David H. Wesorick, MD

A 58‐year‐old man presented to the emergency department with a 1‐month history of progressive, severe left hip pain that had become unbearable. The pain was constant and significantly worse with weight‐bearing, and the patient was now confined to bed. He denied back pain, falls, or trauma.

Although hip pain is a common complaint and a frequent manifestation of chronic degenerative joint disease, the debilitating and subacute nature of the pain suggests a potentially more serious underlying cause. Patients and even clinicians may refer to hip pain when the actual symptoms are periarticular, often presenting over the trochanter laterally, or muscular, presenting as posterior pain. The true hip joint is located in the anterior hip and groin area and often causes symptoms that radiate to the buttock. Pain can also be referred to the hip area from the spine, pelvis, or retroperitoneum, so it is crucial not to restrict the differential diagnosis to hip pathology.

Key diagnostic considerations include (1) inflammatory conditions such as trochanteric bursitis or gout; (2) bacterial infection of the hip joint, adjacent bone, or a nearby structure; (3) benign nerve compression (such as meralgia paresthetica); and (4) tumor (particularly myeloma or metastatic disease to the bone, but also potentially a pelvic or spinal mass with nerve compression). Polymyalgia rheumatica and other systemic rheumatologic complaints are a consideration, but because a single joint is involved, these conditions are less likely. The hip would be an unusual location for a first gout flare, and the duration of symptoms would be unusually long for gout. Avascular necrosis should be considered if the patient has received glucocorticoids for his previously diagnosed rheumatologic disease. If the patient is anticoagulated, consideration of spontaneous hematoma is reasonable, but usually this would present over a course of days, not weeks. The absence of trauma makes a fracture of the hip or pelvis less likely, and the insidious progression of symptoms makes a pathologic fracture less likely.

The patient reported 6 months of worsening proximal upper and lower extremity myalgia and weakness, with arthralgia of the hips and shoulders. The weakness was most notable in his proximal lower extremities, although he had remained ambulatory until the hip pain became limiting. He maintained normal use of his arms. The patient denied current rash but noted photosensitivity and a mild facial rash several months earlier. He described having transient mouth sores intermittently for several years. He denied fever, chills, night sweats, weight loss, dyspnea, recent travel, and outdoor exposures. Several months previously, he had been evaluated for these symptoms at another institution and given the diagnoses of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). At that time, he had initiated treatment with weekly dosing of methotrexate and etanercept.

The patient's medical history was also notable for hypertension, Graves' disease treated previously with radioiodine ablation, quiescent ulcerative colitis, and depression. Current medications included methotrexate, etanercept, levothyroxine, enalapril, hydrochlorothiazide, fluoxetine, ibuprofen, and oxycodone‐acetaminophen. He denied tobacco, alcohol, and recreational drug use.

Weakness occurring in the proximal lower extremities is the classic distribution for polymyositis and dermatomyositis. In contrast to polymyalgia rheumatica, dermatomyositis and polymyositis do not generally feature severe muscle pain, but they can be associated with a painful polyarthritis. Oral ulcers, photosensitivity, and facial rash are consistent with SLE, but dermatomyositis can also lead to a symmetrical erythema of the eyelids (commonly referred to as a heliotrope rash, named after the flower bearing that name) and sometimes can be associated with photosensitivity. Oral ulcers, particularly the painful ones known as canker sores, are extraordinarily common in the general population, and patients and providers may miss the mucosal lesions of SLE because they are usually painless. As methotrexate and etanercept are immunosuppressive, opportunistic pathogens such as typical or atypical mycobacteria and disseminated fungal infections should be considered, with special attention to the possibility of infection in or near the left hip. Given that SLE and RA rarely coexist, it would be helpful to seek outside medical records to know what the prior serologic evaluation entailed, but it is unlikely that this presentation is a manifestation of a diffuse connective tissue process.

Physical examination should focus on the features of dermatomyositis including heliotrope rash, truncal erythema, and papules over the knuckles (Gottron's papules); objective proximal muscle weakness in the shoulder and hip girdle; and findings that might suggest antisynthetase syndrome such as hyperkeratotic mechanic hand palmar and digital changes, and interstitial crackles on lung exam. If necrotic skin lesions are found, this would raise concern for a disseminated infection. The joints should be examined for inflammation and effusions.

His temperature was 36.6C, heart rate 74 beats per minute, blood pressure 134/76 mm Hg, respiratory rate 16 breaths per minute, and O₂ saturation 97% on room air. He was obese but did not have moon facies or a buffalo hump. There were no rashes or mucosal lesions. Active and passive motion of his left hip joint elicited pain with both flexion/extension and internal/external rotation. Muscle strength was limited by pain in the left hip flexors and extenders, but was 5/5 in all other muscle groups. Palpation of the proximal muscles of his arms and legs did not elicit pain. His extremities were without edema, and examination of his shoulders, elbows, wrists, hands, knees, ankles, and feet did not reveal any erythema, synovial thickening, effusion, or deformity. Examination of the heart, chest, and abdomen was normal.

Given the reassuring strength examination, the absence of rashes or skin lesions, and the reassuring joint exam aside from the left hip, a focal infectious, inflammatory, or malignant process seems most likely. The pain with range of motion of the hip does not definitively localize the pathology to the hip joint, because pathology of the nearby structures can lead to pain when the hip is moved. Laboratory evaluation should include a complete blood count to screen for evidence of infection or marrow suppression, complete metabolic panel, and creatine kinase. The history of ulcerative colitis raises the possibility of an enthesitis (inflammation of tendons or ligaments) occurring near the hip. Enthesitis is sometimes a feature of the seronegative spondyloarthropathy‐associated conditions and can occur in the absence of sacroiliitis or spondyloarthropathy.

The patient's myalgias and arthralgias had recently been evaluated in the rheumatology clinic. Laboratory evaluation from that visit was remarkable only for an antinuclear antibody (ANA) test that was positive at a titer of 1:320 in a homogeneous pattern, creatine phosphokinase 366 IU/L (normal range [NR] 38240), and alkaline phosphatase 203 IU/L (NR 30130). All of the following labs from that visit were within normal ranges: cyclic citrullinated peptide, rheumatoid factor, antidouble stranded DNA, aldolase, complement levels, serum and urine protein electrophoresis, thyroglobulin antibody, thyroid microsomal antibody, thyroid‐stimulating hormone, erythrocyte sedimentation rate (10 mm/h), and C‐reactive protein (0.3 mg/dL).

The patient was admitted to the hospital. Initial blood test results on admission included sodium 139 mEq/L, potassium 3.9 mEq/L, chloride 105 mEq/L, bicarbonate 27 mEq/L, urea nitrogen 16 mg/dL, creatinine 0.6 mg/dL, glucose 85 mg/dL, calcium 9.2 mg/dL (NR 8.810.3), phosphate 1.3 mg/dL (NR 2.74.6), albumin 4.7 g/dL (NR 3.54.9), and alkaline phosphatase 195 IU/L (NR 30130). The remainder of a comprehensive metabolic profile, complete blood count with differential, and coagulation studies were all normal.

The homogeneous ANA titer of 1:320 is high enough to raise eyebrows, but is nonspecific for lupus and other ANA‐associated rheumatologic conditions, and may be a red herring, particularly given the low likelihood of a systemic inflammatory process explaining this new focal hip pain. The alkaline phosphatase is only mildly elevated and could be of bone or liver origin. The reassuringly low inflammatory markers are potentially helpful, because if checked now and substantially increased from the prior outpatient visit, they would be suggestive of a new inflammatory process. However, this would not point to a specific cause of inflammation.

Given the focality of the symptoms, imaging is warranted. As opposed to plain films, contrast‐enhanced computed tomography (CT) of the pelvis or magnetic resonance imaging (MRI) may be an efficient first step, because there is low suspicion for fracture and high suspicion for an inflammatory, neoplastic, or infectious process. MRI is more expensive and usually cannot be obtained as rapidly as CT. There is a chance that CT imaging alone will provide enough information to guide the next diagnostic steps, such as aspiration of an abscess or joint, or biopsy of a suspicious lesion. However, for soft tissue lesions and many bone lesions, including osteomyelitis, MRI offers better delineation of pathology.

CT scan of the left femur demonstrated a large lytic lesion in the femoral neck that contained macroscopic fat and had an aggressive appearance with significant thinning of the cortex. MRI confirmed these findings and demonstrated a nondisplaced subtrochanteric femur fracture in the proximity of the lesion (Figure 1). Contrast‐enhanced CT scans of the thorax, abdomen, and pelvis revealed no other neoplastic lesions. Prostate‐specific antigen level was normal. The patient's significant hypophosphatemia persisted, with levels dropping to as low as 0.9 mg/dL despite aggressive oral phosphate replacement.

Figure 1

Although hypophosphatemia is often a nonspecific finding in hospitalized patients and is usually of little clinical importance, profound hypophosphatemia that is refractory to supplementation suggests an underlying metabolic disorder. Phosphate levels less than 1.0 mg/dL, particularly if prolonged, can lead to decreased adenosine triphosphate production and subsequent weakness of respiratory and cardiac muscles. Parathyroid hormone (PTH) excess and production of parathyroid hormone‐related protein (PTHrP) by a malignancy can cause profound hypophosphatemia, but are generally associated with hypercalcemia, a finding not seen in this case. Occasionally, tumors can lead to renal phosphate wasting via nonPTH‐related mechanisms. The best characterized example of this is the paraneoplastic syndrome oncogenic osteomalacia caused by tumor production of a fibroblast growth factor. Tumors that lead to this syndrome are usually benign mesenchymal tumors. This patient's tumor may be of this type, causing local destruction and metabolic disturbance. The next step would be consultation with orthopedic surgery for resection of the tumor and total hip arthroplasty with aggressive perioperative repletion of phosphate. Assessment of intact PTH, ionized calcium, 24‐hour urinary phosphate excretion, and even PTHrP levels may help to rule out other etiologies of hypophosphatemia, but given that surgery is needed regardless, it might be reasonable to proceed to the operating room without these diagnostics. If the phosphate levels return to normal postoperatively, then the diagnosis is clear and no further metabolic testing is needed.

PTH level was 47 pg/mL (NR 1065), 25‐hydroxyvitamin D level was 25 ng/mL (NR 2580), and 1,25‐dihydroxyvitamin D level was 18 pg/mL (NR 1872). Urinalysis was normal without proteinuria or glucosuria. A 24‐hour urine collection contained 1936 mg of phosphate (NR 4001200). The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was 1.3 mg/dL (NR 2.44.2). Tissue obtained by CT‐guided needle biopsy of the femoral mass was consistent with a benign spindle cell neoplasm.

With normal calcium levels, the PTH level is appropriate, and hyperparathyroidism is excluded. The levels of 25‐hydroxyvitamin D and 1‐25‐dihydroxyvitamin D are not low enough to suggest that vitamin D deficiency is driving the impressive hypophosphatemia. What is impressive is the phosphate wasting demonstrated by the 24‐hour urine collection, consistent with paraneoplastic overproduction of fibroblast growth factor 23 (FGF23) by the benign bone tumor. Overproduction of this protein can be detected by blood tests or staining of the tumor specimen, but surgery should be performed as soon as possible independent of any further test results. Once the tumor is resected, phosphate metabolism should normalize.

FGF23 level was 266 RU/mL (NR < 180). The patient was diagnosed with tumor‐induced osteomalacia (TIO). He underwent complete resection of the femoral tumor as well as open reduction and internal fixation of the fracture. After surgery, his symptoms of pain and subjective muscle weakness improved, his serum phosphate level normalized, his need for phosphate supplementation resolved, and his blood levels of FGF23 decreased into the normal range (111 RU/mL). The rapid improvement of his symptoms after surgery suggested that they were related to TIO, and not manifestations of SLE or RA. His immunosuppressant medications were discontinued. Surgical pathology demonstrated a heterogeneous tumor consisting of sheets of uniform spindle cells interspersed with mature adipose tissue. This was diagnosed descriptively as a benign spindle cell and lipomatous neoplasm without further classification. Two months later, the patient was ambulating without pain, and muscle strength was subjectively normal.

DISCUSSION

TIO is a rare paraneoplastic syndrome affecting phosphate and vitamin D metabolism, leading to hypophosphatemia and osteomalacia.[1] TIO is caused by the inappropriate tumor secretion of the phosphatonin hormone, FGF23.

The normal physiology of FGF23 is illustrated in Figure 2. Osteocytes appear to be the primary source of FGF23, but the regulation of FGF23 production is not completely understood. FGF23 production may be influenced by several factors, including 1,25 dihydroxyvitamin D levels, and serum phosphate and PTH concentrations. This hormone binds to the FGF receptor and its coreceptor, Klotho,[2] causing 2 major physiological effects. First, it decreases the expression of the sodium‐phosphate cotransporters in the renal proximal tubular cells,[3, 4] resulting in increased tubular phosphate wasting. This effect appears to be partly PTH dependent.[5] Second, it has effects on vitamin D metabolism, decreasing renal production of activated vitamin D.[3, 4, 6]

Figure 2

In overproduction states, the elevated FGF23 leads to chronically low serum phosphate levels (with renal phosphate wasting) and the clinical syndrome of osteomalacia, manifested by bone pain, fractures, and deformities. Hypophosphatemia can also lead to painful proximal myopathy, cardiorespiratory dysfunction, and a spectrum of neuropsychiatric findings. The clinical findings in TIO are similar to those seen in genetic diseases in which hypophosphatemia results from the same mechanism.[3, 4]

In this case, measurement of the serum phosphate level was important in reaching the diagnosis. Although hypophosphatemia in the hospitalized patient is often easily explained, severe or persistent hypophosphatemia requires a focused evaluation. Causes of hypophosphatemia are categorized in Table 1.[7, 8, 9] In patients with hypophosphatemia that is not explained by the clinical situation (eg, osmotic diuresis, insulin treatment, refeeding syndrome, postparathyroidectomy, chronic diarrhea), measurement of serum calcium, PTH, and 25‐hydroxyvitamin D are used to investigate possible primary or secondary hyperparathyroidism. In addition, low‐normal or low serum 1,25‐dihydroxyvitamin D with normal PTH, normal 25‐hydroxyvitamin D stores, and normal renal function are clues to the presence of TIO. Urine phosphate wasting can be measured by collecting a 24‐hour urine sample. Calculation of the TmP/GFR (a measure of the maximum tubular resorption of phosphate relative to the glomerular filtration rate), as described by the nomogram of Walton and Bijvoet, may improve the accuracy of this assessment and confirm a renal source of the hypophosphatemia.[10]

The patient presented here had inappropriate urinary phosphate losses, and laboratory testing ruled out primary and secondary hyperparathyroidism and Fanconi syndrome. The patient was not taking medications known to cause tubular phosphate wasting. The patient's age and clinical history made hereditary syndromes unlikely. Therefore, the urinary phosphate wasting had to be related to an acquired defect in phosphate metabolism. The diagnostic characteristics of TIO are summarized in Table 2.

The presence of a known neoplasm makes the diagnosis of TIO considerably easier. However, osteomalacia often precedes the tumor diagnosis. In these cases, the discovery of this clinical syndrome necessitates a search for the tumor. The tumors can be small, occult, and often located in the extremities. In addition to standard cross‐sectional imaging, specialized diagnostic modalities can be helpful in localizing culprit tumors. These include F‐18 flourodeoxyglucose positron emission tomography with computed tomography, 111‐Indium octreotide single photon emission CT/CT, 68‐Gallium‐DOTA‐octreotide positron emission tomography with computed tomography, and even selective venous sampling for FGF23 levels.[1, 11] The octreotide tests capitalize on the fact that culprit tumors often express somatostatin receptors.

TIO is most often associated with mesenchymal tumors of the bone or soft tissue. It has also been reported in association with several malignancies (small cell carcinoma, hematologic malignancies, prostate cancer), and with polyostotic fibrous dysplasia, neurofibromatosis, and the epidermal nevus syndrome. The mesenchymal tumors are heterogeneous in appearance and can be variably classified as hemangiopericytomas, hemangiomas, sarcomas, ossifying fibromas, granulomas, giant cell tumors, or osteoblastomas.[1] However, 1 review suggests that most of these tumors actually represent a distinct but heterogeneous, under‐recognized entity that is best classified as a phosphaturic mesenchymal tumor.[11]

TIO is only cured by complete resection of the tumor.[1] Local recurrences have been described, as have rare occurrences of metastatic disease.[1, 12] Medical treatment can be used to normalize serum phosphate levels in patients who are unable to be cured by surgery. The goal is to bring serum phosphate into the low‐normal range via phosphate supplementation (typically 13 g/day of elemental phosphorus is required) and treatment with either calcitriol or alfacalcidol. Due to the inhibition of 1,25‐dihydroxyvitamin D activation in TIO, relatively large doses of calcitriol are needed. A reasonable starting dose of calcitriol is 1.5 g/day, and most patients require 15 to 60 ng/kg per day. Because PTH action is involved in FGF23‐mediated hypophosphatemia, suppression of PTH may also be useful in these patients.[13]

This patient presented with a painful femoral tumor in the setting of muscle and joint pain that had been erroneously attributed to connective tissue disease. However, recognition and thorough evaluation of the patient's hypophosphatemia led to a unifying diagnosis of TIO. This diagnosis altered the surgical approach (emphasizing complete resection to eradicate the FGF23 production) and helped alleviate the patient's painful losses of phosphate.

TEACHING POINTS

1. Hypophosphatemia, especially if severe or persistent, should not be dismissed as an unimportant laboratory finding. A focused evaluation should be performed to determine the etiology.
2. In patients with unexplained hypophosphatemia, the measurement of serum calcium, parathyroid hormone, and vitamin D levels can identify primary or secondary hyperparathyroidism.
3. The differential diagnosis of hypophosphatemia is narrowed if there is clinical evidence of inappropriate urinary phosphate wasting (ie, urinary phosphate levels remain high, despite low serum levels).
4. TIO is a rare paraneoplastic syndrome caused by FGF23, a phosphatonin hormone that causes renal phosphate wasting, hypophosphatemia, and osteomalacia.

Disclosure: Nothing to report.

A 58‐year‐old man presented to the emergency department with a 1‐month history of progressive, severe left hip pain that had become unbearable. The pain was constant and significantly worse with weight‐bearing, and the patient was now confined to bed. He denied back pain, falls, or trauma.

Although hip pain is a common complaint and a frequent manifestation of chronic degenerative joint disease, the debilitating and subacute nature of the pain suggests a potentially more serious underlying cause. Patients and even clinicians may refer to hip pain when the actual symptoms are periarticular, often presenting over the trochanter laterally, or muscular, presenting as posterior pain. The true hip joint is located in the anterior hip and groin area and often causes symptoms that radiate to the buttock. Pain can also be referred to the hip area from the spine, pelvis, or retroperitoneum, so it is crucial not to restrict the differential diagnosis to hip pathology.

Key diagnostic considerations include (1) inflammatory conditions such as trochanteric bursitis or gout; (2) bacterial infection of the hip joint, adjacent bone, or a nearby structure; (3) benign nerve compression (such as meralgia paresthetica); and (4) tumor (particularly myeloma or metastatic disease to the bone, but also potentially a pelvic or spinal mass with nerve compression). Polymyalgia rheumatica and other systemic rheumatologic complaints are a consideration, but because a single joint is involved, these conditions are less likely. The hip would be an unusual location for a first gout flare, and the duration of symptoms would be unusually long for gout. Avascular necrosis should be considered if the patient has received glucocorticoids for his previously diagnosed rheumatologic disease. If the patient is anticoagulated, consideration of spontaneous hematoma is reasonable, but usually this would present over a course of days, not weeks. The absence of trauma makes a fracture of the hip or pelvis less likely, and the insidious progression of symptoms makes a pathologic fracture less likely.

The patient reported 6 months of worsening proximal upper and lower extremity myalgia and weakness, with arthralgia of the hips and shoulders. The weakness was most notable in his proximal lower extremities, although he had remained ambulatory until the hip pain became limiting. He maintained normal use of his arms. The patient denied current rash but noted photosensitivity and a mild facial rash several months earlier. He described having transient mouth sores intermittently for several years. He denied fever, chills, night sweats, weight loss, dyspnea, recent travel, and outdoor exposures. Several months previously, he had been evaluated for these symptoms at another institution and given the diagnoses of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). At that time, he had initiated treatment with weekly dosing of methotrexate and etanercept.

The patient's medical history was also notable for hypertension, Graves' disease treated previously with radioiodine ablation, quiescent ulcerative colitis, and depression. Current medications included methotrexate, etanercept, levothyroxine, enalapril, hydrochlorothiazide, fluoxetine, ibuprofen, and oxycodone‐acetaminophen. He denied tobacco, alcohol, and recreational drug use.

Weakness occurring in the proximal lower extremities is the classic distribution for polymyositis and dermatomyositis. In contrast to polymyalgia rheumatica, dermatomyositis and polymyositis do not generally feature severe muscle pain, but they can be associated with a painful polyarthritis. Oral ulcers, photosensitivity, and facial rash are consistent with SLE, but dermatomyositis can also lead to a symmetrical erythema of the eyelids (commonly referred to as a heliotrope rash, named after the flower bearing that name) and sometimes can be associated with photosensitivity. Oral ulcers, particularly the painful ones known as canker sores, are extraordinarily common in the general population, and patients and providers may miss the mucosal lesions of SLE because they are usually painless. As methotrexate and etanercept are immunosuppressive, opportunistic pathogens such as typical or atypical mycobacteria and disseminated fungal infections should be considered, with special attention to the possibility of infection in or near the left hip. Given that SLE and RA rarely coexist, it would be helpful to seek outside medical records to know what the prior serologic evaluation entailed, but it is unlikely that this presentation is a manifestation of a diffuse connective tissue process.

Physical examination should focus on the features of dermatomyositis including heliotrope rash, truncal erythema, and papules over the knuckles (Gottron's papules); objective proximal muscle weakness in the shoulder and hip girdle; and findings that might suggest antisynthetase syndrome such as hyperkeratotic mechanic hand palmar and digital changes, and interstitial crackles on lung exam. If necrotic skin lesions are found, this would raise concern for a disseminated infection. The joints should be examined for inflammation and effusions.

His temperature was 36.6C, heart rate 74 beats per minute, blood pressure 134/76 mm Hg, respiratory rate 16 breaths per minute, and O₂ saturation 97% on room air. He was obese but did not have moon facies or a buffalo hump. There were no rashes or mucosal lesions. Active and passive motion of his left hip joint elicited pain with both flexion/extension and internal/external rotation. Muscle strength was limited by pain in the left hip flexors and extenders, but was 5/5 in all other muscle groups. Palpation of the proximal muscles of his arms and legs did not elicit pain. His extremities were without edema, and examination of his shoulders, elbows, wrists, hands, knees, ankles, and feet did not reveal any erythema, synovial thickening, effusion, or deformity. Examination of the heart, chest, and abdomen was normal.

Given the reassuring strength examination, the absence of rashes or skin lesions, and the reassuring joint exam aside from the left hip, a focal infectious, inflammatory, or malignant process seems most likely. The pain with range of motion of the hip does not definitively localize the pathology to the hip joint, because pathology of the nearby structures can lead to pain when the hip is moved. Laboratory evaluation should include a complete blood count to screen for evidence of infection or marrow suppression, complete metabolic panel, and creatine kinase. The history of ulcerative colitis raises the possibility of an enthesitis (inflammation of tendons or ligaments) occurring near the hip. Enthesitis is sometimes a feature of the seronegative spondyloarthropathy‐associated conditions and can occur in the absence of sacroiliitis or spondyloarthropathy.

The patient's myalgias and arthralgias had recently been evaluated in the rheumatology clinic. Laboratory evaluation from that visit was remarkable only for an antinuclear antibody (ANA) test that was positive at a titer of 1:320 in a homogeneous pattern, creatine phosphokinase 366 IU/L (normal range [NR] 38240), and alkaline phosphatase 203 IU/L (NR 30130). All of the following labs from that visit were within normal ranges: cyclic citrullinated peptide, rheumatoid factor, antidouble stranded DNA, aldolase, complement levels, serum and urine protein electrophoresis, thyroglobulin antibody, thyroid microsomal antibody, thyroid‐stimulating hormone, erythrocyte sedimentation rate (10 mm/h), and C‐reactive protein (0.3 mg/dL).

The patient was admitted to the hospital. Initial blood test results on admission included sodium 139 mEq/L, potassium 3.9 mEq/L, chloride 105 mEq/L, bicarbonate 27 mEq/L, urea nitrogen 16 mg/dL, creatinine 0.6 mg/dL, glucose 85 mg/dL, calcium 9.2 mg/dL (NR 8.810.3), phosphate 1.3 mg/dL (NR 2.74.6), albumin 4.7 g/dL (NR 3.54.9), and alkaline phosphatase 195 IU/L (NR 30130). The remainder of a comprehensive metabolic profile, complete blood count with differential, and coagulation studies were all normal.

The homogeneous ANA titer of 1:320 is high enough to raise eyebrows, but is nonspecific for lupus and other ANA‐associated rheumatologic conditions, and may be a red herring, particularly given the low likelihood of a systemic inflammatory process explaining this new focal hip pain. The alkaline phosphatase is only mildly elevated and could be of bone or liver origin. The reassuringly low inflammatory markers are potentially helpful, because if checked now and substantially increased from the prior outpatient visit, they would be suggestive of a new inflammatory process. However, this would not point to a specific cause of inflammation.

Given the focality of the symptoms, imaging is warranted. As opposed to plain films, contrast‐enhanced computed tomography (CT) of the pelvis or magnetic resonance imaging (MRI) may be an efficient first step, because there is low suspicion for fracture and high suspicion for an inflammatory, neoplastic, or infectious process. MRI is more expensive and usually cannot be obtained as rapidly as CT. There is a chance that CT imaging alone will provide enough information to guide the next diagnostic steps, such as aspiration of an abscess or joint, or biopsy of a suspicious lesion. However, for soft tissue lesions and many bone lesions, including osteomyelitis, MRI offers better delineation of pathology.

CT scan of the left femur demonstrated a large lytic lesion in the femoral neck that contained macroscopic fat and had an aggressive appearance with significant thinning of the cortex. MRI confirmed these findings and demonstrated a nondisplaced subtrochanteric femur fracture in the proximity of the lesion (Figure 1). Contrast‐enhanced CT scans of the thorax, abdomen, and pelvis revealed no other neoplastic lesions. Prostate‐specific antigen level was normal. The patient's significant hypophosphatemia persisted, with levels dropping to as low as 0.9 mg/dL despite aggressive oral phosphate replacement.

Figure 1

Although hypophosphatemia is often a nonspecific finding in hospitalized patients and is usually of little clinical importance, profound hypophosphatemia that is refractory to supplementation suggests an underlying metabolic disorder. Phosphate levels less than 1.0 mg/dL, particularly if prolonged, can lead to decreased adenosine triphosphate production and subsequent weakness of respiratory and cardiac muscles. Parathyroid hormone (PTH) excess and production of parathyroid hormone‐related protein (PTHrP) by a malignancy can cause profound hypophosphatemia, but are generally associated with hypercalcemia, a finding not seen in this case. Occasionally, tumors can lead to renal phosphate wasting via nonPTH‐related mechanisms. The best characterized example of this is the paraneoplastic syndrome oncogenic osteomalacia caused by tumor production of a fibroblast growth factor. Tumors that lead to this syndrome are usually benign mesenchymal tumors. This patient's tumor may be of this type, causing local destruction and metabolic disturbance. The next step would be consultation with orthopedic surgery for resection of the tumor and total hip arthroplasty with aggressive perioperative repletion of phosphate. Assessment of intact PTH, ionized calcium, 24‐hour urinary phosphate excretion, and even PTHrP levels may help to rule out other etiologies of hypophosphatemia, but given that surgery is needed regardless, it might be reasonable to proceed to the operating room without these diagnostics. If the phosphate levels return to normal postoperatively, then the diagnosis is clear and no further metabolic testing is needed.

PTH level was 47 pg/mL (NR 1065), 25‐hydroxyvitamin D level was 25 ng/mL (NR 2580), and 1,25‐dihydroxyvitamin D level was 18 pg/mL (NR 1872). Urinalysis was normal without proteinuria or glucosuria. A 24‐hour urine collection contained 1936 mg of phosphate (NR 4001200). The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was 1.3 mg/dL (NR 2.44.2). Tissue obtained by CT‐guided needle biopsy of the femoral mass was consistent with a benign spindle cell neoplasm.

With normal calcium levels, the PTH level is appropriate, and hyperparathyroidism is excluded. The levels of 25‐hydroxyvitamin D and 1‐25‐dihydroxyvitamin D are not low enough to suggest that vitamin D deficiency is driving the impressive hypophosphatemia. What is impressive is the phosphate wasting demonstrated by the 24‐hour urine collection, consistent with paraneoplastic overproduction of fibroblast growth factor 23 (FGF23) by the benign bone tumor. Overproduction of this protein can be detected by blood tests or staining of the tumor specimen, but surgery should be performed as soon as possible independent of any further test results. Once the tumor is resected, phosphate metabolism should normalize.

FGF23 level was 266 RU/mL (NR < 180). The patient was diagnosed with tumor‐induced osteomalacia (TIO). He underwent complete resection of the femoral tumor as well as open reduction and internal fixation of the fracture. After surgery, his symptoms of pain and subjective muscle weakness improved, his serum phosphate level normalized, his need for phosphate supplementation resolved, and his blood levels of FGF23 decreased into the normal range (111 RU/mL). The rapid improvement of his symptoms after surgery suggested that they were related to TIO, and not manifestations of SLE or RA. His immunosuppressant medications were discontinued. Surgical pathology demonstrated a heterogeneous tumor consisting of sheets of uniform spindle cells interspersed with mature adipose tissue. This was diagnosed descriptively as a benign spindle cell and lipomatous neoplasm without further classification. Two months later, the patient was ambulating without pain, and muscle strength was subjectively normal.

DISCUSSION

TIO is a rare paraneoplastic syndrome affecting phosphate and vitamin D metabolism, leading to hypophosphatemia and osteomalacia.[1] TIO is caused by the inappropriate tumor secretion of the phosphatonin hormone, FGF23.

The normal physiology of FGF23 is illustrated in Figure 2. Osteocytes appear to be the primary source of FGF23, but the regulation of FGF23 production is not completely understood. FGF23 production may be influenced by several factors, including 1,25 dihydroxyvitamin D levels, and serum phosphate and PTH concentrations. This hormone binds to the FGF receptor and its coreceptor, Klotho,[2] causing 2 major physiological effects. First, it decreases the expression of the sodium‐phosphate cotransporters in the renal proximal tubular cells,[3, 4] resulting in increased tubular phosphate wasting. This effect appears to be partly PTH dependent.[5] Second, it has effects on vitamin D metabolism, decreasing renal production of activated vitamin D.[3, 4, 6]

Figure 2

In overproduction states, the elevated FGF23 leads to chronically low serum phosphate levels (with renal phosphate wasting) and the clinical syndrome of osteomalacia, manifested by bone pain, fractures, and deformities. Hypophosphatemia can also lead to painful proximal myopathy, cardiorespiratory dysfunction, and a spectrum of neuropsychiatric findings. The clinical findings in TIO are similar to those seen in genetic diseases in which hypophosphatemia results from the same mechanism.[3, 4]

In this case, measurement of the serum phosphate level was important in reaching the diagnosis. Although hypophosphatemia in the hospitalized patient is often easily explained, severe or persistent hypophosphatemia requires a focused evaluation. Causes of hypophosphatemia are categorized in Table 1.[7, 8, 9] In patients with hypophosphatemia that is not explained by the clinical situation (eg, osmotic diuresis, insulin treatment, refeeding syndrome, postparathyroidectomy, chronic diarrhea), measurement of serum calcium, PTH, and 25‐hydroxyvitamin D are used to investigate possible primary or secondary hyperparathyroidism. In addition, low‐normal or low serum 1,25‐dihydroxyvitamin D with normal PTH, normal 25‐hydroxyvitamin D stores, and normal renal function are clues to the presence of TIO. Urine phosphate wasting can be measured by collecting a 24‐hour urine sample. Calculation of the TmP/GFR (a measure of the maximum tubular resorption of phosphate relative to the glomerular filtration rate), as described by the nomogram of Walton and Bijvoet, may improve the accuracy of this assessment and confirm a renal source of the hypophosphatemia.[10]

The patient presented here had inappropriate urinary phosphate losses, and laboratory testing ruled out primary and secondary hyperparathyroidism and Fanconi syndrome. The patient was not taking medications known to cause tubular phosphate wasting. The patient's age and clinical history made hereditary syndromes unlikely. Therefore, the urinary phosphate wasting had to be related to an acquired defect in phosphate metabolism. The diagnostic characteristics of TIO are summarized in Table 2.

The presence of a known neoplasm makes the diagnosis of TIO considerably easier. However, osteomalacia often precedes the tumor diagnosis. In these cases, the discovery of this clinical syndrome necessitates a search for the tumor. The tumors can be small, occult, and often located in the extremities. In addition to standard cross‐sectional imaging, specialized diagnostic modalities can be helpful in localizing culprit tumors. These include F‐18 flourodeoxyglucose positron emission tomography with computed tomography, 111‐Indium octreotide single photon emission CT/CT, 68‐Gallium‐DOTA‐octreotide positron emission tomography with computed tomography, and even selective venous sampling for FGF23 levels.[1, 11] The octreotide tests capitalize on the fact that culprit tumors often express somatostatin receptors.

TIO is most often associated with mesenchymal tumors of the bone or soft tissue. It has also been reported in association with several malignancies (small cell carcinoma, hematologic malignancies, prostate cancer), and with polyostotic fibrous dysplasia, neurofibromatosis, and the epidermal nevus syndrome. The mesenchymal tumors are heterogeneous in appearance and can be variably classified as hemangiopericytomas, hemangiomas, sarcomas, ossifying fibromas, granulomas, giant cell tumors, or osteoblastomas.[1] However, 1 review suggests that most of these tumors actually represent a distinct but heterogeneous, under‐recognized entity that is best classified as a phosphaturic mesenchymal tumor.[11]

TIO is only cured by complete resection of the tumor.[1] Local recurrences have been described, as have rare occurrences of metastatic disease.[1, 12] Medical treatment can be used to normalize serum phosphate levels in patients who are unable to be cured by surgery. The goal is to bring serum phosphate into the low‐normal range via phosphate supplementation (typically 13 g/day of elemental phosphorus is required) and treatment with either calcitriol or alfacalcidol. Due to the inhibition of 1,25‐dihydroxyvitamin D activation in TIO, relatively large doses of calcitriol are needed. A reasonable starting dose of calcitriol is 1.5 g/day, and most patients require 15 to 60 ng/kg per day. Because PTH action is involved in FGF23‐mediated hypophosphatemia, suppression of PTH may also be useful in these patients.[13]

This patient presented with a painful femoral tumor in the setting of muscle and joint pain that had been erroneously attributed to connective tissue disease. However, recognition and thorough evaluation of the patient's hypophosphatemia led to a unifying diagnosis of TIO. This diagnosis altered the surgical approach (emphasizing complete resection to eradicate the FGF23 production) and helped alleviate the patient's painful losses of phosphate.

TEACHING POINTS

1. Hypophosphatemia, especially if severe or persistent, should not be dismissed as an unimportant laboratory finding. A focused evaluation should be performed to determine the etiology.
2. In patients with unexplained hypophosphatemia, the measurement of serum calcium, parathyroid hormone, and vitamin D levels can identify primary or secondary hyperparathyroidism.
3. The differential diagnosis of hypophosphatemia is narrowed if there is clinical evidence of inappropriate urinary phosphate wasting (ie, urinary phosphate levels remain high, despite low serum levels).
4. TIO is a rare paraneoplastic syndrome caused by FGF23, a phosphatonin hormone that causes renal phosphate wasting, hypophosphatemia, and osteomalacia.

Disclosure: Nothing to report.

A 58‐year‐old man presented to the emergency department with a 1‐month history of progressive, severe left hip pain that had become unbearable. The pain was constant and significantly worse with weight‐bearing, and the patient was now confined to bed. He denied back pain, falls, or trauma.

Although hip pain is a common complaint and a frequent manifestation of chronic degenerative joint disease, the debilitating and subacute nature of the pain suggests a potentially more serious underlying cause. Patients and even clinicians may refer to hip pain when the actual symptoms are periarticular, often presenting over the trochanter laterally, or muscular, presenting as posterior pain. The true hip joint is located in the anterior hip and groin area and often causes symptoms that radiate to the buttock. Pain can also be referred to the hip area from the spine, pelvis, or retroperitoneum, so it is crucial not to restrict the differential diagnosis to hip pathology.

Key diagnostic considerations include (1) inflammatory conditions such as trochanteric bursitis or gout; (2) bacterial infection of the hip joint, adjacent bone, or a nearby structure; (3) benign nerve compression (such as meralgia paresthetica); and (4) tumor (particularly myeloma or metastatic disease to the bone, but also potentially a pelvic or spinal mass with nerve compression). Polymyalgia rheumatica and other systemic rheumatologic complaints are a consideration, but because a single joint is involved, these conditions are less likely. The hip would be an unusual location for a first gout flare, and the duration of symptoms would be unusually long for gout. Avascular necrosis should be considered if the patient has received glucocorticoids for his previously diagnosed rheumatologic disease. If the patient is anticoagulated, consideration of spontaneous hematoma is reasonable, but usually this would present over a course of days, not weeks. The absence of trauma makes a fracture of the hip or pelvis less likely, and the insidious progression of symptoms makes a pathologic fracture less likely.

The patient reported 6 months of worsening proximal upper and lower extremity myalgia and weakness, with arthralgia of the hips and shoulders. The weakness was most notable in his proximal lower extremities, although he had remained ambulatory until the hip pain became limiting. He maintained normal use of his arms. The patient denied current rash but noted photosensitivity and a mild facial rash several months earlier. He described having transient mouth sores intermittently for several years. He denied fever, chills, night sweats, weight loss, dyspnea, recent travel, and outdoor exposures. Several months previously, he had been evaluated for these symptoms at another institution and given the diagnoses of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). At that time, he had initiated treatment with weekly dosing of methotrexate and etanercept.

The patient's medical history was also notable for hypertension, Graves' disease treated previously with radioiodine ablation, quiescent ulcerative colitis, and depression. Current medications included methotrexate, etanercept, levothyroxine, enalapril, hydrochlorothiazide, fluoxetine, ibuprofen, and oxycodone‐acetaminophen. He denied tobacco, alcohol, and recreational drug use.

Weakness occurring in the proximal lower extremities is the classic distribution for polymyositis and dermatomyositis. In contrast to polymyalgia rheumatica, dermatomyositis and polymyositis do not generally feature severe muscle pain, but they can be associated with a painful polyarthritis. Oral ulcers, photosensitivity, and facial rash are consistent with SLE, but dermatomyositis can also lead to a symmetrical erythema of the eyelids (commonly referred to as a heliotrope rash, named after the flower bearing that name) and sometimes can be associated with photosensitivity. Oral ulcers, particularly the painful ones known as canker sores, are extraordinarily common in the general population, and patients and providers may miss the mucosal lesions of SLE because they are usually painless. As methotrexate and etanercept are immunosuppressive, opportunistic pathogens such as typical or atypical mycobacteria and disseminated fungal infections should be considered, with special attention to the possibility of infection in or near the left hip. Given that SLE and RA rarely coexist, it would be helpful to seek outside medical records to know what the prior serologic evaluation entailed, but it is unlikely that this presentation is a manifestation of a diffuse connective tissue process.

Physical examination should focus on the features of dermatomyositis including heliotrope rash, truncal erythema, and papules over the knuckles (Gottron's papules); objective proximal muscle weakness in the shoulder and hip girdle; and findings that might suggest antisynthetase syndrome such as hyperkeratotic mechanic hand palmar and digital changes, and interstitial crackles on lung exam. If necrotic skin lesions are found, this would raise concern for a disseminated infection. The joints should be examined for inflammation and effusions.

His temperature was 36.6C, heart rate 74 beats per minute, blood pressure 134/76 mm Hg, respiratory rate 16 breaths per minute, and O₂ saturation 97% on room air. He was obese but did not have moon facies or a buffalo hump. There were no rashes or mucosal lesions. Active and passive motion of his left hip joint elicited pain with both flexion/extension and internal/external rotation. Muscle strength was limited by pain in the left hip flexors and extenders, but was 5/5 in all other muscle groups. Palpation of the proximal muscles of his arms and legs did not elicit pain. His extremities were without edema, and examination of his shoulders, elbows, wrists, hands, knees, ankles, and feet did not reveal any erythema, synovial thickening, effusion, or deformity. Examination of the heart, chest, and abdomen was normal.

Given the reassuring strength examination, the absence of rashes or skin lesions, and the reassuring joint exam aside from the left hip, a focal infectious, inflammatory, or malignant process seems most likely. The pain with range of motion of the hip does not definitively localize the pathology to the hip joint, because pathology of the nearby structures can lead to pain when the hip is moved. Laboratory evaluation should include a complete blood count to screen for evidence of infection or marrow suppression, complete metabolic panel, and creatine kinase. The history of ulcerative colitis raises the possibility of an enthesitis (inflammation of tendons or ligaments) occurring near the hip. Enthesitis is sometimes a feature of the seronegative spondyloarthropathy‐associated conditions and can occur in the absence of sacroiliitis or spondyloarthropathy.

The patient's myalgias and arthralgias had recently been evaluated in the rheumatology clinic. Laboratory evaluation from that visit was remarkable only for an antinuclear antibody (ANA) test that was positive at a titer of 1:320 in a homogeneous pattern, creatine phosphokinase 366 IU/L (normal range [NR] 38240), and alkaline phosphatase 203 IU/L (NR 30130). All of the following labs from that visit were within normal ranges: cyclic citrullinated peptide, rheumatoid factor, antidouble stranded DNA, aldolase, complement levels, serum and urine protein electrophoresis, thyroglobulin antibody, thyroid microsomal antibody, thyroid‐stimulating hormone, erythrocyte sedimentation rate (10 mm/h), and C‐reactive protein (0.3 mg/dL).

The patient was admitted to the hospital. Initial blood test results on admission included sodium 139 mEq/L, potassium 3.9 mEq/L, chloride 105 mEq/L, bicarbonate 27 mEq/L, urea nitrogen 16 mg/dL, creatinine 0.6 mg/dL, glucose 85 mg/dL, calcium 9.2 mg/dL (NR 8.810.3), phosphate 1.3 mg/dL (NR 2.74.6), albumin 4.7 g/dL (NR 3.54.9), and alkaline phosphatase 195 IU/L (NR 30130). The remainder of a comprehensive metabolic profile, complete blood count with differential, and coagulation studies were all normal.

The homogeneous ANA titer of 1:320 is high enough to raise eyebrows, but is nonspecific for lupus and other ANA‐associated rheumatologic conditions, and may be a red herring, particularly given the low likelihood of a systemic inflammatory process explaining this new focal hip pain. The alkaline phosphatase is only mildly elevated and could be of bone or liver origin. The reassuringly low inflammatory markers are potentially helpful, because if checked now and substantially increased from the prior outpatient visit, they would be suggestive of a new inflammatory process. However, this would not point to a specific cause of inflammation.

Given the focality of the symptoms, imaging is warranted. As opposed to plain films, contrast‐enhanced computed tomography (CT) of the pelvis or magnetic resonance imaging (MRI) may be an efficient first step, because there is low suspicion for fracture and high suspicion for an inflammatory, neoplastic, or infectious process. MRI is more expensive and usually cannot be obtained as rapidly as CT. There is a chance that CT imaging alone will provide enough information to guide the next diagnostic steps, such as aspiration of an abscess or joint, or biopsy of a suspicious lesion. However, for soft tissue lesions and many bone lesions, including osteomyelitis, MRI offers better delineation of pathology.

CT scan of the left femur demonstrated a large lytic lesion in the femoral neck that contained macroscopic fat and had an aggressive appearance with significant thinning of the cortex. MRI confirmed these findings and demonstrated a nondisplaced subtrochanteric femur fracture in the proximity of the lesion (Figure 1). Contrast‐enhanced CT scans of the thorax, abdomen, and pelvis revealed no other neoplastic lesions. Prostate‐specific antigen level was normal. The patient's significant hypophosphatemia persisted, with levels dropping to as low as 0.9 mg/dL despite aggressive oral phosphate replacement.

Figure 1

Although hypophosphatemia is often a nonspecific finding in hospitalized patients and is usually of little clinical importance, profound hypophosphatemia that is refractory to supplementation suggests an underlying metabolic disorder. Phosphate levels less than 1.0 mg/dL, particularly if prolonged, can lead to decreased adenosine triphosphate production and subsequent weakness of respiratory and cardiac muscles. Parathyroid hormone (PTH) excess and production of parathyroid hormone‐related protein (PTHrP) by a malignancy can cause profound hypophosphatemia, but are generally associated with hypercalcemia, a finding not seen in this case. Occasionally, tumors can lead to renal phosphate wasting via nonPTH‐related mechanisms. The best characterized example of this is the paraneoplastic syndrome oncogenic osteomalacia caused by tumor production of a fibroblast growth factor. Tumors that lead to this syndrome are usually benign mesenchymal tumors. This patient's tumor may be of this type, causing local destruction and metabolic disturbance. The next step would be consultation with orthopedic surgery for resection of the tumor and total hip arthroplasty with aggressive perioperative repletion of phosphate. Assessment of intact PTH, ionized calcium, 24‐hour urinary phosphate excretion, and even PTHrP levels may help to rule out other etiologies of hypophosphatemia, but given that surgery is needed regardless, it might be reasonable to proceed to the operating room without these diagnostics. If the phosphate levels return to normal postoperatively, then the diagnosis is clear and no further metabolic testing is needed.

PTH level was 47 pg/mL (NR 1065), 25‐hydroxyvitamin D level was 25 ng/mL (NR 2580), and 1,25‐dihydroxyvitamin D level was 18 pg/mL (NR 1872). Urinalysis was normal without proteinuria or glucosuria. A 24‐hour urine collection contained 1936 mg of phosphate (NR 4001200). The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was 1.3 mg/dL (NR 2.44.2). Tissue obtained by CT‐guided needle biopsy of the femoral mass was consistent with a benign spindle cell neoplasm.

With normal calcium levels, the PTH level is appropriate, and hyperparathyroidism is excluded. The levels of 25‐hydroxyvitamin D and 1‐25‐dihydroxyvitamin D are not low enough to suggest that vitamin D deficiency is driving the impressive hypophosphatemia. What is impressive is the phosphate wasting demonstrated by the 24‐hour urine collection, consistent with paraneoplastic overproduction of fibroblast growth factor 23 (FGF23) by the benign bone tumor. Overproduction of this protein can be detected by blood tests or staining of the tumor specimen, but surgery should be performed as soon as possible independent of any further test results. Once the tumor is resected, phosphate metabolism should normalize.

FGF23 level was 266 RU/mL (NR < 180). The patient was diagnosed with tumor‐induced osteomalacia (TIO). He underwent complete resection of the femoral tumor as well as open reduction and internal fixation of the fracture. After surgery, his symptoms of pain and subjective muscle weakness improved, his serum phosphate level normalized, his need for phosphate supplementation resolved, and his blood levels of FGF23 decreased into the normal range (111 RU/mL). The rapid improvement of his symptoms after surgery suggested that they were related to TIO, and not manifestations of SLE or RA. His immunosuppressant medications were discontinued. Surgical pathology demonstrated a heterogeneous tumor consisting of sheets of uniform spindle cells interspersed with mature adipose tissue. This was diagnosed descriptively as a benign spindle cell and lipomatous neoplasm without further classification. Two months later, the patient was ambulating without pain, and muscle strength was subjectively normal.

DISCUSSION

TIO is a rare paraneoplastic syndrome affecting phosphate and vitamin D metabolism, leading to hypophosphatemia and osteomalacia.[1] TIO is caused by the inappropriate tumor secretion of the phosphatonin hormone, FGF23.

The normal physiology of FGF23 is illustrated in Figure 2. Osteocytes appear to be the primary source of FGF23, but the regulation of FGF23 production is not completely understood. FGF23 production may be influenced by several factors, including 1,25 dihydroxyvitamin D levels, and serum phosphate and PTH concentrations. This hormone binds to the FGF receptor and its coreceptor, Klotho,[2] causing 2 major physiological effects. First, it decreases the expression of the sodium‐phosphate cotransporters in the renal proximal tubular cells,[3, 4] resulting in increased tubular phosphate wasting. This effect appears to be partly PTH dependent.[5] Second, it has effects on vitamin D metabolism, decreasing renal production of activated vitamin D.[3, 4, 6]

Figure 2

In overproduction states, the elevated FGF23 leads to chronically low serum phosphate levels (with renal phosphate wasting) and the clinical syndrome of osteomalacia, manifested by bone pain, fractures, and deformities. Hypophosphatemia can also lead to painful proximal myopathy, cardiorespiratory dysfunction, and a spectrum of neuropsychiatric findings. The clinical findings in TIO are similar to those seen in genetic diseases in which hypophosphatemia results from the same mechanism.[3, 4]

In this case, measurement of the serum phosphate level was important in reaching the diagnosis. Although hypophosphatemia in the hospitalized patient is often easily explained, severe or persistent hypophosphatemia requires a focused evaluation. Causes of hypophosphatemia are categorized in Table 1.[7, 8, 9] In patients with hypophosphatemia that is not explained by the clinical situation (eg, osmotic diuresis, insulin treatment, refeeding syndrome, postparathyroidectomy, chronic diarrhea), measurement of serum calcium, PTH, and 25‐hydroxyvitamin D are used to investigate possible primary or secondary hyperparathyroidism. In addition, low‐normal or low serum 1,25‐dihydroxyvitamin D with normal PTH, normal 25‐hydroxyvitamin D stores, and normal renal function are clues to the presence of TIO. Urine phosphate wasting can be measured by collecting a 24‐hour urine sample. Calculation of the TmP/GFR (a measure of the maximum tubular resorption of phosphate relative to the glomerular filtration rate), as described by the nomogram of Walton and Bijvoet, may improve the accuracy of this assessment and confirm a renal source of the hypophosphatemia.[10]

The patient presented here had inappropriate urinary phosphate losses, and laboratory testing ruled out primary and secondary hyperparathyroidism and Fanconi syndrome. The patient was not taking medications known to cause tubular phosphate wasting. The patient's age and clinical history made hereditary syndromes unlikely. Therefore, the urinary phosphate wasting had to be related to an acquired defect in phosphate metabolism. The diagnostic characteristics of TIO are summarized in Table 2.

The presence of a known neoplasm makes the diagnosis of TIO considerably easier. However, osteomalacia often precedes the tumor diagnosis. In these cases, the discovery of this clinical syndrome necessitates a search for the tumor. The tumors can be small, occult, and often located in the extremities. In addition to standard cross‐sectional imaging, specialized diagnostic modalities can be helpful in localizing culprit tumors. These include F‐18 flourodeoxyglucose positron emission tomography with computed tomography, 111‐Indium octreotide single photon emission CT/CT, 68‐Gallium‐DOTA‐octreotide positron emission tomography with computed tomography, and even selective venous sampling for FGF23 levels.[1, 11] The octreotide tests capitalize on the fact that culprit tumors often express somatostatin receptors.

TIO is most often associated with mesenchymal tumors of the bone or soft tissue. It has also been reported in association with several malignancies (small cell carcinoma, hematologic malignancies, prostate cancer), and with polyostotic fibrous dysplasia, neurofibromatosis, and the epidermal nevus syndrome. The mesenchymal tumors are heterogeneous in appearance and can be variably classified as hemangiopericytomas, hemangiomas, sarcomas, ossifying fibromas, granulomas, giant cell tumors, or osteoblastomas.[1] However, 1 review suggests that most of these tumors actually represent a distinct but heterogeneous, under‐recognized entity that is best classified as a phosphaturic mesenchymal tumor.[11]

TIO is only cured by complete resection of the tumor.[1] Local recurrences have been described, as have rare occurrences of metastatic disease.[1, 12] Medical treatment can be used to normalize serum phosphate levels in patients who are unable to be cured by surgery. The goal is to bring serum phosphate into the low‐normal range via phosphate supplementation (typically 13 g/day of elemental phosphorus is required) and treatment with either calcitriol or alfacalcidol. Due to the inhibition of 1,25‐dihydroxyvitamin D activation in TIO, relatively large doses of calcitriol are needed. A reasonable starting dose of calcitriol is 1.5 g/day, and most patients require 15 to 60 ng/kg per day. Because PTH action is involved in FGF23‐mediated hypophosphatemia, suppression of PTH may also be useful in these patients.[13]

This patient presented with a painful femoral tumor in the setting of muscle and joint pain that had been erroneously attributed to connective tissue disease. However, recognition and thorough evaluation of the patient's hypophosphatemia led to a unifying diagnosis of TIO. This diagnosis altered the surgical approach (emphasizing complete resection to eradicate the FGF23 production) and helped alleviate the patient's painful losses of phosphate.

TEACHING POINTS

1. Hypophosphatemia, especially if severe or persistent, should not be dismissed as an unimportant laboratory finding. A focused evaluation should be performed to determine the etiology.
2. In patients with unexplained hypophosphatemia, the measurement of serum calcium, parathyroid hormone, and vitamin D levels can identify primary or secondary hyperparathyroidism.
3. The differential diagnosis of hypophosphatemia is narrowed if there is clinical evidence of inappropriate urinary phosphate wasting (ie, urinary phosphate levels remain high, despite low serum levels).
4. TIO is a rare paraneoplastic syndrome caused by FGF23, a phosphatonin hormone that causes renal phosphate wasting, hypophosphatemia, and osteomalacia.

Disclosure: Nothing to report.

Hyperglycemia is common in hospitalized patients, and hyperglycemia has been associated with poor hospital outcomes. The adverse physiologic effects of acute hyperglycemia are well established1 and several clinical studies have linked hyperglycemia with poor clinical outcomes in certain patient populations.28 Although the optimal target range for inpatient glycemic control has not yet been defined, these studies support the goal of metabolic control for hospital patients. However, there are many barriers to achieving adequate glycemic control in the hospital, and blood glucoses in the hospital are often far from recommended targets.9, 10 One barrier appears to be the low priority given to glycemic control in the hospital. Hyperglycemia in the hospital is often ignored,11 and insulin regimens are often chosen for simplicity as opposed to effectiveness.12 Other barriers to glycemic control in the hospital include the physiologic effects (stress) of acute illness, and the frequent nutritional changes and interruptions that occur.

Most hyperglycemic patients on a general medicine unit are treated with subcutaneous insulin, but the optimal strategy for prescribing insulin in the hospital remains uncertain. A technical review of the literature on the management of diabetes in the hospital setting from 2004 recommends prescribing insulin in a way that mimics physiologic insulin secretion (ie, physiologic or basal‐bolus insulin).1 This approach has been promulgated by experts, but there has been very little research to support these recommendations. One small, randomized trial concluded that a basal‐bolus approach achieved better glycemic control than the use of sliding‐scale insulin alone,13 and 2 quality improvement studies using a before/after design have demonstrated improvements in glycemic control after the implementation of interventions designed to encourage physiologic insulin use.14, 15

In this study we hypothesized that a few simple interventions (education for physicians and nurses, and a standardized insulin order form) would lead to a higher rate of basal‐bolus insulin use and simultaneously improve glycemic control and patient safety.

Methods

Results

A total of 245 patients provided 1315 patient‐days. Patient demographics are shown in Table 2. The patients' weight, length‐of‐stay, and primary diagnoses were similar across the 3 groups. There was a higher percentage of males in the IG as compared to the HCG.

Table 3 shows the insulin regimens used in the different groups. The use of basal insulin was similar between groups. Congruent with the goals of the education session and the order set, patients in the IG were more likely to be treated with a combination of basal and nutritional insulin than patients in the other groups. Patients in the HCG were more likely to be treated with a premixed insulin than patients in the other groups. However, even when premixed insulin was categorized as a form of basal plus nutritional insulin and combined into a composite group with the combined basal and nutritional days, this type of regimen remained more common in the IG than in the HCG. The rate of sliding scale insulin use alone (ie, without any scheduled insulin) was similar in the 3 groups.

Other relevant measures are also shown in Table 3. The use of oral diabetes agents was similar in the 3 groups. The use of a nonoral feeding route (eg, tube feeding or parenteral nutrition) was infrequent.

A comparison of glycemic control in the three groups is shown in Table 4. In contrast to the CCG, patients in the IG experienced more days within the target glucose range (17% vs. 10.6%, P < 0.01), fewer days with severe hyperglycemia (48.3% vs. 59.2%, P < 0.01), and had a lower day‐weighted average blood glucose (195.9 vs. 212.6, P < 0.01). Compared to the HCG, patients in the IG experienced similar rates of hyperglycemia, but fewer hypoglycemic days (5.1% vs. 9.2%, P = 0.02).

The percentages of patients with severe hyperglycemia in each group are shown in Figure 1 by hospital day. Severe hyperglycemia was common, but there was a trend towards a decrease in the prevalence of severe hyperglycemia with increasing hospital days for all study groups, although it was consistently higher in the CCG than in the IG. Figure 2 shows the types of insulin regimens used by hospital day (composite for all groups). The use of basal plus nutritional insulin (the recommended regimen) increased gradually with increasing hospital days. When taken together, the information in both figures support the hypothesis that the use of the recommended insulin regimen may have contributed to the modest improvements in glycemic control seen in the IG.

Figure 1

Figure 2

In the final adjusted regression model, the intervention had a positive impact on glycemic control (Table 5). Subjects in the IG had a 72% increase in the odds of being in the target glucose range when compared to subjects in the CCG (P = 0.01). In addition, subjects in the IG had a 35% reduction in the odds of being severely hyperglycemic when compared to those in the CCG (P < 0.01). Finally, the odds ratio (OR) for being hypoglycemic among intervention subjects was 0.59 (P = 0.06) when compared to subjects in the CCG and 0.48 (P = 0.01) when compared to subjects in the HCG.

Discussion

In this study, we investigated the effects of a standardized insulin order set, coupled with physician and nurse education, on glycemic control in hyperglycemic hospitalized patients. These interventions were designed to encourage a standardized approach to the treatment of hyperglycemia in hospitalized patients, based on the principles of physiologic insulin use, as described above. Our data suggest that the interventions did, indeed, alter the way insulin was prescribed, as more patients in the IG received a combination of basal plus nutritional insulin (the recommended regimen) than in the other groups. These interventions were associated with improved glycemic outcomes in the IG as compared to the CCG. The IG experienced a higher percentage of days in the target range and a trend toward fewer hypoglycemic days than the CCG. Although the IG experienced a similar percentage of days in the target range, it had significantly fewer hypoglycemic days than the HCG.

It is useful to consider the results of our study in the context of 2 other similar studies performed by Schnipper et al.14 and Maynard et al.15 Although each of these 3 studies have different study designs, they are similar in intent (to test the effects of simple quality improvement interventions on glycemic control in the hospital) and results (all showed significant improvements in some aspect of glycemic control). In our study, and the study by Maynard et al.,15 the interventions also led to decreases in the rates of hypoglycemia, whereas Schnipper et al.14 observed no difference in hypoglycemia. Of interest, in each of the three studies the interventions were associated with an increase in the use of some type of scheduled insulin. In our study and the study from Schnipper et al.14 the baseline use of basal insulin was quite high, and the interventions were associated with a significant increase in the addition of nutritional insulin. In the Maynard et al.15 study, the baseline use of sliding scale insulin alone was prevalent, and the interventions resulted in an increase in the use of basal insulin. The results of these studies, taken together, prompt us to conclude that the interventions employed in these studies are likely to lead to more frequent prescription of scheduled (anticipatory) insulin, and a modest improvement in glycemic control, without an increase (and perhaps with a decrease) in hypoglycemia.

A few of our study results are unexpected, or difficult to explain. In contrast to the other studies discussed above, our interventions did not affect the frequency of the use of sliding‐scale insulin alone (without any scheduled insulin), which was similar in the 3 groups. Although the reason for this is uncertain, we hypothesize that the high baseline use of basal insulin in our institution, and the lack of a hard stop preventing the use of sliding scale insulin alone explain this finding. Also, it is difficult to explain why measures of hyperglycemia were similar between the IG and the HCG despite the fact that the HCG was less often treated with a combination of basal and nutritional insulin and more often treated with mixed insulin.

There are several different mechanisms by which the interventions might have resulted in improved glycemic control in the IG compared to CCG. Our data clearly shows that insulin was prescribed differently in the IG, and the more frequent use of a combination of scheduled basal and nutritional insulin might have contributed to the differences between the groups. However, the effects of our interventions clearly went beyond physician education into the realm of true process improvement and standardization. The standardized order form was designed to prompt physicians to use a basal‐bolus insulin regimen. The order form also created nursing expectations of how insulin should be ordered, and clarified the roles of the different insulins that were prescribed.

On the medication administration record, each insulin was labeled as basal insulin (to be given even when fasting) or nutritional insulin (to be given along with the meal). The nurses caring for the IG also attended an education program that reinforced the role of the nurse in the bedside management of insulin administration. Specifically, nurses were taught to assess the premeal blood glucose and the patient's nutritional situation before giving the nutritional insulin (ie, Does the patient have food available? Will he tolerate eating the food?). In situations where is was not clear if the patient would be able to tolerate the ordered nutrition, the order set empowered the nurse to give the nutritional insulin after the meal, and to reduce the dose to match the patient's actual intake. These interventions resulted in some fundamental improvements in the nursing process of delivering insulin to the patient, and these changes might have resulted in improvements via mechanisms that are difficult to directly measure. Since the same physicians cared for both the IG and the CCG, interventions other than physician education clearly contributed to the observed improvements in the IG.

This study was not a randomized study, and there could be important undetected differences between the groups. However, all of the patients were admitted to the General Medicine Inpatient Services and the comparison of the general patient demographics and primary diagnoses between the groups do not suggest major differences.

Although the improvements in glycemic control seen in this study were statistically significant, they were quantitatively modest. The rates of hyperglycemia seen in this study, on the other hand, are quite remarkable. Both the American Diabetes Association and the American College of Endocrinology have recommended that blood glucoses in hospitalized patients not exceed a maximum value of 180 mg/dL, but the day‐weighted average blood glucose in this study was above that for each group. Even in the IG, over 80% of all patient‐days included at least 1 blood glucose value outside of the target range. These data suggest that better strategies for achieving metabolic control in hospitalized patients are needed.

It is worth mentioning that our interventions were not aggressively enforced. While the use of the order set was mandatory for the IG, it was flexible enough to allow for substantial practice variation, especially with respect to the dose of insulin prescribed. Although the education sessions discussed the specifics of insulin dosing in hospitalized patients, the order form did not offer dosing guidelines. It is possible that our interventions may have had a larger impact if a starting dose of insulin had been specified on the form. Although the insulin order form prompted physicians to act, there were no forced functions. Also, not all house staff attended the education sessions for physicians, and there was no feedback provided to physicians related to how they might improve their adherence to the recommendations presented in the educational module. Therefore, it is likely that more aggressive interventions could have led to greater changes in physician practice.

In conclusion, this study demonstrates that interventions including physician and nurse education and a standardized insulin order set can lead to improvement in glycemic control and patient safety in hospitalized patients treated with subcutaneous insulin. However, the observed improvements are modest, and poor metabolic control remains common, despite these interventions. These data suggest that standardization of the process of ordering and delivering subcutaneous insulin in the hospital may lead to a reduction in both hyperglycemia and hypoglycemia. However, it is clear that the interventions used in this study were not potent enough to achieve the recommended glycemic targets for the majority of patients. Additional research is needed to determine the best strategy for achieving safe and effective metabolic control in hospitalized, hyperglycemic, noncritically ill patients.

Hyperglycemia is common in hospitalized patients, and hyperglycemia has been associated with poor hospital outcomes. The adverse physiologic effects of acute hyperglycemia are well established1 and several clinical studies have linked hyperglycemia with poor clinical outcomes in certain patient populations.28 Although the optimal target range for inpatient glycemic control has not yet been defined, these studies support the goal of metabolic control for hospital patients. However, there are many barriers to achieving adequate glycemic control in the hospital, and blood glucoses in the hospital are often far from recommended targets.9, 10 One barrier appears to be the low priority given to glycemic control in the hospital. Hyperglycemia in the hospital is often ignored,11 and insulin regimens are often chosen for simplicity as opposed to effectiveness.12 Other barriers to glycemic control in the hospital include the physiologic effects (stress) of acute illness, and the frequent nutritional changes and interruptions that occur.

Most hyperglycemic patients on a general medicine unit are treated with subcutaneous insulin, but the optimal strategy for prescribing insulin in the hospital remains uncertain. A technical review of the literature on the management of diabetes in the hospital setting from 2004 recommends prescribing insulin in a way that mimics physiologic insulin secretion (ie, physiologic or basal‐bolus insulin).1 This approach has been promulgated by experts, but there has been very little research to support these recommendations. One small, randomized trial concluded that a basal‐bolus approach achieved better glycemic control than the use of sliding‐scale insulin alone,13 and 2 quality improvement studies using a before/after design have demonstrated improvements in glycemic control after the implementation of interventions designed to encourage physiologic insulin use.14, 15

In this study we hypothesized that a few simple interventions (education for physicians and nurses, and a standardized insulin order form) would lead to a higher rate of basal‐bolus insulin use and simultaneously improve glycemic control and patient safety.

Methods

Results

A total of 245 patients provided 1315 patient‐days. Patient demographics are shown in Table 2. The patients' weight, length‐of‐stay, and primary diagnoses were similar across the 3 groups. There was a higher percentage of males in the IG as compared to the HCG.

Table 3 shows the insulin regimens used in the different groups. The use of basal insulin was similar between groups. Congruent with the goals of the education session and the order set, patients in the IG were more likely to be treated with a combination of basal and nutritional insulin than patients in the other groups. Patients in the HCG were more likely to be treated with a premixed insulin than patients in the other groups. However, even when premixed insulin was categorized as a form of basal plus nutritional insulin and combined into a composite group with the combined basal and nutritional days, this type of regimen remained more common in the IG than in the HCG. The rate of sliding scale insulin use alone (ie, without any scheduled insulin) was similar in the 3 groups.

Other relevant measures are also shown in Table 3. The use of oral diabetes agents was similar in the 3 groups. The use of a nonoral feeding route (eg, tube feeding or parenteral nutrition) was infrequent.

A comparison of glycemic control in the three groups is shown in Table 4. In contrast to the CCG, patients in the IG experienced more days within the target glucose range (17% vs. 10.6%, P < 0.01), fewer days with severe hyperglycemia (48.3% vs. 59.2%, P < 0.01), and had a lower day‐weighted average blood glucose (195.9 vs. 212.6, P < 0.01). Compared to the HCG, patients in the IG experienced similar rates of hyperglycemia, but fewer hypoglycemic days (5.1% vs. 9.2%, P = 0.02).

The percentages of patients with severe hyperglycemia in each group are shown in Figure 1 by hospital day. Severe hyperglycemia was common, but there was a trend towards a decrease in the prevalence of severe hyperglycemia with increasing hospital days for all study groups, although it was consistently higher in the CCG than in the IG. Figure 2 shows the types of insulin regimens used by hospital day (composite for all groups). The use of basal plus nutritional insulin (the recommended regimen) increased gradually with increasing hospital days. When taken together, the information in both figures support the hypothesis that the use of the recommended insulin regimen may have contributed to the modest improvements in glycemic control seen in the IG.

Figure 1

Figure 2

In the final adjusted regression model, the intervention had a positive impact on glycemic control (Table 5). Subjects in the IG had a 72% increase in the odds of being in the target glucose range when compared to subjects in the CCG (P = 0.01). In addition, subjects in the IG had a 35% reduction in the odds of being severely hyperglycemic when compared to those in the CCG (P < 0.01). Finally, the odds ratio (OR) for being hypoglycemic among intervention subjects was 0.59 (P = 0.06) when compared to subjects in the CCG and 0.48 (P = 0.01) when compared to subjects in the HCG.

Discussion

In this study, we investigated the effects of a standardized insulin order set, coupled with physician and nurse education, on glycemic control in hyperglycemic hospitalized patients. These interventions were designed to encourage a standardized approach to the treatment of hyperglycemia in hospitalized patients, based on the principles of physiologic insulin use, as described above. Our data suggest that the interventions did, indeed, alter the way insulin was prescribed, as more patients in the IG received a combination of basal plus nutritional insulin (the recommended regimen) than in the other groups. These interventions were associated with improved glycemic outcomes in the IG as compared to the CCG. The IG experienced a higher percentage of days in the target range and a trend toward fewer hypoglycemic days than the CCG. Although the IG experienced a similar percentage of days in the target range, it had significantly fewer hypoglycemic days than the HCG.

It is useful to consider the results of our study in the context of 2 other similar studies performed by Schnipper et al.14 and Maynard et al.15 Although each of these 3 studies have different study designs, they are similar in intent (to test the effects of simple quality improvement interventions on glycemic control in the hospital) and results (all showed significant improvements in some aspect of glycemic control). In our study, and the study by Maynard et al.,15 the interventions also led to decreases in the rates of hypoglycemia, whereas Schnipper et al.14 observed no difference in hypoglycemia. Of interest, in each of the three studies the interventions were associated with an increase in the use of some type of scheduled insulin. In our study and the study from Schnipper et al.14 the baseline use of basal insulin was quite high, and the interventions were associated with a significant increase in the addition of nutritional insulin. In the Maynard et al.15 study, the baseline use of sliding scale insulin alone was prevalent, and the interventions resulted in an increase in the use of basal insulin. The results of these studies, taken together, prompt us to conclude that the interventions employed in these studies are likely to lead to more frequent prescription of scheduled (anticipatory) insulin, and a modest improvement in glycemic control, without an increase (and perhaps with a decrease) in hypoglycemia.

A few of our study results are unexpected, or difficult to explain. In contrast to the other studies discussed above, our interventions did not affect the frequency of the use of sliding‐scale insulin alone (without any scheduled insulin), which was similar in the 3 groups. Although the reason for this is uncertain, we hypothesize that the high baseline use of basal insulin in our institution, and the lack of a hard stop preventing the use of sliding scale insulin alone explain this finding. Also, it is difficult to explain why measures of hyperglycemia were similar between the IG and the HCG despite the fact that the HCG was less often treated with a combination of basal and nutritional insulin and more often treated with mixed insulin.

There are several different mechanisms by which the interventions might have resulted in improved glycemic control in the IG compared to CCG. Our data clearly shows that insulin was prescribed differently in the IG, and the more frequent use of a combination of scheduled basal and nutritional insulin might have contributed to the differences between the groups. However, the effects of our interventions clearly went beyond physician education into the realm of true process improvement and standardization. The standardized order form was designed to prompt physicians to use a basal‐bolus insulin regimen. The order form also created nursing expectations of how insulin should be ordered, and clarified the roles of the different insulins that were prescribed.

On the medication administration record, each insulin was labeled as basal insulin (to be given even when fasting) or nutritional insulin (to be given along with the meal). The nurses caring for the IG also attended an education program that reinforced the role of the nurse in the bedside management of insulin administration. Specifically, nurses were taught to assess the premeal blood glucose and the patient's nutritional situation before giving the nutritional insulin (ie, Does the patient have food available? Will he tolerate eating the food?). In situations where is was not clear if the patient would be able to tolerate the ordered nutrition, the order set empowered the nurse to give the nutritional insulin after the meal, and to reduce the dose to match the patient's actual intake. These interventions resulted in some fundamental improvements in the nursing process of delivering insulin to the patient, and these changes might have resulted in improvements via mechanisms that are difficult to directly measure. Since the same physicians cared for both the IG and the CCG, interventions other than physician education clearly contributed to the observed improvements in the IG.

This study was not a randomized study, and there could be important undetected differences between the groups. However, all of the patients were admitted to the General Medicine Inpatient Services and the comparison of the general patient demographics and primary diagnoses between the groups do not suggest major differences.

Although the improvements in glycemic control seen in this study were statistically significant, they were quantitatively modest. The rates of hyperglycemia seen in this study, on the other hand, are quite remarkable. Both the American Diabetes Association and the American College of Endocrinology have recommended that blood glucoses in hospitalized patients not exceed a maximum value of 180 mg/dL, but the day‐weighted average blood glucose in this study was above that for each group. Even in the IG, over 80% of all patient‐days included at least 1 blood glucose value outside of the target range. These data suggest that better strategies for achieving metabolic control in hospitalized patients are needed.

It is worth mentioning that our interventions were not aggressively enforced. While the use of the order set was mandatory for the IG, it was flexible enough to allow for substantial practice variation, especially with respect to the dose of insulin prescribed. Although the education sessions discussed the specifics of insulin dosing in hospitalized patients, the order form did not offer dosing guidelines. It is possible that our interventions may have had a larger impact if a starting dose of insulin had been specified on the form. Although the insulin order form prompted physicians to act, there were no forced functions. Also, not all house staff attended the education sessions for physicians, and there was no feedback provided to physicians related to how they might improve their adherence to the recommendations presented in the educational module. Therefore, it is likely that more aggressive interventions could have led to greater changes in physician practice.

In conclusion, this study demonstrates that interventions including physician and nurse education and a standardized insulin order set can lead to improvement in glycemic control and patient safety in hospitalized patients treated with subcutaneous insulin. However, the observed improvements are modest, and poor metabolic control remains common, despite these interventions. These data suggest that standardization of the process of ordering and delivering subcutaneous insulin in the hospital may lead to a reduction in both hyperglycemia and hypoglycemia. However, it is clear that the interventions used in this study were not potent enough to achieve the recommended glycemic targets for the majority of patients. Additional research is needed to determine the best strategy for achieving safe and effective metabolic control in hospitalized, hyperglycemic, noncritically ill patients.

Hyperglycemia is common in hospitalized patients, and hyperglycemia has been associated with poor hospital outcomes. The adverse physiologic effects of acute hyperglycemia are well established1 and several clinical studies have linked hyperglycemia with poor clinical outcomes in certain patient populations.28 Although the optimal target range for inpatient glycemic control has not yet been defined, these studies support the goal of metabolic control for hospital patients. However, there are many barriers to achieving adequate glycemic control in the hospital, and blood glucoses in the hospital are often far from recommended targets.9, 10 One barrier appears to be the low priority given to glycemic control in the hospital. Hyperglycemia in the hospital is often ignored,11 and insulin regimens are often chosen for simplicity as opposed to effectiveness.12 Other barriers to glycemic control in the hospital include the physiologic effects (stress) of acute illness, and the frequent nutritional changes and interruptions that occur.

Most hyperglycemic patients on a general medicine unit are treated with subcutaneous insulin, but the optimal strategy for prescribing insulin in the hospital remains uncertain. A technical review of the literature on the management of diabetes in the hospital setting from 2004 recommends prescribing insulin in a way that mimics physiologic insulin secretion (ie, physiologic or basal‐bolus insulin).1 This approach has been promulgated by experts, but there has been very little research to support these recommendations. One small, randomized trial concluded that a basal‐bolus approach achieved better glycemic control than the use of sliding‐scale insulin alone,13 and 2 quality improvement studies using a before/after design have demonstrated improvements in glycemic control after the implementation of interventions designed to encourage physiologic insulin use.14, 15

In this study we hypothesized that a few simple interventions (education for physicians and nurses, and a standardized insulin order form) would lead to a higher rate of basal‐bolus insulin use and simultaneously improve glycemic control and patient safety.

Methods

Results

A total of 245 patients provided 1315 patient‐days. Patient demographics are shown in Table 2. The patients' weight, length‐of‐stay, and primary diagnoses were similar across the 3 groups. There was a higher percentage of males in the IG as compared to the HCG.

Table 3 shows the insulin regimens used in the different groups. The use of basal insulin was similar between groups. Congruent with the goals of the education session and the order set, patients in the IG were more likely to be treated with a combination of basal and nutritional insulin than patients in the other groups. Patients in the HCG were more likely to be treated with a premixed insulin than patients in the other groups. However, even when premixed insulin was categorized as a form of basal plus nutritional insulin and combined into a composite group with the combined basal and nutritional days, this type of regimen remained more common in the IG than in the HCG. The rate of sliding scale insulin use alone (ie, without any scheduled insulin) was similar in the 3 groups.

Other relevant measures are also shown in Table 3. The use of oral diabetes agents was similar in the 3 groups. The use of a nonoral feeding route (eg, tube feeding or parenteral nutrition) was infrequent.

A comparison of glycemic control in the three groups is shown in Table 4. In contrast to the CCG, patients in the IG experienced more days within the target glucose range (17% vs. 10.6%, P < 0.01), fewer days with severe hyperglycemia (48.3% vs. 59.2%, P < 0.01), and had a lower day‐weighted average blood glucose (195.9 vs. 212.6, P < 0.01). Compared to the HCG, patients in the IG experienced similar rates of hyperglycemia, but fewer hypoglycemic days (5.1% vs. 9.2%, P = 0.02).

The percentages of patients with severe hyperglycemia in each group are shown in Figure 1 by hospital day. Severe hyperglycemia was common, but there was a trend towards a decrease in the prevalence of severe hyperglycemia with increasing hospital days for all study groups, although it was consistently higher in the CCG than in the IG. Figure 2 shows the types of insulin regimens used by hospital day (composite for all groups). The use of basal plus nutritional insulin (the recommended regimen) increased gradually with increasing hospital days. When taken together, the information in both figures support the hypothesis that the use of the recommended insulin regimen may have contributed to the modest improvements in glycemic control seen in the IG.

Figure 1

Figure 2

In the final adjusted regression model, the intervention had a positive impact on glycemic control (Table 5). Subjects in the IG had a 72% increase in the odds of being in the target glucose range when compared to subjects in the CCG (P = 0.01). In addition, subjects in the IG had a 35% reduction in the odds of being severely hyperglycemic when compared to those in the CCG (P < 0.01). Finally, the odds ratio (OR) for being hypoglycemic among intervention subjects was 0.59 (P = 0.06) when compared to subjects in the CCG and 0.48 (P = 0.01) when compared to subjects in the HCG.

Discussion

In this study, we investigated the effects of a standardized insulin order set, coupled with physician and nurse education, on glycemic control in hyperglycemic hospitalized patients. These interventions were designed to encourage a standardized approach to the treatment of hyperglycemia in hospitalized patients, based on the principles of physiologic insulin use, as described above. Our data suggest that the interventions did, indeed, alter the way insulin was prescribed, as more patients in the IG received a combination of basal plus nutritional insulin (the recommended regimen) than in the other groups. These interventions were associated with improved glycemic outcomes in the IG as compared to the CCG. The IG experienced a higher percentage of days in the target range and a trend toward fewer hypoglycemic days than the CCG. Although the IG experienced a similar percentage of days in the target range, it had significantly fewer hypoglycemic days than the HCG.

It is useful to consider the results of our study in the context of 2 other similar studies performed by Schnipper et al.14 and Maynard et al.15 Although each of these 3 studies have different study designs, they are similar in intent (to test the effects of simple quality improvement interventions on glycemic control in the hospital) and results (all showed significant improvements in some aspect of glycemic control). In our study, and the study by Maynard et al.,15 the interventions also led to decreases in the rates of hypoglycemia, whereas Schnipper et al.14 observed no difference in hypoglycemia. Of interest, in each of the three studies the interventions were associated with an increase in the use of some type of scheduled insulin. In our study and the study from Schnipper et al.14 the baseline use of basal insulin was quite high, and the interventions were associated with a significant increase in the addition of nutritional insulin. In the Maynard et al.15 study, the baseline use of sliding scale insulin alone was prevalent, and the interventions resulted in an increase in the use of basal insulin. The results of these studies, taken together, prompt us to conclude that the interventions employed in these studies are likely to lead to more frequent prescription of scheduled (anticipatory) insulin, and a modest improvement in glycemic control, without an increase (and perhaps with a decrease) in hypoglycemia.

A few of our study results are unexpected, or difficult to explain. In contrast to the other studies discussed above, our interventions did not affect the frequency of the use of sliding‐scale insulin alone (without any scheduled insulin), which was similar in the 3 groups. Although the reason for this is uncertain, we hypothesize that the high baseline use of basal insulin in our institution, and the lack of a hard stop preventing the use of sliding scale insulin alone explain this finding. Also, it is difficult to explain why measures of hyperglycemia were similar between the IG and the HCG despite the fact that the HCG was less often treated with a combination of basal and nutritional insulin and more often treated with mixed insulin.

There are several different mechanisms by which the interventions might have resulted in improved glycemic control in the IG compared to CCG. Our data clearly shows that insulin was prescribed differently in the IG, and the more frequent use of a combination of scheduled basal and nutritional insulin might have contributed to the differences between the groups. However, the effects of our interventions clearly went beyond physician education into the realm of true process improvement and standardization. The standardized order form was designed to prompt physicians to use a basal‐bolus insulin regimen. The order form also created nursing expectations of how insulin should be ordered, and clarified the roles of the different insulins that were prescribed.

On the medication administration record, each insulin was labeled as basal insulin (to be given even when fasting) or nutritional insulin (to be given along with the meal). The nurses caring for the IG also attended an education program that reinforced the role of the nurse in the bedside management of insulin administration. Specifically, nurses were taught to assess the premeal blood glucose and the patient's nutritional situation before giving the nutritional insulin (ie, Does the patient have food available? Will he tolerate eating the food?). In situations where is was not clear if the patient would be able to tolerate the ordered nutrition, the order set empowered the nurse to give the nutritional insulin after the meal, and to reduce the dose to match the patient's actual intake. These interventions resulted in some fundamental improvements in the nursing process of delivering insulin to the patient, and these changes might have resulted in improvements via mechanisms that are difficult to directly measure. Since the same physicians cared for both the IG and the CCG, interventions other than physician education clearly contributed to the observed improvements in the IG.

This study was not a randomized study, and there could be important undetected differences between the groups. However, all of the patients were admitted to the General Medicine Inpatient Services and the comparison of the general patient demographics and primary diagnoses between the groups do not suggest major differences.

Although the improvements in glycemic control seen in this study were statistically significant, they were quantitatively modest. The rates of hyperglycemia seen in this study, on the other hand, are quite remarkable. Both the American Diabetes Association and the American College of Endocrinology have recommended that blood glucoses in hospitalized patients not exceed a maximum value of 180 mg/dL, but the day‐weighted average blood glucose in this study was above that for each group. Even in the IG, over 80% of all patient‐days included at least 1 blood glucose value outside of the target range. These data suggest that better strategies for achieving metabolic control in hospitalized patients are needed.

It is worth mentioning that our interventions were not aggressively enforced. While the use of the order set was mandatory for the IG, it was flexible enough to allow for substantial practice variation, especially with respect to the dose of insulin prescribed. Although the education sessions discussed the specifics of insulin dosing in hospitalized patients, the order form did not offer dosing guidelines. It is possible that our interventions may have had a larger impact if a starting dose of insulin had been specified on the form. Although the insulin order form prompted physicians to act, there were no forced functions. Also, not all house staff attended the education sessions for physicians, and there was no feedback provided to physicians related to how they might improve their adherence to the recommendations presented in the educational module. Therefore, it is likely that more aggressive interventions could have led to greater changes in physician practice.

In conclusion, this study demonstrates that interventions including physician and nurse education and a standardized insulin order set can lead to improvement in glycemic control and patient safety in hospitalized patients treated with subcutaneous insulin. However, the observed improvements are modest, and poor metabolic control remains common, despite these interventions. These data suggest that standardization of the process of ordering and delivering subcutaneous insulin in the hospital may lead to a reduction in both hyperglycemia and hypoglycemia. However, it is clear that the interventions used in this study were not potent enough to achieve the recommended glycemic targets for the majority of patients. Additional research is needed to determine the best strategy for achieving safe and effective metabolic control in hospitalized, hyperglycemic, noncritically ill patients.

Inpatient glycemic control and hypoglycemia are issues with well deserved increased attention in recent years. Prominent guidelines and technical reviews have been published,13 and a recent, randomized controlled trial demonstrated the superiority of basal bolus insulin regimens compared to sliding‐scale regimens.4 Effective glycemic control for inpatients has remained elusive in most medical centers. Recent reports57 detail clinical inertia and the continued widespread use of sliding‐scale subcutaneous insulin regimens, as opposed to the anticipatory, physiologic basal‐nutrition‐correction dose insulin regimens endorsed by these reviews.

Inpatient glycemic control faces a number of barriers, including fears of inducing hypoglycemia, uneven knowledge and training among staff, and competing institutional and patient priorities. These barriers occur in the background of an inherently complex inpatient environment that poses unique challenges in maintaining safe glycemic control. Patients frequently move across a variety of care teams and geographic locations during a single inpatient stay, giving rise to multiple opportunities for failed communication, incomplete handoffs, and inconsistent treatment. In addition, insulin requirements may change dramatically due to variations in the stress of illness, exposure to medications that effect glucose levels, and varied forms of nutritional intake with frequent interruption. Although insulin is recognized as one of the medications most likely to be associated with adverse events in the hospital, many hospitals do not have protocols or order sets in place to standardize its use.

A Call to Action consensus conference,8, 9 hosted by the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA), brought together many thought leaders and organizations, including representation from the Society of Hospital Medicine (SHM), to address these barriers and to outline components necessary for successful implementation of a program to improve inpatient glycemic control in the face of these difficulties. Institutional insulin management protocols and standardized insulin order sets (supported by appropriate educational efforts) were identified as key interventions. It may be tempting to quickly deploy a generic insulin order set in an effort to improve care. This often results in mediocre results, due to inadequate incorporation of standardization and guidance into the order set and other documentation tools, and uneven use of the order set.

The SHM Glycemic Control Task Force (GCTF) recommends the following steps for developing and implementing successful protocols and order sets addressing the needs of the noncritical care inpatient with diabetes/hyperglycemia.

• Form a steering committee for this work, and assess the current processes of care.

• Identify best practices and preferred regimens to manage diabetes and hyperglycemia in the hospital.

• Integrate best practices and preferred institutional choices into an inpatient glycemic control protocol. Crystallize your protocol into a one page summary.

• Place guidance from your protocol into the flow of work, by integrating it into standardized subcutaneous insulin order sets and other documentation and treatment tools.

• Monitor the use of your order sets and protocol. Intervene actively on nonadherents to your protocol and those with poor glycemic control, and revise your protocol/order sets as needed.

IDENTIFYING AND INCORPORATING KEY CONCEPTS AND BEST PRACTICES

A protocol is a document that endorses specific monitoring and treatment strategies in a given institution. This potentially extensive document should provide guidance for transitions, special situations (like steroids and total parenteral nutrition [TPN]) and should outline preferred insulin regimens for all of the most common nutritional situations. One of the most difficult parts of creating a protocol is the assimilation of all of the important information on which to base decisions. Your protocol and order set will be promoting a set of clinical practices. Fortunately, the current best practice for noncritical care hyperglycemic patients has been summarized by several authoritative sources,13, 811 including references from the SHM Glycemic Task Force published in this supplement.4, 12

Table 1 summarizes the key concepts that should be emphasized in a protocol for subcutaneous insulin management in the hospital. We recommend embedding guidance from your protocol into order sets, the medication administration record, and educational materials. Although the details contained in a protocol and order set might vary from one institution to another, the key concepts should not. The remainder of this article provides practical information about how these concepts and guidance for how preferred insulin regimens should be included in these tools. Appendices 1 and 2 give examples of an institutional one‐page summary protocol and subcutaneous insulin order set, respectively.

PULLING IT ALL TOGETHER: MAKE SURE YOUR PROTOCOL/ORDER SET IS EASY TO USE AND WIDELY UTILIZED

When standardizing hospital management of diabetes and hyperglycemia, we recommend building the full protocol first, then crystallizing the protocol into a one‐page summary that can be widely disseminated. The protocol guidance is then incorporated into the order set and nursing medical administration record (MAR). Again, we recommend the most proscriptive and protocol‐driven order set feasible within the constraints of medical staff support. The example order set in Appendix 2 illustrates this approach along with other desirable features:

• 1

  Check‐box simplicity on when to order appropriate glucose monitoring.

• 2

  Prompt for the proper hyperglycemia‐related diagnosis.

• 3

  Prompts to document diagnosis and to order HbA1c level.

• 4

  Use of encouraged insulin terminology: basal, prandial (or nutritional), and correction. Language is a powerful thing, and just getting staff to use these terms goes a long way toward the more physiologic prescribing of insulin.

• 5

  Statement/reminder of a glycemic goal.

• 6

  Prompts and contact information for appropriate consultation.

• 7

  Elimination of unapproved abbreviations (such as U for units).

• 8

  Stating both generic and brand names of insulin preparations.

• 9

  Important timing cues for administration of insulin.

• 10

  Several correction‐dose scales suitable for different insulin sensitivities. One size does NOT fit all.

• 11

  Incorporation of a simple hypoglycemia protocol into the order set.

• 12

  Insulin dosing guidelines available at the point of care (in this case, on the back of the order set).

Additional nursing‐specific cues (such as an admonition to never mix glargine insulin with other types of insulin) can also be included in the MAR whenever glargine is ordered.

Once you have protocols and order sets to guide providers, you need to assure that they are used for the majority of hyperglycemic patients. Educational programs should introduce your interventions and the rationale for them. In order to make your method the default method of care, your team should survey all preprinted or CPOE insulin order sets of your institution. A review of postoperative, transfer, and admission order sets that all services use may reveal a half‐dozen or more embedded sliding‐scale insulin order sets that should be removed, with prompts to use the standardized insulin order set being placed in their stead.

Computerized order sets present both challenges and opportunities. Wording limitations and the scrolling nature can make concepts less clear, yet there is a capability for incorporating a hierarchical structure that allows for guiding the user through a more algorithmic approach. There is also a capacity to provide assistance with dosing calculations that do not exist in the paper world. Education remains of key importance for both methods.

MONITOR THE USE AND EFFECTIVENESS OF YOUR PROTOCOLS AND ORDER SETS

Creating and implementing protocols, order sets, and other tools is not the end of the journey to improve care. It is important to monitor order set utilization, insulin use patterns, and parameters measuring glycemic control and hypoglycemia, as outlined in more detail in another article in this supplement.16 In addition to summary data every month or so, we recommend daily reports that spur action in near real time. Triggers such as uncontrolled hyperglycemia, markedly elevated HbA1c levels, and nonphysiologic insulin regimens should initiate consultation, extra diabetes education, or referral to a glucose control team. If appropriate consultation is not readily available, the glycemic control steering group should lobby the administration to bolster this capability. Qualitative feedback from the frontline caregivers, as well as this quantitative data, can assist the local glycemic control champions in designing even more effective protocols, order sets, focused educational efforts, and concurrent mitigation of suboptimal care.

CONCLUSION

Diabetes, hyperglycemia, and iatrogenic hypoglycemia are common and important conditions affecting the noncritically ill inpatient. Interventional trials to validate the recommended noncritical care unit glycemic targets are needed. Although there is a growing consensus on best practices to care for these patients, numerous barriers and the complexity of caring for inpatients hamper the reliability of best practice delivery. Institutional protocols and protocol driven subcutaneous insulin orders, when implemented with the strategies outlined here, can be the key to delivering these best practices more reliably.

Inpatient glycemic control and hypoglycemia are issues with well deserved increased attention in recent years. Prominent guidelines and technical reviews have been published,13 and a recent, randomized controlled trial demonstrated the superiority of basal bolus insulin regimens compared to sliding‐scale regimens.4 Effective glycemic control for inpatients has remained elusive in most medical centers. Recent reports57 detail clinical inertia and the continued widespread use of sliding‐scale subcutaneous insulin regimens, as opposed to the anticipatory, physiologic basal‐nutrition‐correction dose insulin regimens endorsed by these reviews.

Inpatient glycemic control faces a number of barriers, including fears of inducing hypoglycemia, uneven knowledge and training among staff, and competing institutional and patient priorities. These barriers occur in the background of an inherently complex inpatient environment that poses unique challenges in maintaining safe glycemic control. Patients frequently move across a variety of care teams and geographic locations during a single inpatient stay, giving rise to multiple opportunities for failed communication, incomplete handoffs, and inconsistent treatment. In addition, insulin requirements may change dramatically due to variations in the stress of illness, exposure to medications that effect glucose levels, and varied forms of nutritional intake with frequent interruption. Although insulin is recognized as one of the medications most likely to be associated with adverse events in the hospital, many hospitals do not have protocols or order sets in place to standardize its use.

A Call to Action consensus conference,8, 9 hosted by the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA), brought together many thought leaders and organizations, including representation from the Society of Hospital Medicine (SHM), to address these barriers and to outline components necessary for successful implementation of a program to improve inpatient glycemic control in the face of these difficulties. Institutional insulin management protocols and standardized insulin order sets (supported by appropriate educational efforts) were identified as key interventions. It may be tempting to quickly deploy a generic insulin order set in an effort to improve care. This often results in mediocre results, due to inadequate incorporation of standardization and guidance into the order set and other documentation tools, and uneven use of the order set.

The SHM Glycemic Control Task Force (GCTF) recommends the following steps for developing and implementing successful protocols and order sets addressing the needs of the noncritical care inpatient with diabetes/hyperglycemia.

• Form a steering committee for this work, and assess the current processes of care.

• Identify best practices and preferred regimens to manage diabetes and hyperglycemia in the hospital.

• Integrate best practices and preferred institutional choices into an inpatient glycemic control protocol. Crystallize your protocol into a one page summary.

• Place guidance from your protocol into the flow of work, by integrating it into standardized subcutaneous insulin order sets and other documentation and treatment tools.

• Monitor the use of your order sets and protocol. Intervene actively on nonadherents to your protocol and those with poor glycemic control, and revise your protocol/order sets as needed.

IDENTIFYING AND INCORPORATING KEY CONCEPTS AND BEST PRACTICES

A protocol is a document that endorses specific monitoring and treatment strategies in a given institution. This potentially extensive document should provide guidance for transitions, special situations (like steroids and total parenteral nutrition [TPN]) and should outline preferred insulin regimens for all of the most common nutritional situations. One of the most difficult parts of creating a protocol is the assimilation of all of the important information on which to base decisions. Your protocol and order set will be promoting a set of clinical practices. Fortunately, the current best practice for noncritical care hyperglycemic patients has been summarized by several authoritative sources,13, 811 including references from the SHM Glycemic Task Force published in this supplement.4, 12

Table 1 summarizes the key concepts that should be emphasized in a protocol for subcutaneous insulin management in the hospital. We recommend embedding guidance from your protocol into order sets, the medication administration record, and educational materials. Although the details contained in a protocol and order set might vary from one institution to another, the key concepts should not. The remainder of this article provides practical information about how these concepts and guidance for how preferred insulin regimens should be included in these tools. Appendices 1 and 2 give examples of an institutional one‐page summary protocol and subcutaneous insulin order set, respectively.

PULLING IT ALL TOGETHER: MAKE SURE YOUR PROTOCOL/ORDER SET IS EASY TO USE AND WIDELY UTILIZED

When standardizing hospital management of diabetes and hyperglycemia, we recommend building the full protocol first, then crystallizing the protocol into a one‐page summary that can be widely disseminated. The protocol guidance is then incorporated into the order set and nursing medical administration record (MAR). Again, we recommend the most proscriptive and protocol‐driven order set feasible within the constraints of medical staff support. The example order set in Appendix 2 illustrates this approach along with other desirable features:

• 1

  Check‐box simplicity on when to order appropriate glucose monitoring.

• 2

  Prompt for the proper hyperglycemia‐related diagnosis.

• 3

  Prompts to document diagnosis and to order HbA1c level.

• 4

  Use of encouraged insulin terminology: basal, prandial (or nutritional), and correction. Language is a powerful thing, and just getting staff to use these terms goes a long way toward the more physiologic prescribing of insulin.

• 5

  Statement/reminder of a glycemic goal.

• 6

  Prompts and contact information for appropriate consultation.

• 7

  Elimination of unapproved abbreviations (such as U for units).

• 8

  Stating both generic and brand names of insulin preparations.

• 9

  Important timing cues for administration of insulin.

• 10

  Several correction‐dose scales suitable for different insulin sensitivities. One size does NOT fit all.

• 11

  Incorporation of a simple hypoglycemia protocol into the order set.

• 12

  Insulin dosing guidelines available at the point of care (in this case, on the back of the order set).

Additional nursing‐specific cues (such as an admonition to never mix glargine insulin with other types of insulin) can also be included in the MAR whenever glargine is ordered.

Once you have protocols and order sets to guide providers, you need to assure that they are used for the majority of hyperglycemic patients. Educational programs should introduce your interventions and the rationale for them. In order to make your method the default method of care, your team should survey all preprinted or CPOE insulin order sets of your institution. A review of postoperative, transfer, and admission order sets that all services use may reveal a half‐dozen or more embedded sliding‐scale insulin order sets that should be removed, with prompts to use the standardized insulin order set being placed in their stead.

Computerized order sets present both challenges and opportunities. Wording limitations and the scrolling nature can make concepts less clear, yet there is a capability for incorporating a hierarchical structure that allows for guiding the user through a more algorithmic approach. There is also a capacity to provide assistance with dosing calculations that do not exist in the paper world. Education remains of key importance for both methods.

MONITOR THE USE AND EFFECTIVENESS OF YOUR PROTOCOLS AND ORDER SETS

Creating and implementing protocols, order sets, and other tools is not the end of the journey to improve care. It is important to monitor order set utilization, insulin use patterns, and parameters measuring glycemic control and hypoglycemia, as outlined in more detail in another article in this supplement.16 In addition to summary data every month or so, we recommend daily reports that spur action in near real time. Triggers such as uncontrolled hyperglycemia, markedly elevated HbA1c levels, and nonphysiologic insulin regimens should initiate consultation, extra diabetes education, or referral to a glucose control team. If appropriate consultation is not readily available, the glycemic control steering group should lobby the administration to bolster this capability. Qualitative feedback from the frontline caregivers, as well as this quantitative data, can assist the local glycemic control champions in designing even more effective protocols, order sets, focused educational efforts, and concurrent mitigation of suboptimal care.

CONCLUSION

Diabetes, hyperglycemia, and iatrogenic hypoglycemia are common and important conditions affecting the noncritically ill inpatient. Interventional trials to validate the recommended noncritical care unit glycemic targets are needed. Although there is a growing consensus on best practices to care for these patients, numerous barriers and the complexity of caring for inpatients hamper the reliability of best practice delivery. Institutional protocols and protocol driven subcutaneous insulin orders, when implemented with the strategies outlined here, can be the key to delivering these best practices more reliably.

Inpatient glycemic control and hypoglycemia are issues with well deserved increased attention in recent years. Prominent guidelines and technical reviews have been published,13 and a recent, randomized controlled trial demonstrated the superiority of basal bolus insulin regimens compared to sliding‐scale regimens.4 Effective glycemic control for inpatients has remained elusive in most medical centers. Recent reports57 detail clinical inertia and the continued widespread use of sliding‐scale subcutaneous insulin regimens, as opposed to the anticipatory, physiologic basal‐nutrition‐correction dose insulin regimens endorsed by these reviews.

Inpatient glycemic control faces a number of barriers, including fears of inducing hypoglycemia, uneven knowledge and training among staff, and competing institutional and patient priorities. These barriers occur in the background of an inherently complex inpatient environment that poses unique challenges in maintaining safe glycemic control. Patients frequently move across a variety of care teams and geographic locations during a single inpatient stay, giving rise to multiple opportunities for failed communication, incomplete handoffs, and inconsistent treatment. In addition, insulin requirements may change dramatically due to variations in the stress of illness, exposure to medications that effect glucose levels, and varied forms of nutritional intake with frequent interruption. Although insulin is recognized as one of the medications most likely to be associated with adverse events in the hospital, many hospitals do not have protocols or order sets in place to standardize its use.

A Call to Action consensus conference,8, 9 hosted by the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA), brought together many thought leaders and organizations, including representation from the Society of Hospital Medicine (SHM), to address these barriers and to outline components necessary for successful implementation of a program to improve inpatient glycemic control in the face of these difficulties. Institutional insulin management protocols and standardized insulin order sets (supported by appropriate educational efforts) were identified as key interventions. It may be tempting to quickly deploy a generic insulin order set in an effort to improve care. This often results in mediocre results, due to inadequate incorporation of standardization and guidance into the order set and other documentation tools, and uneven use of the order set.

The SHM Glycemic Control Task Force (GCTF) recommends the following steps for developing and implementing successful protocols and order sets addressing the needs of the noncritical care inpatient with diabetes/hyperglycemia.

• Form a steering committee for this work, and assess the current processes of care.

• Identify best practices and preferred regimens to manage diabetes and hyperglycemia in the hospital.

• Integrate best practices and preferred institutional choices into an inpatient glycemic control protocol. Crystallize your protocol into a one page summary.

• Place guidance from your protocol into the flow of work, by integrating it into standardized subcutaneous insulin order sets and other documentation and treatment tools.

• Monitor the use of your order sets and protocol. Intervene actively on nonadherents to your protocol and those with poor glycemic control, and revise your protocol/order sets as needed.

IDENTIFYING AND INCORPORATING KEY CONCEPTS AND BEST PRACTICES

A protocol is a document that endorses specific monitoring and treatment strategies in a given institution. This potentially extensive document should provide guidance for transitions, special situations (like steroids and total parenteral nutrition [TPN]) and should outline preferred insulin regimens for all of the most common nutritional situations. One of the most difficult parts of creating a protocol is the assimilation of all of the important information on which to base decisions. Your protocol and order set will be promoting a set of clinical practices. Fortunately, the current best practice for noncritical care hyperglycemic patients has been summarized by several authoritative sources,13, 811 including references from the SHM Glycemic Task Force published in this supplement.4, 12

Table 1 summarizes the key concepts that should be emphasized in a protocol for subcutaneous insulin management in the hospital. We recommend embedding guidance from your protocol into order sets, the medication administration record, and educational materials. Although the details contained in a protocol and order set might vary from one institution to another, the key concepts should not. The remainder of this article provides practical information about how these concepts and guidance for how preferred insulin regimens should be included in these tools. Appendices 1 and 2 give examples of an institutional one‐page summary protocol and subcutaneous insulin order set, respectively.

PULLING IT ALL TOGETHER: MAKE SURE YOUR PROTOCOL/ORDER SET IS EASY TO USE AND WIDELY UTILIZED

When standardizing hospital management of diabetes and hyperglycemia, we recommend building the full protocol first, then crystallizing the protocol into a one‐page summary that can be widely disseminated. The protocol guidance is then incorporated into the order set and nursing medical administration record (MAR). Again, we recommend the most proscriptive and protocol‐driven order set feasible within the constraints of medical staff support. The example order set in Appendix 2 illustrates this approach along with other desirable features:

• 1

  Check‐box simplicity on when to order appropriate glucose monitoring.

• 2

  Prompt for the proper hyperglycemia‐related diagnosis.

• 3

  Prompts to document diagnosis and to order HbA1c level.

• 4

  Use of encouraged insulin terminology: basal, prandial (or nutritional), and correction. Language is a powerful thing, and just getting staff to use these terms goes a long way toward the more physiologic prescribing of insulin.

• 5

  Statement/reminder of a glycemic goal.

• 6

  Prompts and contact information for appropriate consultation.

• 7

  Elimination of unapproved abbreviations (such as U for units).

• 8

  Stating both generic and brand names of insulin preparations.

• 9

  Important timing cues for administration of insulin.

• 10

  Several correction‐dose scales suitable for different insulin sensitivities. One size does NOT fit all.

• 11

  Incorporation of a simple hypoglycemia protocol into the order set.

• 12

  Insulin dosing guidelines available at the point of care (in this case, on the back of the order set).

Additional nursing‐specific cues (such as an admonition to never mix glargine insulin with other types of insulin) can also be included in the MAR whenever glargine is ordered.

Once you have protocols and order sets to guide providers, you need to assure that they are used for the majority of hyperglycemic patients. Educational programs should introduce your interventions and the rationale for them. In order to make your method the default method of care, your team should survey all preprinted or CPOE insulin order sets of your institution. A review of postoperative, transfer, and admission order sets that all services use may reveal a half‐dozen or more embedded sliding‐scale insulin order sets that should be removed, with prompts to use the standardized insulin order set being placed in their stead.

Computerized order sets present both challenges and opportunities. Wording limitations and the scrolling nature can make concepts less clear, yet there is a capability for incorporating a hierarchical structure that allows for guiding the user through a more algorithmic approach. There is also a capacity to provide assistance with dosing calculations that do not exist in the paper world. Education remains of key importance for both methods.

MONITOR THE USE AND EFFECTIVENESS OF YOUR PROTOCOLS AND ORDER SETS

Creating and implementing protocols, order sets, and other tools is not the end of the journey to improve care. It is important to monitor order set utilization, insulin use patterns, and parameters measuring glycemic control and hypoglycemia, as outlined in more detail in another article in this supplement.16 In addition to summary data every month or so, we recommend daily reports that spur action in near real time. Triggers such as uncontrolled hyperglycemia, markedly elevated HbA1c levels, and nonphysiologic insulin regimens should initiate consultation, extra diabetes education, or referral to a glucose control team. If appropriate consultation is not readily available, the glycemic control steering group should lobby the administration to bolster this capability. Qualitative feedback from the frontline caregivers, as well as this quantitative data, can assist the local glycemic control champions in designing even more effective protocols, order sets, focused educational efforts, and concurrent mitigation of suboptimal care.

CONCLUSION

Diabetes, hyperglycemia, and iatrogenic hypoglycemia are common and important conditions affecting the noncritically ill inpatient. Interventional trials to validate the recommended noncritical care unit glycemic targets are needed. Although there is a growing consensus on best practices to care for these patients, numerous barriers and the complexity of caring for inpatients hamper the reliability of best practice delivery. Institutional protocols and protocol driven subcutaneous insulin orders, when implemented with the strategies outlined here, can be the key to delivering these best practices more reliably.