Intrathecal baclofen toxicity in a patient with acute kidney injury

Abstract

A 9-year old male patient with a past medical history of congenital cytomegalovirus (CMV) infection and spastic quadriplegic cerebral palsy with an intrathecal baclofen pump was admitted to a tertiary care hospital with respiratory depression and unresponsiveness for approximately two days. He had a recent two-week hospital stay for respiratory failure due to pneumonia. After being prescribed antibiotics and being sent home, he had developed copious diarrhea. On readmission, he was found to be dehydrated and in acute renal failure. A physical exam revealed hypotonia throughout, in a patient who typically had spasticity with contractures. The Pediatric Rehabilitation Medicine service was consulted for possible baclofen toxicity. Some signs and symptoms of baclofen toxicity include respiratory depression, seizures, CNS depression, hypotonia, hypotension, absent deep tendon reflexes, lethargy, ataxia, and cardiac arrhythmias. His intrathecal baclofen (ITB) dose was reduced, and signs/symptoms of ITB overdose began to resolve. As renal function improved, spasticity returned, necessitating increase in ITB dosing toward the premorbid dose.

Table 1

Laboratory values and physical exam findings

	Admission	Hospital day 2	Hospital day 8
WBC (K/uL)	15.4	7.1	11.1
Na (mmol/L)	172	174	144
K (mmol/L)	7.1	2.9	3.4
Cl (mmol/L)	144	144	107
BUN (mg/dL)	158	104	11
Cr (mg/dL)	4.52	2.43	0.55
AST (IU/L)	54	20	–
ALT (IU/L)	28	13	–
Alk Phos (IU/L)	135	115	–
Physical exam	Hypotonic, sedated, no hyperreflexia	Spontaneous clonus in ankles, muscle spasms	Spontaneous clonus and muscle spasms had ceased
ITB Dosing (mcg/day)	148.2	12.3	96.1

1. Introduction

Baclofen is a $\beta$ -( $p$ -chlorophenyl) derivative of the neurotransmitter $\gamma$ -aminobutyric acid (GABA). A GABA-B agonist, it is commonly used to treat muscle spasticity in children and adolescents with spasticity of spinal and cerebral origins, e.g., spinal cord injury and cerebral palsy [1, 2]. Its exact mechanism of action is unknown, but it is shown to inhibit both monosynaptic and polysynaptic reflexes at the spinal afferent level, and may also exert its effects on the brain [1, 3, 4]. Exceptionally high concentrations of GABA-B receptors are found at various supra-spinal sites such as the superior colliculus, interpeduncular nucleus, and pontine nuclei [5]. GABA receptors are also found in areas in the prefrontal and frontal cortex, thalamus, and amygdala [5, 6]. Effects on these brain receptors may explain some of the adverse effects seen in baclofen overdose and withdrawal situations.

The exact mechanism of enteral absorption versus excretion seems to vary between individuals, but both oral and intrathecal baclofen (ITB) are primarily excreted by the kidneys [7, 8]. When administered orally, it is primarily excreted by the kidneys in a relatively unchanged state (70–80%) with the remainder metabolized in the liver (15%) via deamination or processed through the gastrointestinal tract [8]. ITB infusion via implanted pump is another way of administering the drug, and is an increasingly popular treatment for those with moderate to severe spasticity of cerebral origin. Pharmacokinetics of ITB show that plasma levels remain low, while therapeutic levels are reached intrathecally [9], reducing the risk for adverse effects and toxicity. ITB onset of action after bolus is 30 minutes to 1 hour, with peak action being around 4 hours and having a half-life of about 1.5 hours [4]. Oral baclofen onset of action is 1 to 2 hours after administration, with peak action at 3 to 4 hours, a half-life of 2 to 6.8 hours, and lasting 4 to 8 hours [2, 7, 10]. Some signs and symptoms of baclofen toxicity include respiratory depression, seizures, CNS depression, hypotonia, hypotension, absent deep tendon reflexes, lethargy, ataxia, and cardiac arrhythmias [1, 2].

2. Case description

A 9-year old boy with spastic quadriplegic cerebral palsy and an implanted ITB pump for tone management was admitted to the Pediatric Intensive Care Unit on 3/1/2018 due to an over 24-hour history of unresponsiveness and subsequent respiratory failure. He had a 2-week hospital admission within the previous month for respiratory failure due to multifocal pneumonia, and per maternal report had been doing reasonably well at home since discharge. While home, he had continued his course of prescribed amoxicillin, which was completed one day prior to admission. Per mother, for 1 week prior to completion of antibiotics, he had been experiencing large volumes of diarrhea 4 to 5 times a day. For this, he had been receiving increased hydration through his gastrostomy tube. Reportedly, he had recently become unresponsive at home to sternal rub, suctioning, and cold baths, which prompted transportation to the emergency department.

3. Acute care course

On initial hospital evaluation, blood pressure was 64/36 mmHg, respiratory rate 30 RPM, and temperature 36.4 degrees Celsius. He had agonal respirations and was intubated. Head CT was done and showed no acute process. Laboratory studies are shown in Table 1. Results were elevated from baseline and consistent with acute kidney injury (AKI), likely secondary to severe hypovolemia in the setting of prolonged diarrhea. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase were normal. Physical exam revealed hypotonia throughout, in a patient who is normally hypertonic with contractures. The Pediatric Rehabilitation Medicine Team was consulted for possible baclofen toxicity in the setting of implanted ITB pump and AKI. When the patient was examined on hospital day 1, he was found to be globally hypotonic, sedated, not following commands, and remained intubated. The decision was made to change his baclofen pump to the ‘minimal rate’ setting at 12.3 mcg/day, a large decrease from his premorbid daily dose of 148.2 mcg/day. On hospital day 2, exam had changed to include spontaneous clonus in bilateral ankles, along with sporadic muscle spasms. Laboratory tests were repeated and results are seen in Table 1. As his kidney function returned to normal, baclofen was being metabolized and excreted in a closer to normal way. This resulted in lower ITB load for spasticity control, leading to re-emergence of signs and symptoms of spasticity. The decision was made to increase the ITB pump rate to 96.1 mcg/day. On hospital day 3, after this increase had been made, spontaneous clonus stopped, as did the sporadic muscle spasms. Laboratory values on hospital day 8 were normalized (Table 1) and he was extubated. Physical exam remained stable throughout the rest of his stay. As he appeared comfortable, no further changes to the ITB dose were made. His renal failure was managed conservatively by the nephrology team with fluids and he did not require dialysis.

4. Discussion

There have been reports highlighting the need to lower the oral dose of baclofen in people with renal failure, and describing the benefits of hemodialysis [11, 12, 13]; however, this appears to be the first case of baclofen overdose as a result of renal failure in a patient getting ITB pump therapy. It is known that cerebrospinal fluid (CSF) is reabsorbed through the arachnoid villi associated with the superior sagittal sinus and that ITB is largely cleared by bulk flow of CSF [10, 14]. Through the reabsorption of CSF, baclofen is introduced to the bloodstream and is able to be excreted by the kidneys. A positive correlation has been found between the renal excretion of baclofen and creatinine clearance (CrCl), with little correlation to passive tubular reabsorption [7]. Based on our lab reference values for normal serum creatinine and using the original Schwartz estimate for CrCl, a normal CrCl range for this patient was 1.18–2.66 mL/s. On admission, this patient had a calculated CrCl of 0.24 mL/s and at hospital day 8, calculated CrCl was 1.93 mL/s. Admission day CrCl levels were far below the normal range, which was correlated with altered baclofen excretion and subsequent toxicity. Return of this patient’s renal function led to baclofen being excreted more normally with a reversal of toxicity signs and symptoms. At what point does decline in kidney function first begin to affect the excretion of baclofen? Are there concrete blood urea nitrogen or creatinine values at which impaired excretion of baclofen will begin to affect every patient universally? Is an absolute percent decline in function from individual baseline values a more dependable predictor of impending baclofen toxicity? These are some of the questions that remain to be answered.

Hopefully, as PMR physicians who are often called upon to examine, interrogate, and/or reprogram baclofen pumps, this case illustrates the importance of checking renal function in patients on both oral baclofen and ITB who are suspected of having baclofen toxicity.