Eric T. Wittbrodt

Low-Dose Oral Naloxone Reverses Opioid-Induced Constipation and Analgesia

The most common side effect of opioid therapy is constipation. It is often difficult to treat and is believed to be primarily a peripheral effect. Single large doses of oral naloxone have been shown to be efficacious in reversing opioid-induced constipation. However, they often cause the unwanted side effect of analgesia reversal. This study evaluated the effects on constipation and analgesia of low doses of oral naloxone given three times daily. Patients taking stable doses of opioids with complaints of constipation were recruited for this double-blind, randomized, placebo-controlled study. Patients were given 4 mg or 2 mg of oral naloxone, or placebo, three times daily. Stool frequency and symptoms related to constipation were recorded daily. Patients also recorded the daily amount of analgesics required to maintain pain control. Nine patients were recruited for the study. All the patients who received oral naloxone had some improvement in their bowel frequency. Three of the patients also experienced reversal of analgesia, including one who had complete reversal of analgesia. This study demonstrates that reversal of analgesia still occurred despite dividing the oral naloxone into very low doses relative to the total dose of opioid used. Patients using high doses of opioids appear to be the most vulnerable to the analgesic effect of oral naloxone.

Potential risk factors associated with thrombocytopenia in a surgical intensive care unit

We conducted a retrospective chart review of 193 patients admitted during a 3-month period to determine the frequency of and potential risk factors associated with thrombocytopenia, and the association of acquired thrombocytopenia with length of stay in a surgical-trauma intensive care unit (SICU) and mortality. All records were reviewed beginning 24 hours after admission. Patients were followed for the duration of SICU stay or until death. Data collected and analyzed as potential risk factors for thrombocytopenia were age, gender, admitting diagnosis, classification (trauma, surgical, medical), APACHE II score, medical history, all scheduled drugs with start and stop dates, select laboratory values, arterial or central line placement, and complications. Thrombocytopenia occurred in 25 (13%) patients. These patients were more likely (p<0.05) than those without thrombocytopenia to have the following potential risk factors: presence of a central or arterial line (76% vs 46%, p<0.025), nonsurgical diagnosis (60% vs 37%, p<0.05), diagnosis of sepsis (p<0.001), and administration of phenytoin (p<0.01), piperacillin (p<0.005), imipenem-cilastatin (p<0.001), and vancomycin (p<0.005). A longer SICU stay (mean 21 vs 4.5 days, p<0.05) and increased mortality (16% vs 4%, p<0.05) were significantly associated with thrombocytopenia. Cefazolin administration was significantly associated with nonthrombocytopenia (p<0.05). Factors not associated with thrombocytopenia were age, gender, and administration of histamine2-receptor antagonists, heparin, enoxaparin, penicillins, ceftazidime, ceftriaxone, chloramphenicol, and amphotericin B. A central or arterial line was the only factor associated with the development of thrombocytopenia in a multiple linear regression analysis (p=0.0003, multiple r=0.2580). Thrombocytopenia is not a common occurrence in the SICU, but is associated with a longer SICU stay and increased mortality.We conducted a retrospective chart review of 193 patients admitted during a 3‐month period to determine the frequency of and potential risk factors associated with thrombocytopenia, and the association of acquired thrombocytopenia with length of stay in a surgical‐trauma intensive care unit (SICU) and mortality. All records were reviewed beginning 24 hours after admission. Patients were followed for the duration of SICU stay or until death. Data collected and analyzed as potential risk factors for thrombocytopenia were age, gender, admitting diagnosis, classification (trauma, surgical, medical), APACHE II score, medical history, all scheduled drugs with start and stop dates, select laboratory values, arterial or central line placement, and complications. Thrombocytopenia occurred in 25 (13%) patients. These patients were more likely (p<0.05) than those without thrombocytopenia to have the following potential risk factors: presence of a central or arterial line (76% vs 46%, p<0.025), nonsurgical diagnosis (60% vs 37%, p<0.05), diagnosis of sepsis (p<0.001), and administration of phenytoin (p<0.01), piperacillin (p<0.005), imipenem‐cilastatin (p<0.001), and vancomycin (p<0.005). A longer SICU stay (mean 21 vs 4.5 days, p<0.05) and increased mortality (16% vs 4%, p<0.05) were significantly associated with thrombocytopenia. Cefazolin administration was significantly associated with nonthrombocytopenia (p<0.05). Factors not associated with thrombocytopenia were age, gender, and administration of histamine2‐receptor antagonists, heparin, enoxaparin, penicillins, ceftazidime, ceftriaxone, chloramphenicol, and amphotericin B. A central or arterial line was the only factor associated with the development of thrombocytopenia in a multiple linear regression analysis (p=0.0003, multiple r=0.2580). Thrombocytopenia is not a common occurrence in the SICU, but is associated with a longer SICU stay and increased mortality.

Linezolid for the Treatment of Resistant Gram-Positive Cocci

OBJECTIVE: To provide a comprehensive review of linezolid, the first of a new class of antibiotics, the oxazolidinones. Therapeutic issues regarding the emergence of multidrug-resistant bacteria and a brief history of the oxazolidinones are also discussed. DATA SOURCES: A MEDLINE search (1966–March 2001) was conducted to identify pertinent literature, including preclinical trials, clinical trials, and reviews. Unpublished clinical data, adverse effects, and dosing information were abstracted from product labeling. STUDY SELECTION: Clinical efficacy data were extracted from clinical trials, case reports, and abstracts that mentioned linezolid. Additional information concerning antibiotic resistance, the oxazolidinones, in vitro susceptibility, and the pharmacokinetic profile of linezolid also was reviewed. DATA SYNTHESIS: Linezolid exhibits activity against many gram-positive organisms, including vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, and penicillin-resistant Streptococcus pneumoniae. Linezolid inhibits bacterial protein synthesis at an early step in translation and is rapidly and completely absorbed from the gastrointestinal tract following oral administration. Efficacy has been demonstrated in a number of unpublished clinical trials in adults with pneumonia, skin and skin structure infections, and vancomycin-resistant E. faeciuminfections. The adverse effect profile is similar to that of comparator agents (β-lactams, clarithromycin, vancomycin). CONCLUSIONS: Linezolid is the first oral antimicrobial agent approved for the treatment of vancomycin-resistant enterococci. Since the oxazolidinones have a unique mechanism of action and expanded spectrum of activity against virulent and highly resistant gram-positive pathogens, linezolid is a valuable alternative to currently available treatment options. Clinical trials evaluating linezolid and other oxazolidinones for antibiotic-resistant gram-positive infections, as well as comparator studies comparing linezolid with other candidate drugs, such as quinupristin/dalfopristin and chloramphenicol, will further define the role of linezolid.

Daily interruption of continuous sedation.

Sedatives administered by continuous intravenous infusion are an essential component of the care of patients requiring mechanical ventilation. Delayed awakening from sedation has been associated with prolonged stays in the hospital and the intensive care unit (ICU). Incorporation of a daily sedation interruption policy into a medical ICU guideline has significantly reduced ICU stay and days of mechanical ventilation, and has significantly increased the likelihood of planned extubation compared with no intervention. Furthermore, opioid administration and ICU complications were significantly reduced in patients receiving daily sedation interruption. Lack of long‐term deleterious psychiatric effects, such as evidence of posttraumatic stress disorder or recall of events, has been documented with daily sedation interruption during the ICU stay. Resistance to the routine implementation of a daily sedation interruption policy arises from concerns about the need for greater resources and the risk of rebound agitation. The benefits have been documented only in a single center to date. However, the benefit:risk ratio is positive and warrants incorporation of daily sedation interruption into the routine care of patients who are critically ill and require mechanical ventilation.

Sitaxsentan for Treatment of Pulmonary Hypertension

Objective: To review the literature pertinent to the efficacy and safety of sitaxsentan, a selective endothelin (ET)-A receptor antagonist under evaluation for the treatment of pulmonary arterial hypertension (PAH). Data Sources: Articles were identified through searches of the MEDLINE (1966–November 2006) and International Pharmaceutical Abstracts (1970–November 2006) databases, using the key words endothelin antagonist, pulmonary arterial hypertension, pulmonary hypertension, sitaxsentan, and TBC11251. Searches were limited to articles published in English. Study Selection And Data Extraction: Due to the limited number of articles on sitaxsentan, all studies captured in the search results were evaluated. Data Synthesis: Four studies of sitaxsentan in humans with PAH have been published to date. An uncontrolled open-label study and a randomized placebo-controlled study (STRIDE-1; Sitaxsentan to Relieve Impaired Exercise-1) showed sitaxsentan to improve exercise tolerance in patients with PAH, as evidenced by significant increases in the distance walked in 6 minutes. Significant hepatotoxicity developed in patients receiving sitaxsentan 300 mg. The benefits of sitaxsentan with respect to exercise tolerance and hemodynamics were sustained in a one year extension of the placebo-controlled study. The results of a multicenter, randomized, placebo-controlled trial of 2 doses of sitaxsentan with an open-label bosentan arm (STRIDE-2) suggested that only the 100 mg dose provided superior benefit in exercise tolerance and improvement in functional class. Treatment-related adverse effects were similar for all groups. Conclusions: Sitaxsentan appears to be superior to placebo in improving exercise tolerance in patients with PAH but may produce therapeutic outcomes similar to those of bosentan, a comparator agent. The optimal dose of sitaxsentan appears to be 100 mg once daily. Information about the use of sitaxsentan in a greater number of patients with PAH for longer periods is necessary to further define its place in the treatment of PAH.

Maintaining Fluid and Electrolyte Balance During Exercise

The well-documented benefits and popularity of sports and fitness have led to an increased demand for products that not only replace sweat losses but also provide fuel for continued high-intensity metabolic demands. The twin risks of hypohydration and hyponatremia can lead to morbid and even fatal outcomes if rational replacement regimens are not followed, especially in endurance athletes and during hot or humid conditions. The avoidance of these complications of physical activity with oral replacement products has been documented primarily in high-impact, prolonged-duration events. Replacement fluid should contain water, sodium, and perhaps potassium to avoid overhydration-induced hyponatremia. Carbohydrates are added if muscle exertion is to continue for prolonged periods (>60 minutes in duration). The overuse of oral replacement products may yield the dilution of serum and intracellular electrolytes, hyperglycemia, and gastrointestinal distress. Baseline hydration and glucose status should be optimized before activity, and alterations in the amount and type of fluid ingested may be required for special populations such as children and individuals with chronic disease.

The Use of Oral Vasopressors in the Management of Autonomic Dysfunction and Orthostatic Hypotension

OBJECTIVE: To describe a patient with hypotension secondary to autonomic dysfunction who was successfully treated with oral vasopressors. CASE SUMMARY: A 76-year-old African-American man with a history of cerebrovascular accident with right hemiparesis 30 years prior to admission was admitted from another hospital four days after a new posterior inferior cerebellar artery occlusion and poor distal flow as manifested by weakness and hypotension. This was treated with intravenous fluids and dopamine. The dopamine was weaned and changed to phenylephrine to maintain systolic blood pressure >80 mm Hg. Fludrocortisone 0.3 mg orally once daily was initiated; pressure support garments were used for the management of orthostatic hypotension. Ephedrine 25 mg po tid was added and titrated up to 50 mg po tid. Yohimbine 5.4 mg po every eight hours was added due to continued dependence on phenylephrine to maintain adequate blood pressure. Yohimbine was titrated up to 10.8 mg po tid in an unsuccessful effort to wean the patient from phenylephrine. Fludrocortisone was decreased to 0.1 mg po tid and the phenylephrine was tapered off. The patient developed a pan-sensitive Escherichia coli urinary tract infection that was treated with oral trimethoprim/sulfamethoxazole. Over the subsequent days, an 80% left subclavian stenosis was detected; yohimbine and pressure support garments were discontinued. Subsequently, oral ephedrine was tapered off over two days, and fludrocortisone was tapered to 0.1 mg po bid. The patient was transferred in a stable normotensive condition to an inpatient rehabilitation unit. The fludrocortisone was later discontinued with no further hypotension or orthostatic symptoms. DISCUSSION: In this case, orthostatic hypotension associated with autonomic dysfunction was successfully managed with a combination of intravenous vasopressors and hydration, pressure support garments, oral mineralocorticoids, and oral vasopressors. Oral vasopressors and mineralocorticoids are effective treatment options in the management of the vasopressor-dependent patient. In our patient the adverse effects were tolerable. After continued therapy, the oral vasopressors were withdrawn without a return of orthostatic symptoms. CONCLUSIONS: Orthostatic hypotension due to autonomic dysfunction may be successfully managed with combination oral therapy after initial treatment with intravenous vasopressors as evidenced by the absence of orthostasis.

Effect of Pharmacokinetic Sampling Methods on Aminoglycoside Dosing in Critically Ill Surgery Patients

We compared pharmacokinetic parameters derived from three aminoglycoside serum concentration sampling methods and evaluated their effects on recommended aminoglycoside dosing regimens in 60 critically ill surgery patients. Patients had presumed or documented gram‐negative sepsis, and had at least 4 aminoglycoside serum concentrations measured. We used a one‐compartment model for peak and trough, 3‐point series, and 4‐point series sampling methods. Dosing regimens were calculated for each patient based on values derived from each method. We found differences in regimens for nearly 50% of patients if either 4‐ or 3‐point series sampling was used to calculate the recommended dosage rather than peak and trough sampling. However, the 3‐point method required a clinically significant change in regimen in only 12% of patients compared with 4‐point sampling. The variability of all values derived from 3‐point sampling were well accounted for by the 4‐point method (r2 > 0.80). In addition, we noted significantly greater relative precision for 3‐point sampling than peak and trough sampling for estimates of clearance, elimination rate, recommended daily dosage, and recommended dosing frequency. We recommend three optimally timed samples be drawn instead of peak and trough levels in dosing aminoglycosides in critically ill surgery patients.

Recent Trends in the Management of Ventilator-Associated Pneumonia

Ventilator-associated pneumonia (VAP) occurs frequently in mechanically ventilated patients and has a high mortality rate. To date, there is no consensus for the diagnosis of VAP. Effective reduction in VAP-inducedmortality requires amultifaceted approach to include assessment of individual risks for VAP, implementation of effective ventilator handling procedures, routine use of VAP prevention strategies, appropriate use and interpretation of invasive and noninvasive diagnostic tests, and early broad spectrum antibiotic coverage with narrowing of coverage and cessation of therapy based on clinical improvement. Pharmacokinetic and pharmacodynamic principlesmust be used in designingempiric antibiotic regimens. Because an inappropriate empiric regimen in VAP has been associated with increasedmortality, it is imperative to maintain intensive care unit–specific epidemiologic data.