Statistical analysis methods and applications

Critical Pathway: Chronic Renal Failure

Advanced Pathophysiology

Regents Online Degree Program

Critical Pathway: Chronic renal failure

Chronic renal failure is often occasioned by chronic kidney disease, immune disorder, trauma among other conditions. It does not have any specific symptoms and might include feeling unwell generally and experiencing a reduced appetite. It is diagnosed following screening of individuals who are identified to be at risk of kidney problems, like individuals with diabetes or high blood pressure and others who have blood relative with chronic kidney disease. It always seems complex when trying to come up with the right diagnosis for a patient.

M.A. is a 60-year-old man who has a stage V chronic kidney disease mainly as a result of diabetic nephropathy and a 12-year of type 2 diabetes. He has symptomatic peripheral vascular insufficiency, and 3 years ago he had undergone coronary artery bypass 3. Within the ten months that passed, Mr. M.A. had been undergoing hemodialysis 3 days in a week for 3.5 hours via left arm arteriovenous fistula. For the last 3 days he had undergone dialysis following his scheduled dialysis on the day of visit.

Three months before Mr. M.A. was admitted, he had developed a non-healing left foot ulcer and a critical lower limb ischemia. Several attempts such as vascular intervention to restore sufficient limb blood flow did not produce a positive result, and after two-month he had to undergo a transmetatarsal amputation. After the surgery the patient found that he was developing surgical wound infection, which called for a repeated debridement as well as intravenous vancomycin administration.

According to his wife Mr. M.A. was also showing some signs of continuous confusion and had been having visual hallucinations, claiming to be seeing things that never existed in real life. Such signs began some 2 weeks before he was admitted as an intermittent episode. However, the wife could identify any triggering events or temporal pattern for the episodes. Some 2 days which have passed these signs have been more persistent. Such confusion had never been seen from Mr. M.A. As much he was somehow forgetful in the previous years he was still able to take care of himself and perform simple tasks.

As a patient he was receiving medication of atorvastatin, atenolol, aspirin, gabapentin, insulin and the recent medication was vancomycin. For several years the patient had been taking 300mg of gabapentin 4 times in a day and this was effectively controlling his diabetic neuropathic pain. Administering of vancomycin was done during hemodialysis as per the blood levels. His wife made sure that he followed his mediation and dialysis regime strictly.

Physical Examination

Mr M.A. was somnolent and a febrile but arousable. Some of his critical signs included:

Height- 4 feet

Weight- 120 lbs

Pulse rate of 60 beats/min (regular).

Blood pressure of 138/88 mm Hg

Respiration rate of 14 breaths/min

Temperatures 98.1 (oral)

Oxygen saturation while breathing room air of 98%

Left metatarsal stump wound was healing

Euvolemic without pericardial rubs

Waking up periodically

Lab results included the following:

Abnormal

Normal

Hemoglobin

11.1 g/dL

13.5-17.5 g/dL

White blood cells

5.7 x 109/L

3.5 -- 109/L

Platelets

225 x 109/L

150-450 X 109/L

Potassium

5.3mEq/L

3.6-4.8mEq/L

Sodium

140 mEq/L

135-145 mEq/L

Chloride

103 mEq/L

100-108 mEq/L

Bicarbonate

20 mEq/L

22-29 mEq/L

Glucose

130 mg/dL

70-100 mg/dL

Creatinine

5.1 mg/dL

0.8-1.3 mg/dL

Blood urea nitrogen

50 mg / dL

8-24 mg/dL

When head MRI was done it revealed mild brain atrophy without mass lesion, hemorrhage, or ischemia. Revelation of electroencephalography was that nonepileptogenic, mild bitemporal slowing. Mr. M.A. was put on a full dialysis session, and 2 hours after dialysis as well as prior to dosing, the level of gabapentin were 27.0 ?g/Ml. This is due to the fact that circulating gabapentine is an eliminating efficiency at the time of dialysis. Such a level shows the tissue rebound and reveals that the predialysis level of this patient was clearly elevated.

Assessment

Causes of the Patient's altered mental status

Patients with multiple comorbid conditions are at risk of altered mental status and it can be facilitated by various acute illnesses. Sometimes, it can be the sole symptoms of systemic infection. Consequently, some of the infections like urinary tract infections and pneumonia is suppose to be included within the differential diagnosis and then ruled out. But Mr. M.A. was a febrile, did not have urinary or respiratory symptoms, and was just recently when he was treated with antibiotic. Meaning that it is not likely that infection was the cause of these problems.

Stroke is known to be associated with hallucinations and intermittent symptoms of altered mental status, particularly when there are no focal neurologic deficits, implying that it is not likely for stroke to be the cause of these problems. Parkinson-like motor disorder or Parkinson disease is associated with Lewy Body Dementia (LBD). Those patients who are experiencing LBD use to show complex hallucinations and fluctuations in alertness in people. It is known that hallucinations may bring a movement disorder and dementia.

As much as LBD may seem to be consistence with the problem of Mr. M.A., the sudden start as well as fast progression would be extremely uncharacterized in LBD, ruling out its possibility. Following Mr. M.A. having history of adherence to regular dialysis in addition to non-presence of uremia's physical signs indicate that hallucinations and decrease alertness are not a result of uremia. Again, during initiation of dialysis he was uremic but failed to demonstrate the same symptoms.

It is important to note that in recent weeks, the patient was given multiple agents such as contrast agents for computed tomography and magnetic resonance plus postoperative and preoperative antibiotics. Therefore, the potential and likely cause of the patient's problem could have been medication toxicity, particularly in the setting of renal failure. On the day of his admission, the patient underwent dialysis, and there was an immediate improvement of his hallucinations but came back again during the dialysis sessions.

Discussion

Mr. M.A. has been known to have Type 2 diabetes which is a chronic condition that always affects the manner in which the body of a person metabolizes glucose (sugar), which is the main source of fuel. It was once known as non-insulin dependent diabetes or an adult-onset. When a person is diagnosed with type 2 diabetes, it means that the body either is failing to produce enough insulin that helps in maintaining a normal glucose level, or the body is resisting the effects of insulin (a hormone that helps in regulating the movement of sugar into the body cell), (Ahern J, Kruger DF., 1989). Though the condition is untreatable, it can be managed by eating well, doing exercises as well as maintaining a healthy weight.

Following continuous changes that are taking place within the health care system as well as public policy, there has been a shift in the treatment of renal chronic related acute settings like hospitals, towards outpatient managed care organizations and facilities. The need to achieve a cost-effective treatment is on the rise. Health care professionals specializing in the care of people with renal chronic and other similar illnesses are increasingly being recognized as an important group even in the manner in which they carefully attend to these patients. In the attempt to promote health and prevent occurrence of these related disorders, the health care provider have realized the need for self-management. The patients as well as those who take care of them are trained and educated on how to manage themselves or those who they take care of without necessarily having to visit health facility everyday.

Mr. M.A. has also undergone surgery, has wound infection and undergone dialysis. What provided clues for active infection and do away with substantial electrolyte abnormalities and hypoglycemia was an electrolyte panel with measurement concentration of glucose as well as a CBC. Even though there was unlikely of seizure following the history of the patient, useful corroborative information could be based on electroencephalography. MRI of the head can be used to evaluate structural abnormalities like mass lesion and brain atrophy. Elimination of gabapentin takes place from the urine, and accumulates in blood if you are a patient with renal failure. When gabapetin is excessively accumulated it may cause different neurologic toxicities, such as coma and hallucination. Therefore the level of gabapentin should be obtained. It would be of little help to consider arterial blood gas since the patient does not manifest respiratory signs and symptoms of oxygen saturation and labored breathing when the breathing room air was 98%.

Generally, gabapentine is usually well absorbed and has not been identified to exhibit batch-to-batch variations in it bioavailability. While in the blood stream, it is not bound by protein, (Luer MS, Hamani C, Dujovny M, et al. (1999). Therefore having co-administered medications that tend to bind serum protein is not supposed to have an effect on the gabapentin circulation level. Since gabapentin is usually not metabolized hepatically, it should not be affected by variations of the hepatic cytochrome system activities and any of the effects it has is not inhibited or induced by co-administered hepatic medications, (Blum RA, Comstock TJ, Sica DA, et al., 1994). As a result, it is unlikely that pharmacokinetic or molecular drug-drug interactions accounts for accumulation of gabapentin. Mr. M.A. has been following his prescribed medication and any form of acute overdosing has not been revealed by either him or his wife.

Gabapentin is excreted renaly. Reducing the capacity of renal excretion may in turn rise up the blood level of gabapentin, eliciting neurologic symptoms, as was indicated before. The patient had previously started undergoing dialysis and the expectation to achieve a substantial residual renal clearance, (Spafford JD, Zamponi GW., 2003). But, since there was a repeated exposure of the patient to intravenous contrast agent for limb ischemia evaluation, might have eradicated his residual clearance, resulting to accumulation of gabapentin. In the past several months, Mr. M.A. has been adhering to the dialysis regime, and the delivered dialysis has been adequate. Therefore, the issue of inadequate dialysis is not likely to be the man inciting factor. When the patient was questioned further, he admitted that he had a progressive decline in urine output and almost anuric at the time of admission. Due to the loss of residual kidney function might have been the caused by the increasing gabapentin accumulation.

Risk factors

A consideration can be on ?-Blocker since they have been known to slow down the release of certain adrenergic neurotransmitters. Yet, it is generally thought that analgesic effect of gabapentin lie in the blockage of presynaptic release of neurotransmitters, as well as serontonin, norepinephrine, and acetylcholine. It is not known that ?-blockers alter gabapentin's effect. Most of the patient for many years has been taking gabapentin and atenolol concurrently without apparently realizing any toxic. Even with the actively transportation of gabapentin to brain tissues, there have not been signs of atherosclerotic vascular changes to alter the pattern of its distribution or diminishing its entry to brain tissue, (Wong MO, Eldon MA, Keane WF, et al.(1995). It has remained effective for controlling pain in patients who have severe atherosclerotic vascular disease.

The major cause of kidney failure of Mr. M.A was diabetic nephropathy. On the other hand, diabetic nephropathy has not been known to bring forth a prediction for gabapentin-induced neurotoxicity, as well as hallucinations, over the rest of kidney failure causes. Gabapentin inhibiting presynaptic Ca 2+ influx tend to be the main putative mechanism leading to the desired effects of analgesic, (Catterall WA., 2000). This mechanism may account for the fundamental neurotoxicity causes.

Severe, mild, or dementia tends to be associated with an augmented incidents of gabapentin-induced changes within the mental status, (Dogukan A, Aygen B, 2006). For patients who happens to have mild dementia, the evidence shows that gabapentin worsen dramatically the neuropsychiatric disturbances, resulting to a complex dominated psychoagitation through persistent hallucinations and ideas of reference. Since Mr. M.A. is having loss of memory, indicating some signs of dementia, a condition might have been the one that landed him to neuropsychiatric symptoms that was triggered by gabapentin toxicity.

Interventions

An individual with normal kidney clearance will have a kidney that excretes gabapentin with a half life of 5 to 7 hours. For patients who are experiencing a reduced kidney function, the increase of their half-life is up to 132 hours without dialysis. Dosing range for gabapentin patients experiencing chronic kidney dysfunction from stage III to V is always 100 to 1400 mg/d. But, dosing should be further raised for individual patients based on the level of kidney failure as well as the estimated drug half-life.Gabapentin's tissue content tend to be linearly proportional to the blood level, and there is effective removal of circulating gabapentin by hemodialysis. When the dosage is reduced while dosage frequently remains may lead to an initial sub-therapeutic drug level once the dialysis and a supratherapeutic level has been carried out before the next session of dialysis.

Consequently, it is not appropriate to cut just down the dosage such as by 100 mg 3 times daily. The dosage is supposed to be reduced by frequency of 300 mg once a dialysis has been carried out and this maintains sufficient blood level, and this is what Mr. M.A. needs. Since he was experiencing neuropathic pain, gabapentin should be used in controlling the pain. Central nervous system depression secondary to benzodiazepines will be reversed by Flumazenil. It has been known for treatment of gabapentin toxicity, (Raudino F, Mascalzi MG, Zagami A., 2004). Mr. M.A. received a measure by withholding gabapentin for a day and reinintitiated at 300 mg after 3 times per week. As a result the level of his predialysis gabapentin went down to 16.6 ?g/mL, thereby restoring his mental baseline.

Discussion

The case of Mr. M.A. is an example of complexity experienced when caring for patients with chronic kidney disease as well as multiple comorbid conditions. It shows how a devastating toxicity may take place with what one may consider to be a well-tolerated medication; which can even be at the reference dosing range. Chronic kidney failure is well-known global epidemic, and among the main causes is diabetes, (Coresh J, Selvin E, Stevens LA, et al., 2007). Those who are suffering form diabetes and nephropathy tend to display a common concurrent diabetic neuropathy. Palliating of neuropathic pain has been frequently done by gabapentin.

In United States gabapentin became released in 1993 to act as an anticonvulsant agent. Several clinical and preclinical trials across different states, has identified gabapentin to be a well tolerated and effective anticonvulsant agent and also anxiolytic as well as analgesic agent, (Rossi P, Serrao M, Pozzessere G., 2002). Recently, its use has increasingly been off-label for expanded indications, such as diabetic neuropathy, hot flashes, uremic pruritus, and phantom limb pain.

An analogue of ?-aminobutyric acid (C9H17NO2) and a water-soluble 1-(aminomethyl)-cyclohexaneacetic acid crosses readily the blood brain barrier and transported actively into the brain tissues through system L. It is shown that the concentration of gabapentin in brain tisues is the same as or higher than the one in blood, (Brawek B, Loffler M, 2008). Even though the experimental data shows that gabapentin mediates analgesia through presynaptic VSCC inhibition, those who investigate have again discovered the existence of lower well-defined, "2"-1 -- mediated regulatory pathways, that is independed to the functions of VSCC. Therefore, there has not been a fully elucidated complete effect of spectrum of gabapentin-mediated pharmacologic and toxicologic. In addition, under physiologic conditions, gabapentin usually shows minimal effects, however, it clearly alters synaptic neurotransmitter's profile at the time of neuronal hyperexcitability. Hence, end results in patients who experience functional and structural alterations of the brain.