1.71 (1.342.19)	<0.001
CA	674 (22.3)	1.42 (1.091.86)	0.012
CKD	344 (11.4)	2.04 (1.492.80)	<0.001
CAD	1479 (49.0)	1.51 (1.181.92)	0.001
CHF	911 (30.2)	2.41 (1.893.08)	<0.001
CVA/TIA	802 (26.6)	1.08 (0.821.41)	0.587
Lipid	865 (28.6)	0.81 (0.611.06)	0.123
Blood chemistry	Creatinine > 2	228 (7.5)	3.11 (2.224.36)	<0.001
	Albumin 3.5	629 (20.8)	3.60 (2.804.62)	<0.001
Medication use	Aspirin	1773 (58.7)	1.12 (0.881.44)	0.355
	ACE, inhibitor	1238 (41.0)	0.81 (0.631.04)	0.090
Statin	1214 (40.2)	0.66 (0.510.86)	0.001
Beta blocker	1202 (39.8)	0.76 (0.590.98)	0.031
Clonidine	115 (3.8)	1.65 (0.972.80)	0.080
Insulin	474 (15.7)	1.47 (1.091.98)	0.013
Number of study drugs used	None	545 (18.0)	1	0.018
	One of 4	783 (25.9)	1.06 (0.751.51)
Two of 4	736 (24.4)	0.94 (0.651.35)
Three of 4	652 (21.6)	0.73 (0.491.08)
All four	304 (10.1)	0.66 (0.391.09)
Type of surgery	Carotid	861 (28.5)	1	<0.001
	Bypass	1078 (35.7)	1.57 (1.072.29)
Aorta	229 (7.6)	1.92 (1.123.31)
Amputation	852 (28.2)	4.00 (2.815.70)
RCRI category	0	665 (22.0)	1	<0.001
	1	976 (32.3)	1.12 (0.761.66)
2	846 (28.0)	1.66 (1.142.42)
3	553 (17.6)	2.83 (1.934.14)
Surgery year	1998	539 (17.8)	1	0.804
	1999	463 (15.3)	1.36 (0.892.07)
2000	418 (13.8)	1.07 (0.681.68)
2001	407 (13.5)	1.23 (0.791.92)
2002	368 (12.2)	1.34 (0.962.10)
2003	371 (12.3)	1.25 (0.801.97)
2004	395 (13.1)	1.17 (0.741.84)
2005	59 (2.0)	0.80 (0.282.30)

The most common single‐drug exposure was aspirin, 14% (416), followed by ACE inhibitors, 5% (163) (Table 2). The more common 2‐drug exposures included ACE inhibitors and aspirin, 7% (203), aspirin and beta‐blockers, 5% (161), and aspirin and statins, 5% (141). The common 3‐drug combinations included aspirin, beta‐blockers, and statins, 8% (229); ACE inhibitors, aspirin, and statins, 6% (167); and ACE inhibitors, aspirin, and beta‐blockers, 5% (152). ACE inhibitor exposure was common in all combinations, eg, 20.8% of the 1‐drug group had exposure to an ACE inhibitor, 40.5% in the 2‐drug group, 64.9% in the 3‐drug group, and all patients in the 4‐drug group. Overall, 39.3% of patients in the study had ACE inhibitor exposure. The gross unadjusted mortality for each drug exposure group was 10.6% for the no drug group, 11.2% for the 1‐drug group, 10.1% for the 2‐drug group, 8% for the 3‐drug group, and 7.2% for the 4‐drug group.

Table 2.Frequencies of Combination Drug Exposure Classes Before and 6 Months After Surgery

Drugs Used	Presurgery		6 Months Postsurgery
	Frequency	%	Frequency	%
* There were 294 deaths. Abbreviation: ACE, angiotensin‐converting enzyme.
None	545	18.1	669	24.5
1 Drug
Aspirin	416	53.1	169	28.3
ACE inhibitor	163	20.8	135	22.6
Beta‐blocker	110	14.1	163	27.2
Statin	94	12.0	131	21.9
All 1 drug	783	100.0	598	100.0
2 Drugs
Aspirin + ACE inhibitor	203	27.6	102	14.4
Aspirin + Beta‐blocker	161	21.8	117	16.5
Aspirin + Statin	141	19.2	86	12.1
ACE inhibitor + Beta‐blocker	56	7.6	103	14.5
ACE inhibitor + Statin	89	12.1	126	17.7
Beta‐blocker + Statin	86	11.7	176	24.8
All 2 drugs	36	100.0	710	100.0
3 Drugs
Aspirin + ACE inhibitor + Beta‐blocker	152	23.3	96	16.5
Aspirin + ACE inhibitor + Statin	167	25.6	103	17.7
Aspirin + Beta‐ blocker + Statin	229	35.1	165	28.4
ACE inhibitor + Beta‐blocker Statin	104	16.0	218	37.4
All 3 drugs	652	100.0	582	100.0
All 4 drugs	304	10.1	167	6.1
Total	3020	100.0	2726*	100.0

During the 6 complete years of the study (1998‐2004) the frequency of combination exposure for all 4 study drugs increased from 3.5% to 13.4%; 3‐drug exposure also increased, 14.7% to 27.8%; 2‐drug exposure remained relatively stable, 24.5% to 22%; and single‐drug exposure declined, 24.9% to 12.7% (Figure 1). Individual study drug exposures over the 6 years of the study generally also increased with respect to the other combinations: ACE inhibitor use increased, 34.5% to 42.5%; beta‐blocker, 27.8% to 53.4%; statin, 22.6% to 52.2%. The exception was aspirin, which was relatively stable, 54.5% in 1998, and 57.2% in 2004 (Figure 2).

Figure 1

Figure 2

We also compared the use of the study drug exposures at 6 months after surgery to use within 30 days before surgery (Table 2). In the VA healthcare system aspirin is cheaper for some patients to purchase over‐the‐counter. Aspirin is likely underestimated in this dataset. The frequency of follow‐up drug exposure at 6 months was overall similar to the drug exposure within 30 days before surgery. When aspirin was 1 of the combination exposures, the frequencies declined, and when aspirin was not 1 of the exposures, the frequencies generally increased. The frequency of no‐drug exposures increased from 18.1% before surgery to 24.5% 6 months after surgery, and the frequency of all 4 drug exposures decreased from 10.1% to 6.1%, respectively.

Discussion

This retrospective cohort study has demonstrated that the combination use of 4 drugs (aspirin, beta‐blockers, statins, and ACE inhibitors) compared to the use of none of these drugs had a trend toward decreased mortality, with a 49% decrease in propensity‐adjusted 6‐month mortality after vascular surgery and an NNT of 19. In addition, the combination use of 3 drug exposures was significantly associated with a 40% decrease in mortality, with propensity adjustment and NNT of 38; and the 2‐drug combination exposure showed a significant association, with a propensity‐adjusted 32% decreased mortality, and an NNT of 170. Both the unadjusted and adjusted analyses showed a linear trend, suggesting a dose‐response effect of more study‐drug exposure association with less 6‐month mortality and smaller NNT.

The lack of statistical significance for the 4‐drug exposure group is likely due to few patients and events in this group, and the exclusion of the first 2 quintiles (n = 339) due to having zero deaths with which to compare. It is not unusual to exclude patients from analyses in propensity methods. The patients we excluded were low‐risk who had survived to 6‐months after surgery, so they would have also been excluded in a propensity‐matched analysis. We did not perform propensity matching, as we had adequate homogeneity between our quintile strata, and were not powered to perform matching.

This is the first evidence of which we are aware of an association with decreased mortality for the combination perioperative use of aspirin, beta‐blockers, statins, and ACE inhibitors in vascular surgery patients. Aspirin has been associated with decreased mortality in patients undergoing coronary artery bypass graft surgery,25 but the effects of aspirin on noncardiac surgery outcomes is less clear.26

Beta‐blockers and statins have been associated with decreased short‐term and long‐term mortality after vascular surgery in the past,814 but more recent beta‐blocker studies have been negative, introducing controversy for the topic.1517, 27 Beta‐blockers are currently recommended as: Class I (should be used), Evidence Level B (limited population risk strata evaluated) for vascular surgery patients already taking a beta‐blocker or with positive ischemia on stress testing; Class IIa (reasonable to use), Evidence Level B for 1 or more clinical risk factors; or Class IIb (may be considered), Evidence Level B for no clinical risk factors, in the 2007 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for perioperative evaluation.28 Perioperative beta‐blocker trials that have titrated the dose to a goal heart rate have consistently been associated with improved outcomes after vascular surgery,10, 12, 29, 30 and perioperative beta‐blocker trials that have used fixed dosing after surgery have been negative,1517, 27 including the POISE trial, which was associated with increased strokes and mortality.

This is also the first evidence of which we are aware that ACE inhibitors in combination with other drugs may be associated with decreased mortality after vascular surgery. While our study design does not support a causal relationship between ACE inhibitor exposure and decreased mortality, the increasing exposure in each drug exposure group for ACE inhibitors and correlated decreasing mortality is of sufficient interest to warrant further study. The use of ACE inhibitors has been associated with decreased mortality in patients with atherosclerotic vascular disease and CAD.31 There has been a concern expressed in the literature about the perioperative use of ACE inhibitors due to the potential for intraoperative hypotension.3236 Many centers advise patients to discontinue ACE inhibitor use the day before surgery. The number of patients studied remains small. More research is needed to clarify this issue. Use of angiotensin‐receptor blockers was not assessed; their use was considered to be rare, because use was restricted to patients intolerant of ACE inhibitors during the study period.

The 2005 ACC/AHA guideline for patients with peripheral arterial disease recommends the use of aspirin and statins.37 ACE inhibitors are recommended for both asymptomatic and symptomatic peripheral artery disease patients. The 2006 ACC/AHA guidelines for secondary prevention for patients with coronary or other atherosclerotic vascular disease recommends the use of chronic beta‐blockers.38 There appears to be some benefit in mortality from the combination aspirin, beta‐blocker, statin, and ACE inhibitor drug regimen in patients with established atherosclerotic vascular disease.

We expect the frequency of aspirin exposure to be underestimated in this study population (due to over‐the‐counter undocumented use), so our findings may be somewhat underestimated as well. This may also explain why the frequency of aspirin remained constant over time while the other drug exposures increased over time.

Our study has several limitations. First, our design was a retrospective cohort. Propensity analysis attempts to correct for confounding by indication in nonrandomized studies as patients that are exposed to a study drug are different from patients that are not exposed to the same study drug. For example, without adjustment for the propensity scores, the drug exposure classes were significantly associated with demographic and clinical characteristics when compare to the no‐drug‐exposure patients. However, with the propensity score adjustment, these associations were no longer statistically significant, with the exception of hyperlipidemia in patients taking all 4 drugs, which supports a rigorous propensity adjustment. We also controlled for the use of clonidine and serum albumin, both strong predictors of death after noncardiac surgery.22, 39 Second, we utilized administrative ICD‐9 code data for abstraction, and utilized only documented and coded comorbidities in the VA database. Unmeasured confounders may exist. Further, we cannot identify which combinations of specific study drugs were most associated with a reduction in 6‐month mortality, but we believe our data supports the case that all 4 of the study drugs be considered for each patient undergoing vascular surgery. It is important to also note that patient baseline risk, which can be difficult to clarify in retrospective cohort studies, will have a large impact on the results of the NNT. Lastly, this study needs to be repeated in a population that includes a greater number of female participants.

The combination exposure of 2 to 3 study drugs: aspirin, beta‐blockers, statins, and ACE inhibitors was consistently associated with decreased 6‐month mortality after vascular surgery, with a high prevalence of ACE inhibitor use, and the combination exposure of all 4 study drugs was marginally associated with decreased mortality. Consideration for the individual patient undergoing vascular surgery should include whether or not the patient may benefit from these 4 drugs. Further research with prospective and randomized studies is needed to clarify the optimum timing of these drugs and their combination efficacy in vascular surgery patients with attention to patient‐specific risk.

Vascular surgery is the most morbid of the noncardiac surgeries, with a 30‐day mortality estimated to be 3% to 10% and 6‐month mortality estimated to be 10% to 30%.14 Adverse outcomes are highly correlated with the presence of perioperative ischemia and infarction. Perioperative ischemia is associated with a 9‐fold increase in the odds of unstable angina, nonfatal myocardial infarction, and cardiac death, while a perioperative myocardial infarction increases the odds of death 20‐fold up to 2 years after surgery.57 Prior research has centered on the single or combination use of perioperative beta‐blockers and statins, which has been associated with decreased short‐term and long‐term mortality after vascular surgery,814 with the exceptions of the Metoprolol After Vascular Surgery (MAVS)15 and the Perioperative Beta‐Blockade (POBBLE) studies,16 which were negative beta‐blocker randomized controlled trials exclusively in vascular surgery patients, and the Perioperative Ischemic Evaluation (POISE) study,17 which was the largest perioperative beta‐blocker trial to date in noncardiac surgery, with 41% of the patients undergoing vascular surgery.

There have been few studies assessing clinical outcomes in patients taking multiple concurrent cardioprotective medications. Clinicians are challenged to apply research results to their patients, who generally take multiple drugs. A retrospective cohort study of acute coronary syndrome patients did assess the use of evidence‐based, combination therapies, including aspirin, ACE inhibitors, beta‐blockers, and statins, compared to the use of none of these agents and found an association with decreased 6‐month mortality.18 There are no prior noncardiac surgery studies assessing the concurrent use of multiple possibly cardioprotective drugs. There is 1 cohort study of coronary artery bypass graft surgery patients that assessed aspirin, ACE inhibitor, beta‐blocker, and statin use and found associations with decreased mortality.19 As preoperative coronary revascularization has not been found to produce improved survival after vascular surgery, clarifying which perioperative medicines alone or in combination may improve outcomes becomes even more important.20 We sought to ascertain if the use of concurrent combination aspirin, ACE inhibitors, beta‐blockers, and statins compared to nonuse was associated with a decrease in 6‐month mortality after vascular surgery.

Patients and Methods

Results

Patient Characteristics

There were 3020 patients with a median age of 67 years, and interquartile range of 59 to 75 years. Ninety‐nine percent were male, and all patients were assessed for death at 6 months after surgery (Table 1). Ten percent (304) had combination all‐4‐drug exposure, 22% (652) had 3‐drug exposure, 24% (736) had 2‐drug exposure, 26% (783) had 1‐drug exposure, and 18% (545) had no study drug exposures. Eight percent (229) of surgeries were aortic, 28% (861) were carotid, 28% (852) were lower extremity amputation, and 36% (1078) were lower extremity bypass. Twenty‐two percent (665) of patients were low risk, with a RCRI of 0, 60% (1822) were moderate risk with a RCRI of 1 to 2, and 18% (553) were high risk with a RCRI of 3. Overall the 6‐month mortality was 9.7% (294). The 6‐month mortality for carotid endarterectomy was 5.0% (43/861), for lower extremity bypass 7.6% (82/1078), for aorta repair 9.2% (21/229), and for lower extremity amputation 17.4% (148/852).

Table 1.Patient Demographics and Unadjusted Relative Risk of 6‐month Mortality

Variable	Level	N (%) Overall N = 3020	Relative Risk (95% CI)	Chi Square P‐Value
NOTE: Overall 6 month mortality: 9.7% (294). Abbreviations: Ace, angiotensin‐converting enzyme; CA, cancer; CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVA, cerebral vascular disease; DM, diabetes mellitus; HTN, hypertension; IQR, interquartile range; Lipid, hyperlipidemia; RCRI, Revised cardiac risk index; TIA, transient ischemic attack. * Age was continuous. P for linear trend. Chi‐square for overall group effect.
Age: year, median (IQR)		67 (59, 75)	1.04 (1.031.06)	<0.001*
Sex	Female	44 (1.5)	1	0.490
	Male	2976 (98.5)	1.48 (0.464.81)
Preoperative medical conditions	HTN	2388 (79.1)	1.40 (0.011.93)	0.036
	DM	1455 (48.2)	1.45 (1.131.84)	0.003
COPD	912 (30.2)	1.71 (1.342.19)	<0.001
CA	674 (22.3)	1.42 (1.091.86)	0.012
CKD	344 (11.4)	2.04 (1.492.80)	<0.001
CAD	1479 (49.0)	1.51 (1.181.92)	0.001
CHF	911 (30.2)	2.41 (1.893.08)	<0.001
CVA/TIA	802 (26.6)	1.08 (0.821.41)	0.587
Lipid	865 (28.6)	0.81 (0.611.06)	0.123
Blood chemistry	Creatinine > 2	228 (7.5)	3.11 (2.224.36)	<0.001
	Albumin 3.5	629 (20.8)	3.60 (2.804.62)	<0.001
Medication use	Aspirin	1773 (58.7)	1.12 (0.881.44)	0.355
	ACE, inhibitor	1238 (41.0)	0.81 (0.631.04)	0.090
Statin	1214 (40.2)	0.66 (0.510.86)	0.001
Beta blocker	1202 (39.8)	0.76 (0.590.98)	0.031
Clonidine	115 (3.8)	1.65 (0.972.80)	0.080
Insulin	474 (15.7)	1.47 (1.091.98)	0.013
Number of study drugs used	None	545 (18.0)	1	0.018
	One of 4	783 (25.9)	1.06 (0.751.51)
Two of 4	736 (24.4)	0.94 (0.651.35)
Three of 4	652 (21.6)	0.73 (0.491.08)
All four	304 (10.1)	0.66 (0.391.09)
Type of surgery	Carotid	861 (28.5)	1	<0.001
	Bypass	1078 (35.7)	1.57 (1.072.29)
Aorta	229 (7.6)	1.92 (1.123.31)
Amputation	852 (28.2)	4.00 (2.815.70)
RCRI category	0	665 (22.0)	1	<0.001
	1	976 (32.3)	1.12 (0.761.66)
2	846 (28.0)	1.66 (1.142.42)
3	553 (17.6)	2.83 (1.934.14)
Surgery year	1998	539 (17.8)	1	0.804
	1999	463 (15.3)	1.36 (0.892.07)
2000	418 (13.8)	1.07 (0.681.68)
2001	407 (13.5)	1.23 (0.791.92)
2002	368 (12.2)	1.34 (0.962.10)
2003	371 (12.3)	1.25 (0.801.97)
2004	395 (13.1)	1.17 (0.741.84)
2005	59 (2.0)	0.80 (0.282.30)

The most common single‐drug exposure was aspirin, 14% (416), followed by ACE inhibitors, 5% (163) (Table 2). The more common 2‐drug exposures included ACE inhibitors and aspirin, 7% (203), aspirin and beta‐blockers, 5% (161), and aspirin and statins, 5% (141). The common 3‐drug combinations included aspirin, beta‐blockers, and statins, 8% (229); ACE inhibitors, aspirin, and statins, 6% (167); and ACE inhibitors, aspirin, and beta‐blockers, 5% (152). ACE inhibitor exposure was common in all combinations, eg, 20.8% of the 1‐drug group had exposure to an ACE inhibitor, 40.5% in the 2‐drug group, 64.9% in the 3‐drug group, and all patients in the 4‐drug group. Overall, 39.3% of patients in the study had ACE inhibitor exposure. The gross unadjusted mortality for each drug exposure group was 10.6% for the no drug group, 11.2% for the 1‐drug group, 10.1% for the 2‐drug group, 8% for the 3‐drug group, and 7.2% for the 4‐drug group.

Table 2.Frequencies of Combination Drug Exposure Classes Before and 6 Months After Surgery

Drugs Used	Presurgery		6 Months Postsurgery
	Frequency	%	Frequency	%
* There were 294 deaths. Abbreviation: ACE, angiotensin‐converting enzyme.
None	545	18.1	669	24.5
1 Drug
Aspirin	416	53.1	169	28.3
ACE inhibitor	163	20.8	135	22.6
Beta‐blocker	110	14.1	163	27.2
Statin	94	12.0	131	21.9
All 1 drug	783	100.0	598	100.0
2 Drugs
Aspirin + ACE inhibitor	203	27.6	102	14.4
Aspirin + Beta‐blocker	161	21.8	117	16.5
Aspirin + Statin	141	19.2	86	12.1
ACE inhibitor + Beta‐blocker	56	7.6	103	14.5
ACE inhibitor + Statin	89	12.1	126	17.7
Beta‐blocker + Statin	86	11.7	176	24.8
All 2 drugs	36	100.0	710	100.0
3 Drugs
Aspirin + ACE inhibitor + Beta‐blocker	152	23.3	96	16.5
Aspirin + ACE inhibitor + Statin	167	25.6	103	17.7
Aspirin + Beta‐ blocker + Statin	229	35.1	165	28.4
ACE inhibitor + Beta‐blocker Statin	104	16.0	218	37.4
All 3 drugs	652	100.0	582	100.0
All 4 drugs	304	10.1	167	6.1
Total	3020	100.0	2726*	100.0

During the 6 complete years of the study (1998‐2004) the frequency of combination exposure for all 4 study drugs increased from 3.5% to 13.4%; 3‐drug exposure also increased, 14.7% to 27.8%; 2‐drug exposure remained relatively stable, 24.5% to 22%; and single‐drug exposure declined, 24.9% to 12.7% (Figure 1). Individual study drug exposures over the 6 years of the study generally also increased with respect to the other combinations: ACE inhibitor use increased, 34.5% to 42.5%; beta‐blocker, 27.8% to 53.4%; statin, 22.6% to 52.2%. The exception was aspirin, which was relatively stable, 54.5% in 1998, and 57.2% in 2004 (Figure 2).

Figure 1

Figure 2

We also compared the use of the study drug exposures at 6 months after surgery to use within 30 days before surgery (Table 2). In the VA healthcare system aspirin is cheaper for some patients to purchase over‐the‐counter. Aspirin is likely underestimated in this dataset. The frequency of follow‐up drug exposure at 6 months was overall similar to the drug exposure within 30 days before surgery. When aspirin was 1 of the combination exposures, the frequencies declined, and when aspirin was not 1 of the exposures, the frequencies generally increased. The frequency of no‐drug exposures increased from 18.1% before surgery to 24.5% 6 months after surgery, and the frequency of all 4 drug exposures decreased from 10.1% to 6.1%, respectively.

Discussion

This retrospective cohort study has demonstrated that the combination use of 4 drugs (aspirin, beta‐blockers, statins, and ACE inhibitors) compared to the use of none of these drugs had a trend toward decreased mortality, with a 49% decrease in propensity‐adjusted 6‐month mortality after vascular surgery and an NNT of 19. In addition, the combination use of 3 drug exposures was significantly associated with a 40% decrease in mortality, with propensity adjustment and NNT of 38; and the 2‐drug combination exposure showed a significant association, with a propensity‐adjusted 32% decreased mortality, and an NNT of 170. Both the unadjusted and adjusted analyses showed a linear trend, suggesting a dose‐response effect of more study‐drug exposure association with less 6‐month mortality and smaller NNT.

The lack of statistical significance for the 4‐drug exposure group is likely due to few patients and events in this group, and the exclusion of the first 2 quintiles (n = 339) due to having zero deaths with which to compare. It is not unusual to exclude patients from analyses in propensity methods. The patients we excluded were low‐risk who had survived to 6‐months after surgery, so they would have also been excluded in a propensity‐matched analysis. We did not perform propensity matching, as we had adequate homogeneity between our quintile strata, and were not powered to perform matching.

This is the first evidence of which we are aware of an association with decreased mortality for the combination perioperative use of aspirin, beta‐blockers, statins, and ACE inhibitors in vascular surgery patients. Aspirin has been associated with decreased mortality in patients undergoing coronary artery bypass graft surgery,25 but the effects of aspirin on noncardiac surgery outcomes is less clear.26

Beta‐blockers and statins have been associated with decreased short‐term and long‐term mortality after vascular surgery in the past,814 but more recent beta‐blocker studies have been negative, introducing controversy for the topic.1517, 27 Beta‐blockers are currently recommended as: Class I (should be used), Evidence Level B (limited population risk strata evaluated) for vascular surgery patients already taking a beta‐blocker or with positive ischemia on stress testing; Class IIa (reasonable to use), Evidence Level B for 1 or more clinical risk factors; or Class IIb (may be considered), Evidence Level B for no clinical risk factors, in the 2007 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for perioperative evaluation.28 Perioperative beta‐blocker trials that have titrated the dose to a goal heart rate have consistently been associated with improved outcomes after vascular surgery,10, 12, 29, 30 and perioperative beta‐blocker trials that have used fixed dosing after surgery have been negative,1517, 27 including the POISE trial, which was associated with increased strokes and mortality.

This is also the first evidence of which we are aware that ACE inhibitors in combination with other drugs may be associated with decreased mortality after vascular surgery. While our study design does not support a causal relationship between ACE inhibitor exposure and decreased mortality, the increasing exposure in each drug exposure group for ACE inhibitors and correlated decreasing mortality is of sufficient interest to warrant further study. The use of ACE inhibitors has been associated with decreased mortality in patients with atherosclerotic vascular disease and CAD.31 There has been a concern expressed in the literature about the perioperative use of ACE inhibitors due to the potential for intraoperative hypotension.3236 Many centers advise patients to discontinue ACE inhibitor use the day before surgery. The number of patients studied remains small. More research is needed to clarify this issue. Use of angiotensin‐receptor blockers was not assessed; their use was considered to be rare, because use was restricted to patients intolerant of ACE inhibitors during the study period.

The 2005 ACC/AHA guideline for patients with peripheral arterial disease recommends the use of aspirin and statins.37 ACE inhibitors are recommended for both asymptomatic and symptomatic peripheral artery disease patients. The 2006 ACC/AHA guidelines for secondary prevention for patients with coronary or other atherosclerotic vascular disease recommends the use of chronic beta‐blockers.38 There appears to be some benefit in mortality from the combination aspirin, beta‐blocker, statin, and ACE inhibitor drug regimen in patients with established atherosclerotic vascular disease.

We expect the frequency of aspirin exposure to be underestimated in this study population (due to over‐the‐counter undocumented use), so our findings may be somewhat underestimated as well. This may also explain why the frequency of aspirin remained constant over time while the other drug exposures increased over time.

Our study has several limitations. First, our design was a retrospective cohort. Propensity analysis attempts to correct for confounding by indication in nonrandomized studies as patients that are exposed to a study drug are different from patients that are not exposed to the same study drug. For example, without adjustment for the propensity scores, the drug exposure classes were significantly associated with demographic and clinical characteristics when compare to the no‐drug‐exposure patients. However, with the propensity score adjustment, these associations were no longer statistically significant, with the exception of hyperlipidemia in patients taking all 4 drugs, which supports a rigorous propensity adjustment. We also controlled for the use of clonidine and serum albumin, both strong predictors of death after noncardiac surgery.22, 39 Second, we utilized administrative ICD‐9 code data for abstraction, and utilized only documented and coded comorbidities in the VA database. Unmeasured confounders may exist. Further, we cannot identify which combinations of specific study drugs were most associated with a reduction in 6‐month mortality, but we believe our data supports the case that all 4 of the study drugs be considered for each patient undergoing vascular surgery. It is important to also note that patient baseline risk, which can be difficult to clarify in retrospective cohort studies, will have a large impact on the results of the NNT. Lastly, this study needs to be repeated in a population that includes a greater number of female participants.

The combination exposure of 2 to 3 study drugs: aspirin, beta‐blockers, statins, and ACE inhibitors was consistently associated with decreased 6‐month mortality after vascular surgery, with a high prevalence of ACE inhibitor use, and the combination exposure of all 4 study drugs was marginally associated with decreased mortality. Consideration for the individual patient undergoing vascular surgery should include whether or not the patient may benefit from these 4 drugs. Further research with prospective and randomized studies is needed to clarify the optimum timing of these drugs and their combination efficacy in vascular surgery patients with attention to patient‐specific risk.

Vascular surgery is the most morbid of the noncardiac surgeries, with a 30‐day mortality estimated to be 3% to 10% and 6‐month mortality estimated to be 10% to 30%.14 Adverse outcomes are highly correlated with the presence of perioperative ischemia and infarction. Perioperative ischemia is associated with a 9‐fold increase in the odds of unstable angina, nonfatal myocardial infarction, and cardiac death, while a perioperative myocardial infarction increases the odds of death 20‐fold up to 2 years after surgery.57 Prior research has centered on the single or combination use of perioperative beta‐blockers and statins, which has been associated with decreased short‐term and long‐term mortality after vascular surgery,814 with the exceptions of the Metoprolol After Vascular Surgery (MAVS)15 and the Perioperative Beta‐Blockade (POBBLE) studies,16 which were negative beta‐blocker randomized controlled trials exclusively in vascular surgery patients, and the Perioperative Ischemic Evaluation (POISE) study,17 which was the largest perioperative beta‐blocker trial to date in noncardiac surgery, with 41% of the patients undergoing vascular surgery.

There have been few studies assessing clinical outcomes in patients taking multiple concurrent cardioprotective medications. Clinicians are challenged to apply research results to their patients, who generally take multiple drugs. A retrospective cohort study of acute coronary syndrome patients did assess the use of evidence‐based, combination therapies, including aspirin, ACE inhibitors, beta‐blockers, and statins, compared to the use of none of these agents and found an association with decreased 6‐month mortality.18 There are no prior noncardiac surgery studies assessing the concurrent use of multiple possibly cardioprotective drugs. There is 1 cohort study of coronary artery bypass graft surgery patients that assessed aspirin, ACE inhibitor, beta‐blocker, and statin use and found associations with decreased mortality.19 As preoperative coronary revascularization has not been found to produce improved survival after vascular surgery, clarifying which perioperative medicines alone or in combination may improve outcomes becomes even more important.20 We sought to ascertain if the use of concurrent combination aspirin, ACE inhibitors, beta‐blockers, and statins compared to nonuse was associated with a decrease in 6‐month mortality after vascular surgery.

Patients and Methods

Results

Patient Characteristics

There were 3020 patients with a median age of 67 years, and interquartile range of 59 to 75 years. Ninety‐nine percent were male, and all patients were assessed for death at 6 months after surgery (Table 1). Ten percent (304) had combination all‐4‐drug exposure, 22% (652) had 3‐drug exposure, 24% (736) had 2‐drug exposure, 26% (783) had 1‐drug exposure, and 18% (545) had no study drug exposures. Eight percent (229) of surgeries were aortic, 28% (861) were carotid, 28% (852) were lower extremity amputation, and 36% (1078) were lower extremity bypass. Twenty‐two percent (665) of patients were low risk, with a RCRI of 0, 60% (1822) were moderate risk with a RCRI of 1 to 2, and 18% (553) were high risk with a RCRI of 3. Overall the 6‐month mortality was 9.7% (294). The 6‐month mortality for carotid endarterectomy was 5.0% (43/861), for lower extremity bypass 7.6% (82/1078), for aorta repair 9.2% (21/229), and for lower extremity amputation 17.4% (148/852).

Table 1.Patient Demographics and Unadjusted Relative Risk of 6‐month Mortality

Variable	Level	N (%) Overall N = 3020	Relative Risk (95% CI)	Chi Square P‐Value
NOTE: Overall 6 month mortality: 9.7% (294). Abbreviations: Ace, angiotensin‐converting enzyme; CA, cancer; CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVA, cerebral vascular disease; DM, diabetes mellitus; HTN, hypertension; IQR, interquartile range; Lipid, hyperlipidemia; RCRI, Revised cardiac risk index; TIA, transient ischemic attack. * Age was continuous. P for linear trend. Chi‐square for overall group effect.
Age: year, median (IQR)		67 (59, 75)	1.04 (1.031.06)	<0.001*
Sex	Female	44 (1.5)	1	0.490
	Male	2976 (98.5)	1.48 (0.464.81)
Preoperative medical conditions	HTN	2388 (79.1)	1.40 (0.011.93)	0.036
	DM	1455 (48.2)	1.45 (1.131.84)	0.003
COPD	912 (30.2)	1.71 (1.342.19)	<0.001
CA	674 (22.3)	1.42 (1.091.86)	0.012
CKD	344 (11.4)	2.04 (1.492.80)	<0.001
CAD	1479 (49.0)	1.51 (1.181.92)	0.001
CHF	911 (30.2)	2.41 (1.893.08)	<0.001
CVA/TIA	802 (26.6)	1.08 (0.821.41)	0.587
Lipid	865 (28.6)	0.81 (0.611.06)	0.123
Blood chemistry	Creatinine > 2	228 (7.5)	3.11 (2.224.36)	<0.001
	Albumin 3.5	629 (20.8)	3.60 (2.804.62)	<0.001
Medication use	Aspirin	1773 (58.7)	1.12 (0.881.44)	0.355
	ACE, inhibitor	1238 (41.0)	0.81 (0.631.04)	0.090
Statin	1214 (40.2)	0.66 (0.510.86)	0.001
Beta blocker	1202 (39.8)	0.76 (0.590.98)	0.031
Clonidine	115 (3.8)	1.65 (0.972.80)	0.080
Insulin	474 (15.7)	1.47 (1.091.98)	0.013
Number of study drugs used	None	545 (18.0)	1	0.018
	One of 4	783 (25.9)	1.06 (0.751.51)
Two of 4	736 (24.4)	0.94 (0.651.35)
Three of 4	652 (21.6)	0.73 (0.491.08)
All four	304 (10.1)	0.66 (0.391.09)
Type of surgery	Carotid	861 (28.5)	1	<0.001
	Bypass	1078 (35.7)	1.57 (1.072.29)
Aorta	229 (7.6)	1.92 (1.123.31)
Amputation	852 (28.2)	4.00 (2.815.70)
RCRI category	0	665 (22.0)	1	<0.001
	1	976 (32.3)	1.12 (0.761.66)
2	846 (28.0)	1.66 (1.142.42)
3	553 (17.6)	2.83 (1.934.14)
Surgery year	1998	539 (17.8)	1	0.804
	1999	463 (15.3)	1.36 (0.892.07)
2000	418 (13.8)	1.07 (0.681.68)
2001	407 (13.5)	1.23 (0.791.92)
2002	368 (12.2)	1.34 (0.962.10)
2003	371 (12.3)	1.25 (0.801.97)
2004	395 (13.1)	1.17 (0.741.84)
2005	59 (2.0)	0.80 (0.282.30)

The most common single‐drug exposure was aspirin, 14% (416), followed by ACE inhibitors, 5% (163) (Table 2). The more common 2‐drug exposures included ACE inhibitors and aspirin, 7% (203), aspirin and beta‐blockers, 5% (161), and aspirin and statins, 5% (141). The common 3‐drug combinations included aspirin, beta‐blockers, and statins, 8% (229); ACE inhibitors, aspirin, and statins, 6% (167); and ACE inhibitors, aspirin, and beta‐blockers, 5% (152). ACE inhibitor exposure was common in all combinations, eg, 20.8% of the 1‐drug group had exposure to an ACE inhibitor, 40.5% in the 2‐drug group, 64.9% in the 3‐drug group, and all patients in the 4‐drug group. Overall, 39.3% of patients in the study had ACE inhibitor exposure. The gross unadjusted mortality for each drug exposure group was 10.6% for the no drug group, 11.2% for the 1‐drug group, 10.1% for the 2‐drug group, 8% for the 3‐drug group, and 7.2% for the 4‐drug group.

Table 2.Frequencies of Combination Drug Exposure Classes Before and 6 Months After Surgery

Drugs Used	Presurgery		6 Months Postsurgery
	Frequency	%	Frequency	%
* There were 294 deaths. Abbreviation: ACE, angiotensin‐converting enzyme.
None	545	18.1	669	24.5
1 Drug
Aspirin	416	53.1	169	28.3
ACE inhibitor	163	20.8	135	22.6
Beta‐blocker	110	14.1	163	27.2
Statin	94	12.0	131	21.9
All 1 drug	783	100.0	598	100.0
2 Drugs
Aspirin + ACE inhibitor	203	27.6	102	14.4
Aspirin + Beta‐blocker	161	21.8	117	16.5
Aspirin + Statin	141	19.2	86	12.1
ACE inhibitor + Beta‐blocker	56	7.6	103	14.5
ACE inhibitor + Statin	89	12.1	126	17.7
Beta‐blocker + Statin	86	11.7	176	24.8
All 2 drugs	36	100.0	710	100.0
3 Drugs
Aspirin + ACE inhibitor + Beta‐blocker	152	23.3	96	16.5
Aspirin + ACE inhibitor + Statin	167	25.6	103	17.7
Aspirin + Beta‐ blocker + Statin	229	35.1	165	28.4
ACE inhibitor + Beta‐blocker Statin	104	16.0	218	37.4
All 3 drugs	652	100.0	582	100.0
All 4 drugs	304	10.1	167	6.1
Total	3020	100.0	2726*	100.0

During the 6 complete years of the study (1998‐2004) the frequency of combination exposure for all 4 study drugs increased from 3.5% to 13.4%; 3‐drug exposure also increased, 14.7% to 27.8%; 2‐drug exposure remained relatively stable, 24.5% to 22%; and single‐drug exposure declined, 24.9% to 12.7% (Figure 1). Individual study drug exposures over the 6 years of the study generally also increased with respect to the other combinations: ACE inhibitor use increased, 34.5% to 42.5%; beta‐blocker, 27.8% to 53.4%; statin, 22.6% to 52.2%. The exception was aspirin, which was relatively stable, 54.5% in 1998, and 57.2% in 2004 (Figure 2).

Figure 1

Figure 2

We also compared the use of the study drug exposures at 6 months after surgery to use within 30 days before surgery (Table 2). In the VA healthcare system aspirin is cheaper for some patients to purchase over‐the‐counter. Aspirin is likely underestimated in this dataset. The frequency of follow‐up drug exposure at 6 months was overall similar to the drug exposure within 30 days before surgery. When aspirin was 1 of the combination exposures, the frequencies declined, and when aspirin was not 1 of the exposures, the frequencies generally increased. The frequency of no‐drug exposures increased from 18.1% before surgery to 24.5% 6 months after surgery, and the frequency of all 4 drug exposures decreased from 10.1% to 6.1%, respectively.

Discussion

This retrospective cohort study has demonstrated that the combination use of 4 drugs (aspirin, beta‐blockers, statins, and ACE inhibitors) compared to the use of none of these drugs had a trend toward decreased mortality, with a 49% decrease in propensity‐adjusted 6‐month mortality after vascular surgery and an NNT of 19. In addition, the combination use of 3 drug exposures was significantly associated with a 40% decrease in mortality, with propensity adjustment and NNT of 38; and the 2‐drug combination exposure showed a significant association, with a propensity‐adjusted 32% decreased mortality, and an NNT of 170. Both the unadjusted and adjusted analyses showed a linear trend, suggesting a dose‐response effect of more study‐drug exposure association with less 6‐month mortality and smaller NNT.

The lack of statistical significance for the 4‐drug exposure group is likely due to few patients and events in this group, and the exclusion of the first 2 quintiles (n = 339) due to having zero deaths with which to compare. It is not unusual to exclude patients from analyses in propensity methods. The patients we excluded were low‐risk who had survived to 6‐months after surgery, so they would have also been excluded in a propensity‐matched analysis. We did not perform propensity matching, as we had adequate homogeneity between our quintile strata, and were not powered to perform matching.

This is the first evidence of which we are aware of an association with decreased mortality for the combination perioperative use of aspirin, beta‐blockers, statins, and ACE inhibitors in vascular surgery patients. Aspirin has been associated with decreased mortality in patients undergoing coronary artery bypass graft surgery,25 but the effects of aspirin on noncardiac surgery outcomes is less clear.26

Beta‐blockers and statins have been associated with decreased short‐term and long‐term mortality after vascular surgery in the past,814 but more recent beta‐blocker studies have been negative, introducing controversy for the topic.1517, 27 Beta‐blockers are currently recommended as: Class I (should be used), Evidence Level B (limited population risk strata evaluated) for vascular surgery patients already taking a beta‐blocker or with positive ischemia on stress testing; Class IIa (reasonable to use), Evidence Level B for 1 or more clinical risk factors; or Class IIb (may be considered), Evidence Level B for no clinical risk factors, in the 2007 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for perioperative evaluation.28 Perioperative beta‐blocker trials that have titrated the dose to a goal heart rate have consistently been associated with improved outcomes after vascular surgery,10, 12, 29, 30 and perioperative beta‐blocker trials that have used fixed dosing after surgery have been negative,1517, 27 including the POISE trial, which was associated with increased strokes and mortality.

This is also the first evidence of which we are aware that ACE inhibitors in combination with other drugs may be associated with decreased mortality after vascular surgery. While our study design does not support a causal relationship between ACE inhibitor exposure and decreased mortality, the increasing exposure in each drug exposure group for ACE inhibitors and correlated decreasing mortality is of sufficient interest to warrant further study. The use of ACE inhibitors has been associated with decreased mortality in patients with atherosclerotic vascular disease and CAD.31 There has been a concern expressed in the literature about the perioperative use of ACE inhibitors due to the potential for intraoperative hypotension.3236 Many centers advise patients to discontinue ACE inhibitor use the day before surgery. The number of patients studied remains small. More research is needed to clarify this issue. Use of angiotensin‐receptor blockers was not assessed; their use was considered to be rare, because use was restricted to patients intolerant of ACE inhibitors during the study period.

The 2005 ACC/AHA guideline for patients with peripheral arterial disease recommends the use of aspirin and statins.37 ACE inhibitors are recommended for both asymptomatic and symptomatic peripheral artery disease patients. The 2006 ACC/AHA guidelines for secondary prevention for patients with coronary or other atherosclerotic vascular disease recommends the use of chronic beta‐blockers.38 There appears to be some benefit in mortality from the combination aspirin, beta‐blocker, statin, and ACE inhibitor drug regimen in patients with established atherosclerotic vascular disease.

We expect the frequency of aspirin exposure to be underestimated in this study population (due to over‐the‐counter undocumented use), so our findings may be somewhat underestimated as well. This may also explain why the frequency of aspirin remained constant over time while the other drug exposures increased over time.

Our study has several limitations. First, our design was a retrospective cohort. Propensity analysis attempts to correct for confounding by indication in nonrandomized studies as patients that are exposed to a study drug are different from patients that are not exposed to the same study drug. For example, without adjustment for the propensity scores, the drug exposure classes were significantly associated with demographic and clinical characteristics when compare to the no‐drug‐exposure patients. However, with the propensity score adjustment, these associations were no longer statistically significant, with the exception of hyperlipidemia in patients taking all 4 drugs, which supports a rigorous propensity adjustment. We also controlled for the use of clonidine and serum albumin, both strong predictors of death after noncardiac surgery.22, 39 Second, we utilized administrative ICD‐9 code data for abstraction, and utilized only documented and coded comorbidities in the VA database. Unmeasured confounders may exist. Further, we cannot identify which combinations of specific study drugs were most associated with a reduction in 6‐month mortality, but we believe our data supports the case that all 4 of the study drugs be considered for each patient undergoing vascular surgery. It is important to also note that patient baseline risk, which can be difficult to clarify in retrospective cohort studies, will have a large impact on the results of the NNT. Lastly, this study needs to be repeated in a population that includes a greater number of female participants.

The combination exposure of 2 to 3 study drugs: aspirin, beta‐blockers, statins, and ACE inhibitors was consistently associated with decreased 6‐month mortality after vascular surgery, with a high prevalence of ACE inhibitor use, and the combination exposure of all 4 study drugs was marginally associated with decreased mortality. Consideration for the individual patient undergoing vascular surgery should include whether or not the patient may benefit from these 4 drugs. Further research with prospective and randomized studies is needed to clarify the optimum timing of these drugs and their combination efficacy in vascular surgery patients with attention to patient‐specific risk.

A 63‐year‐old man with multiple medical problems was transferred from a nursing home to the emergency room with progressively worsening diffuse abdominal pain of 3 days' duration. His vital signs were significant for heart rate of 94 beats per minute, blood pressure of 126/84 mmHg, respiratory rate of 20 breaths per minute, and oxygen saturation of 98% on room air. Abdominal examination showed diffuse tenderness in all quadrants. Active bowel sounds were heard; guarding or rigidity was absent. Examination of respiratory and cardiovascular system was unremarkable. His laboratory tests showed leukocytosis with left shift. Topogram done for planning computed tomography (CT) scan of abdomen (Figure 1) showed the following findings:

• 1

  The dilated sigmoid loops (outlined by linear black arrows) have closely apposed medial walls (arrowheads), giving the appearance of a coffee bean. In addition, the apex of the loop is seen under the left hemidiaphragm.

• 2

  The dilated sigmoid loop is seen to overlap the descending colon (the left flank overlap sign). The lateral margin of descending colon is shown with bold white arrows.

• 3

  The level of convergence of the 2 limbs of the loop is seen to lie below the lumbosacral junction and to the left of the midline (inferior convergence sign, shown by the bold black arrow).

• 4

  The small bowel and large bowel loops are dilated due to distal obstruction and are seen overlapping with the distended sigmoid colon.

• 5

  The rectal gas is not visualized.

Figure 1

These features were suggestive of sigmoid volvulus.

Patients with sigmoid volvulus are often in the sixth to eighth decades of life and frequently have concomitant chronic illnesses, such as cardiac, pulmonary, and renal disease, that significantly influence their outcome.14 Males develop sigmoid volvulus more commonly than do females. In a large series of patients with sigmoid volvulus, 30% had a history of psychiatric disease and 13% were institutionalized at the time of diagnosis.4 Abdominal tenderness is present in less than one‐third of patients with volvulus, and severe pain or signs of peritonitis suggest impending or actual colonic necrosis and perforation.

Plain radiograph of the abdomen is usually diagnostic and reveals a dilated ahaustral sigmoid colon with features of closed‐loop obstruction (bent inner‐tube appearance). The apex of the loop usually extends above the T10 vertebra. The various signs described for sigmoid volvulus on plain radiograph and the sensitivity and specificity for these are given in Table 1.5 A diagnosis of sigmoid volvulus can be made with abdominal radiographs alone in as many as 85% of instances.3 A CT scan helps detect the changes of bowel ischemia and can confirm or provide an alternate diagnosis. A single contrast barium enema examination may be done if signs of bowel ischemia or perforation are absent. This may reveal a mucosal spiral pattern or bird's beak appearance (due to abrupt termination of the barium column) at the site of twist.

In patients with abdominal films most consistent with a sigmoid volvulus, initial rigid or flexible proctosigmoidoscopy may allow prompt decompression of the volvulus. Early recognition and treatment are necessary to prevent mortality. Placement of a rectal tube for 48 hours may minimize the possibility of early recurrence. Successful reduction of sigmoid volvulus also has been reported with colonoscopy; however, the procedure must be performed carefully with minimal insufflation of air (or preferably carbon dioxide) to minimize the risk of perforation of the distended, inflamed bowel. Endoscopic reduction of sigmoid volvulus alone is associated with a recurrence rate of 25% to 50%.1, 2, 6, 7 Hence, elective sigmoid resection and coloproctostomy, or in medically compromised patients, end colostomy, should follow proctoscopic decompression and mechanical preparation of the bowel. Recurrence rates with this approach are 3% to 6%.1, 2, 7 Patients requiring emergent laparotomy for strangulated sigmoid volvulus require sigmoid resection with end colostomy and a Hartmann pouch. The patient's volvulus was successfully decompressed with colonoscopy. He was offered elective sigmoid resection and coloproctostomy as a definitive therapy, which he declined.

A 63‐year‐old man with multiple medical problems was transferred from a nursing home to the emergency room with progressively worsening diffuse abdominal pain of 3 days' duration. His vital signs were significant for heart rate of 94 beats per minute, blood pressure of 126/84 mmHg, respiratory rate of 20 breaths per minute, and oxygen saturation of 98% on room air. Abdominal examination showed diffuse tenderness in all quadrants. Active bowel sounds were heard; guarding or rigidity was absent. Examination of respiratory and cardiovascular system was unremarkable. His laboratory tests showed leukocytosis with left shift. Topogram done for planning computed tomography (CT) scan of abdomen (Figure 1) showed the following findings:

• 1

  The dilated sigmoid loops (outlined by linear black arrows) have closely apposed medial walls (arrowheads), giving the appearance of a coffee bean. In addition, the apex of the loop is seen under the left hemidiaphragm.

• 2

  The dilated sigmoid loop is seen to overlap the descending colon (the left flank overlap sign). The lateral margin of descending colon is shown with bold white arrows.

• 3

  The level of convergence of the 2 limbs of the loop is seen to lie below the lumbosacral junction and to the left of the midline (inferior convergence sign, shown by the bold black arrow).

• 4

  The small bowel and large bowel loops are dilated due to distal obstruction and are seen overlapping with the distended sigmoid colon.

• 5

  The rectal gas is not visualized.

Figure 1

These features were suggestive of sigmoid volvulus.

Patients with sigmoid volvulus are often in the sixth to eighth decades of life and frequently have concomitant chronic illnesses, such as cardiac, pulmonary, and renal disease, that significantly influence their outcome.14 Males develop sigmoid volvulus more commonly than do females. In a large series of patients with sigmoid volvulus, 30% had a history of psychiatric disease and 13% were institutionalized at the time of diagnosis.4 Abdominal tenderness is present in less than one‐third of patients with volvulus, and severe pain or signs of peritonitis suggest impending or actual colonic necrosis and perforation.

Plain radiograph of the abdomen is usually diagnostic and reveals a dilated ahaustral sigmoid colon with features of closed‐loop obstruction (bent inner‐tube appearance). The apex of the loop usually extends above the T10 vertebra. The various signs described for sigmoid volvulus on plain radiograph and the sensitivity and specificity for these are given in Table 1.5 A diagnosis of sigmoid volvulus can be made with abdominal radiographs alone in as many as 85% of instances.3 A CT scan helps detect the changes of bowel ischemia and can confirm or provide an alternate diagnosis. A single contrast barium enema examination may be done if signs of bowel ischemia or perforation are absent. This may reveal a mucosal spiral pattern or bird's beak appearance (due to abrupt termination of the barium column) at the site of twist.

In patients with abdominal films most consistent with a sigmoid volvulus, initial rigid or flexible proctosigmoidoscopy may allow prompt decompression of the volvulus. Early recognition and treatment are necessary to prevent mortality. Placement of a rectal tube for 48 hours may minimize the possibility of early recurrence. Successful reduction of sigmoid volvulus also has been reported with colonoscopy; however, the procedure must be performed carefully with minimal insufflation of air (or preferably carbon dioxide) to minimize the risk of perforation of the distended, inflamed bowel. Endoscopic reduction of sigmoid volvulus alone is associated with a recurrence rate of 25% to 50%.1, 2, 6, 7 Hence, elective sigmoid resection and coloproctostomy, or in medically compromised patients, end colostomy, should follow proctoscopic decompression and mechanical preparation of the bowel. Recurrence rates with this approach are 3% to 6%.1, 2, 7 Patients requiring emergent laparotomy for strangulated sigmoid volvulus require sigmoid resection with end colostomy and a Hartmann pouch. The patient's volvulus was successfully decompressed with colonoscopy. He was offered elective sigmoid resection and coloproctostomy as a definitive therapy, which he declined.

A 63‐year‐old man with multiple medical problems was transferred from a nursing home to the emergency room with progressively worsening diffuse abdominal pain of 3 days' duration. His vital signs were significant for heart rate of 94 beats per minute, blood pressure of 126/84 mmHg, respiratory rate of 20 breaths per minute, and oxygen saturation of 98% on room air. Abdominal examination showed diffuse tenderness in all quadrants. Active bowel sounds were heard; guarding or rigidity was absent. Examination of respiratory and cardiovascular system was unremarkable. His laboratory tests showed leukocytosis with left shift. Topogram done for planning computed tomography (CT) scan of abdomen (Figure 1) showed the following findings:

• 1

  The dilated sigmoid loops (outlined by linear black arrows) have closely apposed medial walls (arrowheads), giving the appearance of a coffee bean. In addition, the apex of the loop is seen under the left hemidiaphragm.

• 2

  The dilated sigmoid loop is seen to overlap the descending colon (the left flank overlap sign). The lateral margin of descending colon is shown with bold white arrows.

• 3

  The level of convergence of the 2 limbs of the loop is seen to lie below the lumbosacral junction and to the left of the midline (inferior convergence sign, shown by the bold black arrow).

• 4

  The small bowel and large bowel loops are dilated due to distal obstruction and are seen overlapping with the distended sigmoid colon.

• 5

  The rectal gas is not visualized.

Figure 1

These features were suggestive of sigmoid volvulus.

Patients with sigmoid volvulus are often in the sixth to eighth decades of life and frequently have concomitant chronic illnesses, such as cardiac, pulmonary, and renal disease, that significantly influence their outcome.14 Males develop sigmoid volvulus more commonly than do females. In a large series of patients with sigmoid volvulus, 30% had a history of psychiatric disease and 13% were institutionalized at the time of diagnosis.4 Abdominal tenderness is present in less than one‐third of patients with volvulus, and severe pain or signs of peritonitis suggest impending or actual colonic necrosis and perforation.

Plain radiograph of the abdomen is usually diagnostic and reveals a dilated ahaustral sigmoid colon with features of closed‐loop obstruction (bent inner‐tube appearance). The apex of the loop usually extends above the T10 vertebra. The various signs described for sigmoid volvulus on plain radiograph and the sensitivity and specificity for these are given in Table 1.5 A diagnosis of sigmoid volvulus can be made with abdominal radiographs alone in as many as 85% of instances.3 A CT scan helps detect the changes of bowel ischemia and can confirm or provide an alternate diagnosis. A single contrast barium enema examination may be done if signs of bowel ischemia or perforation are absent. This may reveal a mucosal spiral pattern or bird's beak appearance (due to abrupt termination of the barium column) at the site of twist.

In patients with abdominal films most consistent with a sigmoid volvulus, initial rigid or flexible proctosigmoidoscopy may allow prompt decompression of the volvulus. Early recognition and treatment are necessary to prevent mortality. Placement of a rectal tube for 48 hours may minimize the possibility of early recurrence. Successful reduction of sigmoid volvulus also has been reported with colonoscopy; however, the procedure must be performed carefully with minimal insufflation of air (or preferably carbon dioxide) to minimize the risk of perforation of the distended, inflamed bowel. Endoscopic reduction of sigmoid volvulus alone is associated with a recurrence rate of 25% to 50%.1, 2, 6, 7 Hence, elective sigmoid resection and coloproctostomy, or in medically compromised patients, end colostomy, should follow proctoscopic decompression and mechanical preparation of the bowel. Recurrence rates with this approach are 3% to 6%.1, 2, 7 Patients requiring emergent laparotomy for strangulated sigmoid volvulus require sigmoid resection with end colostomy and a Hartmann pouch. The patient's volvulus was successfully decompressed with colonoscopy. He was offered elective sigmoid resection and coloproctostomy as a definitive therapy, which he declined.

A 56‐year‐old man with a 1‐year history of a verrucous nodule on his left foot presented to our department due to the unexpected growth. He was previously diagnosed with a plantar wart so underwent salicylic ointment application, liquid‐nitrogen cryotherapy and electrocoagulation, with no improvement of the condition.

Clinical examination revealed a 22‐mm flesh‐colored, centrally hypopigmented and ulcerated, exophytic nodule, with an adjacent 5 4 mm pink papule with telangiectasia (Figure 1A and B).

Figure 1

Histological examination established the diagnosis of ulcerated amelanotic malignant melanoma (Clark's level IV, Breslow's thickness of 3 mm) with a satellite nodule. Radical inguinal lymph node dissection yielded a negative result. Total‐body computed tomographic scan was unremarkable. One‐year follow‐up revealed no metastatic disease.

Melanoma of the foot accounts for 3% to 15% of all cutaneous melanoma. In acral skin, melanomas tend to have unusual clinical appearances. Amelanotic variants may masquerade as several benign hyperkeratotic dermatoses (warts, calluses, fungal disorders, foreign bodies, moles, keratoacanthomas, hematomas) increasing misdiagnosis and inadequate treatment rates, with a poorer patient outcome.1 Pedal lesions require close observation and biopsy when diagnostic uncertainty exists or when therapeutic interventions fail.

A 56‐year‐old man with a 1‐year history of a verrucous nodule on his left foot presented to our department due to the unexpected growth. He was previously diagnosed with a plantar wart so underwent salicylic ointment application, liquid‐nitrogen cryotherapy and electrocoagulation, with no improvement of the condition.

Clinical examination revealed a 22‐mm flesh‐colored, centrally hypopigmented and ulcerated, exophytic nodule, with an adjacent 5 4 mm pink papule with telangiectasia (Figure 1A and B).

Figure 1

Histological examination established the diagnosis of ulcerated amelanotic malignant melanoma (Clark's level IV, Breslow's thickness of 3 mm) with a satellite nodule. Radical inguinal lymph node dissection yielded a negative result. Total‐body computed tomographic scan was unremarkable. One‐year follow‐up revealed no metastatic disease.

Melanoma of the foot accounts for 3% to 15% of all cutaneous melanoma. In acral skin, melanomas tend to have unusual clinical appearances. Amelanotic variants may masquerade as several benign hyperkeratotic dermatoses (warts, calluses, fungal disorders, foreign bodies, moles, keratoacanthomas, hematomas) increasing misdiagnosis and inadequate treatment rates, with a poorer patient outcome.1 Pedal lesions require close observation and biopsy when diagnostic uncertainty exists or when therapeutic interventions fail.

A 56‐year‐old man with a 1‐year history of a verrucous nodule on his left foot presented to our department due to the unexpected growth. He was previously diagnosed with a plantar wart so underwent salicylic ointment application, liquid‐nitrogen cryotherapy and electrocoagulation, with no improvement of the condition.

Clinical examination revealed a 22‐mm flesh‐colored, centrally hypopigmented and ulcerated, exophytic nodule, with an adjacent 5 4 mm pink papule with telangiectasia (Figure 1A and B).

Figure 1

Histological examination established the diagnosis of ulcerated amelanotic malignant melanoma (Clark's level IV, Breslow's thickness of 3 mm) with a satellite nodule. Radical inguinal lymph node dissection yielded a negative result. Total‐body computed tomographic scan was unremarkable. One‐year follow‐up revealed no metastatic disease.

Melanoma of the foot accounts for 3% to 15% of all cutaneous melanoma. In acral skin, melanomas tend to have unusual clinical appearances. Amelanotic variants may masquerade as several benign hyperkeratotic dermatoses (warts, calluses, fungal disorders, foreign bodies, moles, keratoacanthomas, hematomas) increasing misdiagnosis and inadequate treatment rates, with a poorer patient outcome.1 Pedal lesions require close observation and biopsy when diagnostic uncertainty exists or when therapeutic interventions fail.

A 53‐year‐old man with a history of heavy tobacco use presented with shortness of breath. Eight days prior to his presentation he was diagnosed with multiple rib fractures after suffering an assault. Since then he had developed dyspnea and a nonproductive cough. A chest x‐ray revealed a large pneumothorax on the right with approximately 80% volume loss (arrow, Figure 1).

Figure 1

Tube thoracostomy was performed. Repeat chest x‐ray showed that the pneumothorax had resolved, revealing a consolidation likely caused by either reexpansion pulmonary edema1, 2 or, given its location in the superior segment of the right lower lobe, aspiration pneumonia (thin arrow, Figure 2). Also seen in the x‐ray is an old scar (thick arrow, Figure 2) and apical bullous changes with hyperinflated lungs suggestive of chronic obstructive pulmonary disease (COPD).

Figure 2

DISCUSSION

Pneumothorax is a common complication of blunt trauma and rib fractures.3 While the patient did not have a preceding diagnosis of COPD, his extensive smoking history and his radiographic changes are consistent with COPD, which is a risk factor for pneumothroax. Secondary pneumothorax is defined as pneumothorax that occurs as a complication of underlying lung disease and is most commonly associated with COPD,4 with rupturing of apical blebs as the proposed mechanism. This patient suffered a pneumothorax due to trauma, but given his COPD he is at increased risk for developing spontaneous pneumothorax in the future.

A 53‐year‐old man with a history of heavy tobacco use presented with shortness of breath. Eight days prior to his presentation he was diagnosed with multiple rib fractures after suffering an assault. Since then he had developed dyspnea and a nonproductive cough. A chest x‐ray revealed a large pneumothorax on the right with approximately 80% volume loss (arrow, Figure 1).

Figure 1

Tube thoracostomy was performed. Repeat chest x‐ray showed that the pneumothorax had resolved, revealing a consolidation likely caused by either reexpansion pulmonary edema1, 2 or, given its location in the superior segment of the right lower lobe, aspiration pneumonia (thin arrow, Figure 2). Also seen in the x‐ray is an old scar (thick arrow, Figure 2) and apical bullous changes with hyperinflated lungs suggestive of chronic obstructive pulmonary disease (COPD).

Figure 2

DISCUSSION

Pneumothorax is a common complication of blunt trauma and rib fractures.3 While the patient did not have a preceding diagnosis of COPD, his extensive smoking history and his radiographic changes are consistent with COPD, which is a risk factor for pneumothroax. Secondary pneumothorax is defined as pneumothorax that occurs as a complication of underlying lung disease and is most commonly associated with COPD,4 with rupturing of apical blebs as the proposed mechanism. This patient suffered a pneumothorax due to trauma, but given his COPD he is at increased risk for developing spontaneous pneumothorax in the future.

A 53‐year‐old man with a history of heavy tobacco use presented with shortness of breath. Eight days prior to his presentation he was diagnosed with multiple rib fractures after suffering an assault. Since then he had developed dyspnea and a nonproductive cough. A chest x‐ray revealed a large pneumothorax on the right with approximately 80% volume loss (arrow, Figure 1).

Figure 1

Tube thoracostomy was performed. Repeat chest x‐ray showed that the pneumothorax had resolved, revealing a consolidation likely caused by either reexpansion pulmonary edema1, 2 or, given its location in the superior segment of the right lower lobe, aspiration pneumonia (thin arrow, Figure 2). Also seen in the x‐ray is an old scar (thick arrow, Figure 2) and apical bullous changes with hyperinflated lungs suggestive of chronic obstructive pulmonary disease (COPD).

Figure 2

DISCUSSION

Pneumothorax is a common complication of blunt trauma and rib fractures.3 While the patient did not have a preceding diagnosis of COPD, his extensive smoking history and his radiographic changes are consistent with COPD, which is a risk factor for pneumothroax. Secondary pneumothorax is defined as pneumothorax that occurs as a complication of underlying lung disease and is most commonly associated with COPD,4 with rupturing of apical blebs as the proposed mechanism. This patient suffered a pneumothorax due to trauma, but given his COPD he is at increased risk for developing spontaneous pneumothorax in the future.

A 68‐year‐old man with a history of congestive heart failure and hypertension presented to the emergency department with fatigue and dyspnea of 3 weeks duration. Physical examination was consistent with heart failure. In addition, a right upper extremity resting tremor was noticed. An electrocardiogram (ECG) revealed an atrial flutter with a conduction ratio of 4:1 (Figure 1A). He denied palpitations or a previous history of atrial flutter/fibrillation. Unlike typical atrial flutter, these flutter like waves were distinctly absent in lead III, the only limb lead not connected to the right arm.

Figure 1

While holding the patient's right arm to control the tremor, a second ECG tracing was obtained. As expected the flutter like waves disappeared (Figure 1B). These ECG findings were attributed to the patient's tremor. A neurological consultation established a clinical diagnosis of Parkinson's disease. His congestive heart failure (CHF) was treated with increasing diuretics and appropriate treatment for Parkinson's disease was initiated.

A 68‐year‐old man with a history of congestive heart failure and hypertension presented to the emergency department with fatigue and dyspnea of 3 weeks duration. Physical examination was consistent with heart failure. In addition, a right upper extremity resting tremor was noticed. An electrocardiogram (ECG) revealed an atrial flutter with a conduction ratio of 4:1 (Figure 1A). He denied palpitations or a previous history of atrial flutter/fibrillation. Unlike typical atrial flutter, these flutter like waves were distinctly absent in lead III, the only limb lead not connected to the right arm.

Figure 1

While holding the patient's right arm to control the tremor, a second ECG tracing was obtained. As expected the flutter like waves disappeared (Figure 1B). These ECG findings were attributed to the patient's tremor. A neurological consultation established a clinical diagnosis of Parkinson's disease. His congestive heart failure (CHF) was treated with increasing diuretics and appropriate treatment for Parkinson's disease was initiated.

A 68‐year‐old man with a history of congestive heart failure and hypertension presented to the emergency department with fatigue and dyspnea of 3 weeks duration. Physical examination was consistent with heart failure. In addition, a right upper extremity resting tremor was noticed. An electrocardiogram (ECG) revealed an atrial flutter with a conduction ratio of 4:1 (Figure 1A). He denied palpitations or a previous history of atrial flutter/fibrillation. Unlike typical atrial flutter, these flutter like waves were distinctly absent in lead III, the only limb lead not connected to the right arm.

Figure 1

While holding the patient's right arm to control the tremor, a second ECG tracing was obtained. As expected the flutter like waves disappeared (Figure 1B). These ECG findings were attributed to the patient's tremor. A neurological consultation established a clinical diagnosis of Parkinson's disease. His congestive heart failure (CHF) was treated with increasing diuretics and appropriate treatment for Parkinson's disease was initiated.

Quality of care in US hospitals is inconsistent and often below accepted standards.1 This observation has catalyzed a number of performance measurement initiatives intended to publicize gaps and spur quality improvement.2 As the field has evolved, organizational factors such as teaching status, ownership model, nurse staffing levels, and hospital volume have been found to be associated with performance on quality measures.1, 3‐7 Hospitalists represent a more recent change in the organization of inpatient care8 that may impact hospital‐level performance. In fact, most hospitals provide financial support to hospitalists, not only for hopes of improving efficiency, but also for improving quality and safety.9

Only a few single‐site studies have examined the impact of hospitalists on quality of care for common medical conditions (ie, pneumonia, congestive heart failure, and acute myocardial infarction), and each has focused on patient‐level effects. Rifkin et al.10, 11 did not find differences between hospitalists' and nonhospitalists' patients in terms of pneumonia process measures. Roytman et al.12 found hospitalists more frequently prescribed afterload‐reducing agents for congestive heart failure (CHF), but other studies have shown no differences in care quality for heart failure.13, 14 Importantly, no studies have examined the role of hospitalists in the care of patients with acute myocardial infarction (AMI). In addition, studies have not addressed the effect of hospitalists at the hospital level to understand whether hospitalists have broader system‐level effects reflected by overall hospital performance.

We hypothesized that the presence of hospitalists within a hospital would be associated with improvements in hospital‐level adherence to publicly reported quality process measures, and having a greater percentage of patients admitted by hospitalists would be associated with improved performance. To test these hypotheses, we linked data from a statewide census of hospitalists with data collected as part of a hospital quality‐reporting initiative.

Materials and Methods

Results