Underdosing of common antibiotics for obese patients in the ED.

BACKGROUND: Obesity is a growing problem in the United States. Obesity alters the pharmacokinetic profiles of various drugs. Although there are guidelines for dose adjustments for many of the antibiotics commonly used in the emergency department (ED), they are seldom used. METHODS: This is an institutional review board-approved retrospective study at an American Society of Metabolic and Bariatric Surgery Center of Excellence and a level I trauma center with annual ED volumes of more than 80,000 visits. Data were retrospectively collected from ED pharmacy records during a 3-month period in 2008. Any first dose of cefepime, cefazolin, or ciprofloxacin administered in our ED to a patient recorded as both more than 100 kg and with a body mass index greater than 40 kg/m(2) was compared with our hospital guidelines and found to either adhere or not adhere to those guidelines. RESULTS: There were 1910 orders found to meet the study criteria: 775 orders for cefepime, 625 orders for cefazolin, and 510 orders for ciprofloxacin. Adherence rates for first dose of cefepime, cefazolin, and ciprofloxacin administered, respectively, were 8.0%, 3.0%, and 1.2%. CONCLUSION: Emergency physicians frequently underdose cefepime, cefazolin, and ciprofloxacin in obese patients. Underdosing antimicrobials presents risk of treatment failure and may promote antimicrobial resistance. Education is necessary to improve early antibiotic administration to obese patients.

Peritoneal acidosis mediates immunoprotection in laparoscopic surgery.

BACKGROUND: We have shown previously that abdominal insufflation with CO(2) increases serum levels of IL-10 and TNFalpha and increases survival among animals with lipopolysaccharide (LPS)-induced sepsis, even after a laparotomy. We demonstrated previously that the effect of CO(2) is not from changes in systemic pH, although the peritoneum is locally acidotic during abdominal insufflation with CO(2) even when systemic pH is corrected. We hypothesized that acidification of the peritoneum via means other than CO(2) insufflation would produce alterations in the inflammatory response similar to those associated with CO(2) pneumoperitoneum. METHODS: In total, 42 rats were randomized into 7 groups (n = 6): 1) LPS only, 2) anesthesia control, 3) helium pneumoperitoneum, 4) CO(2) pneumoperitoneum, 5) buffered mild acid lavage, 6) buffered strong acid lavage, and 7) buffered strong acid lavage + helium pneumoperitoneum. Animals received anesthesia with vaporized isoflurane (except the LPS-only group) and their respective abdominal treatment (pneumoperitoneum and/or lavage) for 30 min followed immediately by stimulation with systemic LPS (1 mg/kg, IV). Blood was harvested via cardiac puncture 60 min after LPS injection, and serum levels of IL-10 and TNFalpha levels were determined by enzyme-linked immunosorbent assay. RESULTS: Mean peritoneal pH decreased (P < .05) after CO(2) pneumoperitoneum, buffered strong acid lavage, and buffered strong acid lavage + helium pneumoperitoneum, and it decreased (P = .1) after helium pneumoperitoneum alone and buffered mild acid lavage. IL-10 levels were increased (P < .01), and TNFalpha levels decreased (P < .001) among animals with acidic peritoneal cavities compared with animals with pH-normal peritoneal cavities. Decreasing peritoneal pH correlated with both increasing IL-10 levels (r = -.465, P < .01) and decreasing TNFalpha levels (r = 0.448, P < .01). Among animals with peritoneal acidosis, there were no differences in levels of IL-10 or TNFalpha regardless of insufflation status (P > .05 for both cytokines). CONCLUSIONS: Acidification of the peritoneal cavity whether by abdominal insufflation or by peritoneal acid lavage increases serum IL-10 and decreases serum TNFalpha levels in response to systemic LPS challenge. The degree of peritoneal acidification correlates with the degree of inflammatory response reduction. These results support the hypothesis that pneumoperitoneum-mediated attenuation of the inflammatory response after laparoscopic surgery occurs via a mechanism of peritoneal cell acidification.

General anesthesia delays the inflammatory response and increases survival for mice with endotoxic shock.

Anesthesia is an indispensable component of any operative procedure. In this study, we demonstrate that continuous isoflurane anesthesia for 1 h after a lethal dose (20 mg/kg of body weight) of Escherichia coli lipopolysaccharide (LPS) results in a significant increase in survival of C57BL/6J (B6) mice in comparison with survival of nonanesthetized mice. Protection by anesthesia correlates with a delay in plasma LPS circulation, resulting in a delayed inflammatory response, particularly DNA binding activity of NF-kappaB and serum levels of tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-10. Disparate classes of anesthetic agents produce the same effects on the inflammatory response, which is also independent of the inbred mouse strain used. These results suggest that anesthesia has an important impact on the outcome from endotoxemia. Moreover, the immunomodulatory effects of anesthetics should be considered when interpreting data from experimental animal models.

CO2 abdominal insufflation pretreatment increases survival after a lipopolysaccharide-contaminated laparotomy.

Carbon dioxide (CO(2))-pneumoperitoneum is known to favorably modify the systemic immune response during laparoscopic surgery. The presented studies were designed to determine whether treating animals with CO(2) abdominal insufflation before undergoing a lipopolysaccharide (LPS)-contaminated laparotomy would serve as "shock prophylaxis" and thus improve survival and attenuate cytokine production. Rats were randomized into five groups: CO(2)-pneumoperitoneum, helium-pneumoperitoneum, anesthesia control, laparotomy/LPS control, and LPS only control. Animals in the first four groups all received a laparotomy and a lethal dose of LPS. Immediately preceding their laparotomy, animals in the pneumoperitoneum groups received a 30-minute pretreatment of abdominal insufflation with either CO(2) or helium. The anesthesia control group received a 30-minute pretreatment of isoflurane. Animal mortality was then recorded during the ensuing 72 hours. Subsequently, a similar protocol was repeated for measurements of cytokines. CO(2)-pneumoperitoneum increased survival at 48 hours compared with LPS control (P <.05), and decreased interleukin-6 plasma levels at 2 hours (P <.05). Abdominal insufflation with CO(2) before the performance of a laparotomy contaminated with endotoxin increases survival and attenuates interleukin-6. The beneficial immune-modulating effects of CO(2)-pneumoperitoneum endure after abdominal insufflation. CO(2)-pneumoperitoneum pretreatment may improve outcomes among patients undergoing gastrointestinal surgery who are at high risk for abdominal fecal contamination.

Abdominal insufflation with CO2 causes peritoneal acidosis independent of systemic pH.

We have shown that the inflammation-attenuating effects of CO(2) pneumoperitoneum during laparoscopy are not due to changes in systemic pH. However, acidification of peritoneal macrophages in an in vitro CO(2) environment has been shown to reduce LPS-mediated cytokine release. We tested the hypothesis that the peritoneum is locally acidotic during abdominal insufflation with CO(2)--even when systemic pH is corrected. Rats (n = 20) were anesthetized and randomized into two groups: continued spontaneous ventilation (SV) or intubation and mechanical ventilation (MV). All animals were then subjected to abdominal insufflation with CO(2). Mean arterial pH among SV rats decreased significantly from baseline after 15 and 30 minutes of CO(2) pneumoperitoneum (7.329 --> 7.210 --> 7.191, P < 0.05), while arterial pH among MV rats remained relatively constant (7.388 --> 7.245 --> 7.316, P = NS). In contrast, peritoneal pH dropped significantly from baseline and remained low for both groups during CO(2) abdominal insufflation (SV 6.74 --> 6.41 --> 6.40, P < 0.05; MV 6.94 --> 6.45 --> 6.45, P < 0.05). In a second experiment, rats (n = 10) were randomized to receive abdominal insufflation with either CO(2) or helium. Abdominal insufflation with helium did not significantly affect peritoneal pH (7.10 --> 7.02 --> 6.95, P = NS), and the decrease in pH among CO(2)-insufflated animals was significant compared with helium-insufflated animals (P < 0.05). Peritoneal pH returned to baseline levels in all groups within 15 minutes of desufflation in both experiments. A significant local peritoneal acidosis occurs during laparoscopy which is specifically attributable to the use of CO(2) and which is independent of systemic pH. These data provide additional evidence that localized peritoneal acidosis is central to the mechanism of CO(2)-mediated attenuation of the inflammatory response following laparoscopic surgery.

Anesthesia-specific protection from endotoxic shock is not mediated through the vagus nerve.

BACKGROUND: We have shown recently that volatile anesthetics significantly decrease inflammatory cytokine production and dramatically increase survival among rodents challenged with lipopolysaccharide (LPS). Because acetylcholine's interaction with nicotine receptors on tissue macrophages during vagus nerve stimulation has been implicated in the modulation of LPS-stimulated tumor necrosis factor alpha (TNF-alpha) production, we hypothesized that the mechanism of anesthetic immunoprotection is mediated through the vagus nerve. METHODS: Male Sprague-Dawley rats underwent bilateral cervical vagotomy (n = 20) or sham operation (n = 6). Twenty-four hours postoperatively, vagotomized rats were randomized into 3 groups: LPS injection (V+LPS, n = 6), LPS injection followed by 60 minutes of isoflurane anesthesia (V+LPS+ISO, n = 7), or saline injection (V+S, n = 7). Sham animals were also given LPS (Sham+LPS). A sublethal dose of LPS (8 mg/kg) was used. Blood samples were collected via cardiac puncture 90 minutes after LPS or saline injection, and plasma was isolated for the measurement of cytokines by enzyme-linked immunosorbent assay. Statistical differences between groups were detected by 1-way analysis of variance. RESULTS: Serum TNF-alpha was reduced significantly and interleukin (IL)-6 was abrogated completely among V+LPS+ISO rats, compared with both V+LPS and Sham+LPS animals (P < or = .05 for all). In contrast, levels of the anti-inflammatory cytokine IL-10 were similar among all LPS groups. CONCLUSIONS: Isoflurane anesthesia administered simultaneously with the injection of LPS decreases serum production of TNF-alpha and IL-6 despite bilateral transection of the vagus nerve. Isoflurane-mediated attenuation of proinflammatory cytokine production occurs via a mechanism other than modulation of vagal output.

Protection from lethal endotoxic shock after testosterone depletion is linked to chromosome X.

Men are considered more susceptible to sepsis after severe injury than are women, which has been attributed to a suppressing effect of male sex steroids on the inflammatory response. Moreover, the effect of sex steroids on the inflammatory process depends on the genetic background. The present study examined the genetic contribution to survival after endotoxic shock in mice depleted of testosterone by surgical castration. Six-week-old male mice, from strains A/J, AKR/J, C57BL/6J (B6), BALBc/J, DBA/2J, and C3H/HeN, were castrated (CX) or nonoperated (NoOp). Two weeks after surgery, mice were injected intraperitoneally with Escherichia coli lipopolysaccharide (15 mg/kg) and the frequency of mortality was monitored. CX A/J mice showed a significantly higher survival rate than NoOp mice, but this protective effect was not observed in the other strains. Administration of 5-alpha-dihydrotestosterone to CX A/J mice reverted the protection by CX. The protective effect of CX was also observed in crosses of female A/J and male B6 (AXB), but not female B6 and male A/J (BXA), suggesting that protection is linked to the A/J X chromosome. This possibility was corroborated by using consomic mice containing A/J chromosome X and the remaining chromosomes from B6. These results suggest that testosterone is a negative factor in the recovery from endotoxic shock, depending on the genetic background.

Videoendoscopic endotracheal intubation in the rat: a comprehensive rodent model of laparoscopic surgery.

BACKGROUND: Peritoneal absorption of CO(2) during abdominal insufflation in laparoscopy may disrupt the acid-base equilibrium and alter the physiological response to stress. Current nonventilated rodent models of laparoscopy do not manage the CO(2) load of pneumoperitoneum, but ventilated surgical rodent models are invasive (tracheotomy) and may independently induce the inflammatory response. MATERIALS AND METHODS: A comprehensive rodent model of laparoscopy was developed. Rats were randomized to receive anesthesia alone, anesthesia plus CO(2) pneumoperitoneum, or anesthesia plus CO(2) pneumoperitoneum with videoendoscopic intubation and mechanical ventilation. Arterial blood-gas analysis was performed at baseline and after 30 min of intervention. RESULTS: Baseline pH, pCO(2), and HCO(3)(-) arterial blood gas parameters were normal for all rats. After 30 min, pCO(2) and pH changed slightly but remained normal among rats receiving anesthesia alone (pCO(2) = 46.5 +/- 1.9; pH = 7.365 +/- 0.009) whereas animals receiving anesthesia plus CO(2) pneumoperitoneum that were dependent on spontaneous respiration for ventilation developed significant hypercarbic acidosis (pCO(2) = 53.2 +/- 1.9, P < 0.05; pH = 7.299 +/- 0.011, P < 0.001). This acidosis was completely corrected with increased minute ventilation in intubated rats receiving mechanical ventilation (pCO(2) = 36.8 +/- 1.5, P < 0.001; pH = 7.398 +/- 0.011, P < 0.001). CONCLUSIONS: CO(2) pneumoperitoneum induces significant hypercarbic acidosis in nonventilated rats. Noninvasive endotracheal intubation is feasible in the rat with videoendoscopic assistance. Our noninvasive rodent model of laparoscopic surgery controls for anesthesia- and capnoperitoneum-related acid-base changes and provides an environment in which the biological response to pneumoperitoneum can be studied precisely.