Controlled release ibuprofen-poloxamer gel for epidural use - A pharmacokinetic study using microdialysis in pigs.

In order to avoid the risks of sideeffects of epidural local anesthetics and opioids, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) epidurally would be an interesting option of analgesic therapy. The fairly short duration of action of spinally administered NSAIDs, e.g., ibuprofen, may be prolonged by using controlled release poloxamer gel formulation. Using a microdialysis technique we studied the epidural and intrathecal pharmacokinetics of ibuprofen after its epidural administration as a poloxamer 407 formulation or a solution formulation. In addition, plasma ibuprofen concentrations were analyzed from central venous blood samples. Ibuprofen concentrations in the epidural space were significantly higher and longer lasting after the epidural gel injection compared with the epidural solution injection. The epidural AUC of ibuprofen was over threefold greater after epidural ibuprofen gel injection compared with the ibuprofen solution injection (p<0.001). The systemic absorption of ibuprofen from 25% poloxamer 407 gel was very low. The in situ forming poloxamer gel acted as a reservoir allowing targeted ibuprofen release at the epidural injection site and restricted ibuprofen molecules to a smaller spinal area. Ibuprofen diffusion from the epidural space to the intrathecal space was steady and prolonged. These results demonstrate that the use of epidurally injectable poloxamer gel can increase and prolong ibuprofen delivery from epidural space to the CSF enhancing thus ibuprofen entry into the central neuroaxis for spinal analgesia. Further toxicological and dose-finding studies are justified.

Effect of chronic ß-blockade on the utility of an epinephrine-containing test dose to detect intravascular injection in nonsedated patients.

BACKGROUND AND OBJECTIVES: A test dose containing epinephrine is routinely used during epidural blockade to detect accidental intravenous needle or catheter placement before the administration of local anesthetics to avert local anesthetic systemic toxicity. ß-Blocker therapy may interfere with the expected hemodynamic response from an intravascular injection. This study describes a cohort of 24 patients and their response to an epinephrine test dose (ie, if expected increased heart rates during test-dose administration are valid in this population.) METHODS: Twenty-four nonsedated, chronically ß-blocked patients were enrolled in a prospective, order-randomized, crossover, double-blind study with injections of both placebo and a 15-µg epinephrine test dose in each individual. After injection into a peripheral vein, we observed blood pressure and pulse rate for 5 minutes, injected the other remaining solution (placebo or epinephrine), and observed hemodynamic parameters in the same fashion. RESULTS: Epinephrine raised the heart rate 17.8 beats per minute (bpm) (95% confidence interval [CI], 15.5-20.1) versus placebo 2.0 bpm (95% CI, - 0.3-4.3 P < 0.001) and the systolic blood pressure 23 mm Hg (95% CI, 17.2-28.9) versus placebo 4.4 (95% CI, - 1.5-10.3); P < 0.001 in our chronically ß-blocked population. A threshold increase of 20 bpm yielded a sensitivity of 37.5% (95% CI, 18.8%-59.4%) and specificity of 100% (95% CI, 85.8%-100%). Revising a threshold to include a change of 10 bpm or increase in systolic blood pressure of 15 mm Hg or greater yielded 100% (95% CI, 85.8%-100%) sensitivity and 87.5% (95% CI, 67.6%-97.3%) specificity. CONCLUSIONS: Epinephrine test-dose administration in nonsedated, chronically ß-blocked patients cannot distinguish intravenous injection at the classic threshold increase of 20 bpm. The response in individuals is varied, and thresholds for a positive test need revising for this population of patients on therapeutic ß-blockers.

Measured density and calculated baricity of custom-compounded drugs for chronic intrathecal infusion.

BACKGROUND AND OBJECTIVES: To minimize the frequency that intrathecal pumps require refilling, drugs are custom compounded at very high concentrations. Unfortunately, the baricity of these custom solutions is unknown, which is problematic, given baricity's importance in determining the spread of intrathecally administered drugs. Consequently, we measured the density and calculated the baricity of clinically relevant concentrations of multiple drugs used for intrathecal infusion. METHODS: Morphine, clonidine, bupivacaine, and baclofen were weighed to within 0.0001 g and diluted in volumetric flasks to produce solutions of known concentrations (morphine 1, 10, 25, and 50 mg/mL; clonidine 0.05, 0.5, 1, and 3 mg/mL; bupivacaine 2.5, 5, 10, and 20 mg/mL; baclofen 1, 1.5, 2, and 4 mg/mL). The densities of the solutions were measured at 37°C using the mechanical oscillation method. A "best-fit" curve was calculated for plots of concentration versus density for each drug. RESULTS: All prepared solutions of clonidine and baclofen were hypobaric. Higher concentrations of morphine and bupivacaine were hyperbaric, whereas lower concentrations were hypobaric. The relationship between concentration and density is linear for morphine (r > 0.99) and bupivacaine (r > 0.99) and logarithmic for baclofen (r = 0.96) and clonidine (r = 0.98). CONCLUSIONS: This is the first study to examine the relationship between concentration and density for custom drug concentrations commonly used in implanted intrathecal pumps. We calculated an equation that defines the relationship between concentration and density for each drug. Using these equations, clinicians can calculate the density of any solution made from the drugs studied here.

ASRA practice advisory on local anesthetic systemic toxicity.

The American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity assimilates and summarizes current knowledge regarding the prevention, diagnosis, and treatment of this potentially fatal complication. It offers evidence-based and/or expert opinion-based recommendations for all physicians and advanced practitioners who routinely administer local anesthetics in potentially toxic doses. The advisory does not address issues related to local anesthetic-related neurotoxicity, allergy, or methemoglobinemia. Recommendations are based primarily on animal and human experimental trials, case series, and case reports. When objective evidence is lacking or incomplete, recommendations are supplemented by expert opinion from the Practice Advisory Panel plus input from other experts, medical specialty groups, and open forum. Specific recommendations are offered for the prevention, diagnosis, and treatment of local anesthetic systemic toxicity.

Cerebrospinal fluid and spinal cord distribution of hyperbaric bupivacaine and baclofen during slow intrathecal infusion in pigs.

BACKGROUND: Despite the widespread use of implanted pumps for continuous intrathecal drug delivery, there have been no studies aimed at defining the effect of baricity and posture on drug distribution in the cerebrospinal fluid and spinal cord during the very slow infusion rates typically used for chronic intrathecal drug administration. METHODS: Intrathecal microdialysis probes were placed at six points along the neuraxis in both the anterior and posterior intrathecal space of anesthetized pigs to permit cerebrospinal fluid sampling. Animals were then positioned either vertically or horizontally (prone), and a hyperbaric solution containing bupivacaine (7.5 mg/ml) and baclofen (2 mg/ml) was infused at 20 microl/h for 6 h, while the cerebrospinal fluid was collected for measurement of drug concentration. At the end of the experiment, the animals were killed, and the spinal cord was removed and divided into 1-cm sections that were further divided into anterior and posterior portions for measurement of drug concentration. RESULTS: Bupivacaine and baclofen distribution was biased caudally in the vertical group and cephalad in the horizontal group. Drug concentration decreased rapidly in the cerebrospinal fluid and spinal cord as a function of distance from the site of administration in both groups, resulting in most drugs being located in very close proximity to the site of infusion. CONCLUSION: Even at very slow infusion rates, drug distribution within the cerebral spinal fluid and spinal cord are affected by baricity/posture. These findings suggest that patient position and solution baricity may be important clinical factors determining the distribution and ultimate efficacy of chronic intrathecal drug infusions.

Does a paresthesia during spinal needle insertion indicate intrathecal needle placement?

BACKGROUND AND OBJECTIVES: Paresthesias are relatively common during spinal needle insertion, however, the clinical significance of the paresthesia is unknown. A paresthesia may result from needle-to-nerve contact with a spinal nerve in the epidural space, or, with far lateral needle placement, may result from contact with a spinal nerve within the intervertebral foramen. However, it is also possible and perhaps more likely, that paresthesias occur when the spinal needle contacts a spinal nerve root within the subarachnoid space. This study was designed to test this latter hypothesis. METHODS: Patients (n = 104) scheduled for surgery under spinal anesthesia were observed during spinal needle insertion. If a paresthesia occurred, the needle was fixed in place and the stylet removed to observe whether cerebrospinal fluid (CSF) flowed from the hub. The presence of CSF was considered proof that the needle had entered the subarachnoid space. RESULTS: Paresthesias occurred in 14/103 (13.6%) of patients; 1 patient experienced a paresthesia twice. All paresthesias were transient. Following a paresthesia, CSF was observed in the needle hub 86.7% (13/15) of the time. CONCLUSIONS: Our data suggest that the majority of transient paresthesias occur when the spinal needle enters the subarachnoid space and contacts a spinal nerve root. Therefore, when transient paresthesias occur during spinal needle placement it is appropriate to stop and assess for the presence of CSF in the needle hub, rather than withdraw and redirect the spinal needle away from the side of the paresthesia as some authors have suggested.

Respiratory and sleep effects of remifentanil in volunteers with moderate obstructive sleep apnea.

BACKGROUND: There is concern that opioid-based analgesia will worsen sleep-related respiratory insufficiency in patients with obstructive sleep apnea (OSA), resulting in serious morbidity or mortality. However, there are no studies that directly address the merit of this concern. Consequently, the authors designed this study as the first prospective, double-blind, placebo-controlled investigation of opioid pharmacology in patients with documented OSA. METHODS: Patients (n = 19) with moderate OSA documented by polysomnography (sleep study) were randomized to undergo an additional sleep study while receiving either a saline infusion or a remifentanil infusion (0.075 microg x kg x h). Sleep stages, apneas, hypopneas, and arterial hemoglobin oxygen saturation were continually recorded during saline or remifentanil infusion, and were compared with values obtained during the patients' earlier sleep study. RESULTS: Saline infusion had no effect on sleep or respiratory variables. In contrast, remifentanil increased Stage 1 sleep, markedly decreased rapid eye movement sleep, increased arousals from sleep, and decreased sleep efficiency. Remifentanil actually decreased the number of obstructive apneas, but markedly increased the number of central apneas. Arterial hemoglobin oxygen saturation was also significantly lower in OSA patients receiving remifentanil. CONCLUSIONS: The decrease in obstructive apneas likely resulted from the marked decrease in rapid eye movement sleep caused by remifentanil. Despite fewer obstructions, OSA was worse during remifentanil infusion because of a marked increase in the number of central apneas. These data suggest that caution is warranted when administering opioids to subjects with moderate OSA, but that the primary risk may be central apnea, not obstructive apnea.

ASRA Practice Advisory on Neurologic Complications in Regional Anesthesia and Pain Medicine.

Neurologic complications associated with regional anesthesia and pain medicine practice are extremely rare. The ASRA Practice Advisory on Neurologic Complications in Regional Anesthesia and Pain Medicine addresses the etiology, differential diagnosis, prevention, and treatment of these complications. This Advisory does not focus on hemorrhagic and infectious complications, because they have been addressed by other recent ASRA Practice Advisories. The current Practice Advisory offers recommendations to aid in the understanding and potential limitation of neurologic complications that may arise during the practice of regional anesthesia and pain medicine.

Regional anesthesia in anesthetized or heavily sedated patients.

The American Society of Regional Anesthesia and Pain Medicine (ASRA) Practice Advisory on Neurologic Complications in Regional Anesthesia and Pain Medicine includes an evidence- and expert opinion-based section on performing procedures on anesthetized or heavily sedated patients. This practice advisory is based on existing scientific literature, pathophysiological principles, and expert opinion. The advisory panel examined the ability of anesthetized or heavily sedated patients to recognize and report intravascular injection of local anesthetic or impending neurologic injury. The advisory panel also considered whether or not the ability to recognize and report symptoms could actually affect the occurrence of nerve injury or local anesthetic systemic toxicity. The advisory contains recommendations pertaining to both adult and pediatric patients.

Concurrent expansion of plasma volume and left ventricular end-diastolic volume in patients after rapid infusion of 5% albumin and lactated Ringer's solution.

STUDY OBJECTIVE: To examine the effects of plasma volume expansion on plasma volume, left ventricular end-diastolic volume (LVEDV), and cardiac index (CI) after rapid fluid infusion, as knowledge of the degree of concordance between plasma and cardiac preload expansion could optimize LVEDV expansion without administering excessive fluid. DESIGN: Randomized, double-blinded study. SETTING: Academic community hospital. PATIENTS: 20 patients undergoing elective coronary artery bypass surgery. INTERVENTIONS: Patients were administered either 5% albumin (5 mL/kg) or lactated Ringer's solution (25 mL/kg) over 30 minutes, just before incision. MEASUREMENTS: Serial measurements of plasma volume, LVEDV by transesophageal echocardiography, and CI were recorded. MAIN RESULTS: Albumin expanded plasma volume and LVEDV to a similar degree (11.3% and 13.2%). In contrast, lactated Ringer's solution increased plasma volume more than LVEDV (21.7% vs 14.4%; P = 0.0005). Increased LVEDV significantly but poorly correlated with increased CI (r(2) = 0.2, P < 0.0001) for both fluids. However, LVEDV expansion was brief and returned to baseline or less within 30 minutes for both fluids despite continued plasma volume expansion and increased CI. Correspondingly, rates of decline from peak expansion were significantly faster for LVEDV than plasma volume expansion for both albumin (-1.9% + 1.9%/min vs -0.1% + 0.1%/min; P = 0.0008) and lactated Ringer's (-1.1% + 0.8%/min vs -0.4% + 0.2%/min; P = 0.006). CONCLUSIONS: Intravenous fluids increased LVEDV to a lesser extent and duration than did plasma volume expansion. Monitoring of LVEDV was a poor guide for fluid administration to maximize CI.

Cerebrospinal fluid and spinal cord distribution of baclofen and bupivacaine during slow intrathecal infusion in pigs.

BACKGROUND: Increasing numbers of patients are receiving chronic intrathecal infusions of local anesthetics, baclofen, opioids, and other analgesics via implanted pumps. These infusions typically deliver drugs at rates measured in microliters per hour. However, to date, there have been no studies aimed at characterizing drug distribution within cerebrospinal fluid (CSF) and spinal cord during these slow infusion rates. Therefore, this study was designed to address this knowledge gap. METHODS: Anesthetized pigs were instrumented with eight intrathecal microdialysis probes placed at multiple points along the neuroaxis in both the anterior and posterior intrathecal space to permit continuous CSF sampling for measurement of bupivacaine and baclofen concentrations. Animals were divided into three groups and received bupivacaine and baclofen infusions at 20 or 1,000 microl/h or as a 1,000-microl bolus over 5 min every hour. Drug administration continued for 8 h, at which time the animals were killed, and the spinal cord was removed and divided into 1-cm-long sections that were further divided into anterior and posterior portions for measurement of bupivacaine and baclofen concentrations. RESULTS: In all groups, drug concentration in CSF and spinal cord decreased rapidly as a function of distance from the site of administration, with most drug found within a few centimeters. In addition, there were significant anterior-posterior differences in both CSF and spinal cord drug concentrations. CONCLUSIONS: During slow intrathecal infusion, drug distribution in CSF and spinal cord is severely limited in all groups, although significantly more so in the 20-microl/h infusion group.

Pharmacokinetics of intrathecal oligodeoxynucleotides.

BACKGROUND: Intrathecal administration of antisense oligonucleotides is a frequently used technique to alter gene expression for research purposes. However, in the future, antisense oligonucleotides will likely be administered intrathecally to humans for therapeutic purposes. To date, there have been no systematic studies of the pharmacokinetics of intrathecal oligonucleotides. This study was designed to fill that knowledge gap. METHODS: Microdialysis probes were placed intrathecally at the L4, L1, and T11 vertebral levels and epidurally at the L4 vertebral level in pigs. One of the study oligodeoxynucleotides (10-, 18-, or 30-nucleotide-long sequences of the human MDR-1 gene) was injected intrathecally at the L4 level at time 0. Microdialysis samples were obtained for measurement of oligodeoxynucleotide samples at 5-min intervals until 20 min, 10-min intervals until 60 min, and 20-min intervals until 180 min. Noncompartmental pharmacokinetic analysis was performed using PK Solutions software. RESULTS: Mean residence time and terminal elimination half-life did not differ significantly among the three oligodeoxynucleotides at any sampling site. In contrast, area under the concentration-time curve differed significantly among the oligodeoxynucleotides at all sampling sites and was inversely related to oligodeoxynucleotide length at the L4 and L1 intrathecal sites but not the T11 or epidural sampling sites. Similarly, clearance and volumes of distribution at the L4 level differed significantly among the oligodeoxynucleotides and were directly related to oligodeoxynucleotide length. CONCLUSION: The intrathecal pharmacokinetics of oligodeoxynucleotides are largely determined by oligodeoxynucleotide length. This contrasts with smaller drug molecules, such as opioids, for which intrathecal and epidural pharmacokinetics are largely determined by lipid solubility, not size. The potential clinical utility of this information is that oligodeoxynucleotide distribution within the central nervous system may be controllable to some degree by varying oligodeoxynucleotide length.

Recent insights into the pharmacokinetics of spinal opioids and the relevance to opioid selection.

PURPOSE OF REVIEW: Spinal opioid administration was introduced into clinical practice nearly 25 years ago in the hope of producing intense spinal analgesia that was devoid of the dose-limiting side effects associated with systemic opioid administration. While spinal opioid administration can clearly be an effective analgesic technique, there is a widespread misconception that any opioid administered epidurally or intrathecally will produce analgesia by a selective spinal mechanism. This is simply not true; multiple opioids that are commonly administered spinally produce analgesia by uptake into the systemic circulation with subsequent redistribution to brainstem opioid receptors. In an effort to help clinicians understand why some opioids are not suitable for selective spinal analgesia, this review describes recent insights into the fate of intrathecally and epidurally administered opioids. RECENT FINDINGS: A series of animal studies published over the last 4 or more years have provided the first measurements of opioid concentration in the epidural space, intrathecal space, spinal cord and peri-spinal tissues following intrathecal and epidural opioid administration. These studies characterize, for the first time, the factors governing the rate and extent to which different opioids redistribute from the epidural and intrathecal spaces to reach target opioid receptors in the spinal cord dorsal horn. The findings indicate that increasing lipid solubility decreases the spinal cord bioavailability of spinally administered opioids. SUMMARY: These animal data help to explain multiple clinical studies that have demonstrated that the analgesic effect of spinally administered lipid-soluble opioids is due in part, if not exclusively, to uptake into plasma and distribution to brainstem opioid receptors.

Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 1): differences among opioids.

BACKGROUND: The pharmacokinetics of epidurally administered drugs has been the subject of many studies, yet drug concentration in the epidural space has never been measured. This study was undertaken to characterize the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids on the basis of measurement of drug concentration in each of these compartments after epidural administration. METHODS: Morphine plus alfentanil, fentanyl, or sufentanil were administered epidurally in anesthetized pigs. Microdialysis was used to sample the epidural space and the cerebrospinal fluid for measurement of opioid concentration over time. Plasma samples were obtained from the central venous plasma and the epidural venous plasma. These data were used to calculate relevant pharmacokinetic parameters, including mean residence time, elimination half-lives, areas under the concentration versus time curves, clearance, and volume of distribution for each opioid in each compartment. RESULTS: Some of the more important findings were that the cerebrospinal fluid and plasma pharmacokinetics of the opioids did not parallel their epidural pharmacokinetics and that their hydrophobic character governed multiple aspects of their lumbar epidural pharmacokinetics. CONCLUSIONS: The findings indicate that the spinal pharmacokinetics of these drugs are complex and, in some ways, counterintuitive. Also, the bioavailability of opioids in the cerebrospinal fluid and epidural space is determined primarily by their hydrophobicity, with less hydrophobic drugs having greater bioavailability.

Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 2): effect of epinephrine.

BACKGROUND: The ability of epinephrine to improve the efficacy of epidurally administered drugs is assumed to result from local vasoconstriction and a consequent decrease in drug clearance. However, because drug concentration in the epidural space has never been measured, our understanding of the effect of epinephrine on epidural pharmacokinetics is incomplete. This study was designed to characterize the effect of epinephrine on the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids. METHODS: Morphine plus alfentanil, fentanyl, or sufentanil was administered epidurally with and without epinephrine (1:200,000) to pigs. Opioid concentration was subsequently measured in the epidural space, central venous plasma, and epidural venous plasma, and these data were used to calculate relevant pharmacokinetic parameters. RESULTS: The pharmacokinetic effects of epinephrine varied by opioid and by sampling site. For example, in the lumbar epidural space, epinephrine increased the mean residence time of morphine but decreased that of fentanyl and sufentanil. Epinephrine had no effect on the terminal elimination half-life of morphine in the epidural space, but it decreased that of fentanyl and sufentanil. In contrast, in the lumbar intrathecal space, epinephrine had no effect on the pharmacokinetics of alfentanil, fentanyl, or sufentanil, but it increased the area under the concentration-time curve of morphine and decreased its elimination half-life. CONCLUSIONS: The findings indicate that the effects of epinephrine on the spinal pharmacokinetics of these opioids are complex and often antithetical across compartments and opioids. In addition, the data clearly indicate that the pharmacokinetic effects of epinephrine in spinal "compartments" cannot be predicted from measurements of drug concentration in plasma, as has been assumed for decades.

A model to evaluate the pharmacokinetic and pharmacodynamic variables of extended-release products using in vivo tissue microdialysis in humans: bupivacaine-loaded microcapsules.

UNLABELLED: Biodegradable microcapsules produce an ultra-long duration of local anesthesia. We hypothesized that this duration is caused by the sustained-release of bupivacaine from the microcapsules into the surrounding tissue. Previous studies investigated the pharmacokinetics (PKs) of bupivacaine after release from microcapsules and absorption into the systemic circulation. Microdialysis sampling can determine the PKs of any drug at its site of injection. This study was performed to characterize the PKs of bupivacaine and dexamethasone released from microcapsules at a subcutaneous injection site over a 96-h period in volunteers. Bupivacaine concentrations were compared with clinical variables of local anesthetic blockade. This study demonstrates that bupivacaine is released in a sustained manner from microcapsules, that bupivacaine concentrations increase for 24-34 h after microcapsule injection, and that analgesia parallels the tissue bupivacaine concentration obtained by microdialysis. Analgesia was equally rapid in onset with aqueous and microcapsule bupivacaine (P = 0.23). Analgesia was still present at 78% of microcapsule-injected sites after 96 h, significantly longer than for aqueous bupivacaine (P < 0.001). Mild pruritus was the most common side effect, occurring with 56% of the microcapsule injections. Dexamethasone-containing bupivacaine microcapsules are well tolerated and produce a prolonged duration of skin analgesia. Systemic absorption of bupivacaine produces higher peak plasma levels after aqueous injection than after microcapsule injection, despite the injection of a threefold larger load of bupivacaine in the latter. IMPLICATIONS: Microcapsules loaded with bupivacaine and dexamethasone and administered by subcutaneous injection produce prolonged cutaneous anesthesia and analgesia. Determination of local tissue pharmacokinetic variables of bupivacaine by microdialysis confirms that the prolonged duration of anesthesia is caused by the extended release characteristics of the microcapsules.

Chronic cocaine exposure alters carbon dioxide reactivity but does not affect cerebral blood flow autoregulation in anesthetized dogs.

BACKGROUND: Cocaine use is common in trauma victims. Consequently, understanding how cocaine alters normal physiology is important to providing appropriate medical care for these patients. This study was designed to identify how chronic cocaine exposure alters cerebrovascular physiology. METHODS: Ten dogs (seven experimental, three control) were studied. Transcranial Doppler was used to measure CO2 reactivity and autoregulation of cerebral blood flow velocity (CBFvel). Measurements were made in anesthetized animals (0.6% or 1.8% isoflurane in oxygen and intravenous fentanyl) at baseline before cocaine exposure and then at weekly intervals for 4 weeks. During the 4-week study period, cocaine was administered intravenously four times per day. RESULTS: Cocaine did not alter autoregulation of CBFvel in response to changes in mean arterial pressure. However, cocaine markedly impaired CO2 reactivity in three of the seven animals. In this subset of animals, increasing Paco2 decreased CBFvel, which is consistent with vasoconstriction rather than vasodilation. CONCLUSION: Chronic cocaine exposure does not alter autoregulation of CBFvel but does alter CO2 reactivity in a subset of susceptible animals. If confirmed in humans, these findings have implications for traumatic brain injury patients who are chronic cocaine users. Specifically, the findings suggest that hyperventilation could exacerbate intracranial hypertension in a subset of these patients.