Michael A. E. Ramsay

Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit

Objective:To revise the “Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult” published in Critical Care Medicine in 2002. Methods:The American College of Critical Care Medicine assembled a 20-person, multidisciplinary, multi-institutional task force with expertise in guideline development, pain, agitation and sedation, delirium management, and associated outcomes in adult critically ill patients. The task force, divided into four subcommittees, collaborated over 6 yr in person, via teleconferences, and via electronic communication. Subcommittees were responsible for developing relevant clinical questions, using the Grading of Recommendations Assessment, Development and Evaluation method (http://www.gradeworkinggroup.org) to review, evaluate, and summarize the literature, and to develop clinical statements (descriptive) and recommendations (actionable). With the help of a professional librarian and Refworks® database software, they developed a Web-based electronic database of over 19,000 references extracted from eight clinical search engines, related to pain and analgesia, agitation and sedation, delirium, and related clinical outcomes in adult ICU patients. The group also used psychometric analyses to evaluate and compare pain, agitation/sedation, and delirium assessment tools. All task force members were allowed to review the literature supporting each statement and recommendation and provided feedback to the subcommittees. Group consensus was achieved for all statements and recommendations using the nominal group technique and the modified Delphi method, with anonymous voting by all task force members using E-Survey (http://www.esurvey.com). All voting was completed in December 2010. Relevant studies published after this date and prior to publication of these guidelines were referenced in the text. The quality of evidence for each statement and recommendation was ranked as high (A), moderate (B), or low/very low (C). The strength of recommendations was ranked as strong (1) or weak (2), and either in favor of (+) or against (–) an intervention. A strong recommendation (either for or against) indicated that the intervention’s desirable effects either clearly outweighed its undesirable effects (risks, burdens, and costs) or it did not. For all strong recommendations, the phrase “We recommend …” is used throughout. A weak recommendation, either for or against an intervention, indicated that the trade-off between desirable and undesirable effects was less clear. For all weak recommendations, the phrase “We suggest …” is used throughout. In the absence of sufficient evidence, or when group consensus could not be achieved, no recommendation (0) was made. Consensus based on expert opinion was not used as a substitute for a lack of evidence. A consistent method for addressing potential conflict of interest was followed if task force members were coauthors of related research. The development of this guideline was independent of any industry funding. Conclusion:These guidelines provide a roadmap for developing integrated, evidence-based, and patient-centered protocols for preventing and treating pain, agitation, and delirium in critically ill patients.

Hepatopulmonary syndrome and portopulmonary hypertension: a report of the multicenter liver transplant database.

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PortoPH) are pulmonary vascular consequences of advanced liver disease associated with significant mortality after orthotopic liver transplantation (OLT). Data from 10 liver transplant centers were collected from 1996 to 2001 that characterized the outcome of patients with either HPS (n = 40) or PortoPH (n = 66) referred for OLT. Key variables (PaO2 for HPS, mean pulmonary artery pressure [MPAP], pulmonary vascular resistance [PVR], and cardiac output [CO] for PortoPH) were analyzed with respect to 3 definitive outcomes (those denied OLT, transplant hospitalization survivors, and transplant hospitalization nonsurvivors). OLT was denied in 8 of 40 patients (20%) with HPS and 30 of 66 patients (45%) with PortoPH. Patients with HPS who were denied OLT had significantly worse PaO2 compared with patients who underwent transplantation (47 vs. 52 mm Hg, P < .005). Transplant hospitalization survival was associated with higher pre‐OLT PaO2 (55 vs. 37 mm Hg; P < .005). MPAP was significantly higher (53 vs. 45 mm Hg; P < .015) and PVR was significantly worse (614 vs. 335 dynes · s · cm−5; P < .05) in patients with PortoPH who were denied OLT compared with patients who underwent transplantation. Transplant hospitalization mortality was 16% (5/32) in patients with HPS and 36% (13/36) in patients with PortoPH. All of the deaths in patients with PortoPH occurred within 18 days of OLT; 5 of the 13 deaths in patients with PortoPH occurred intraoperatively. We concluded that patients with HPS (based on a combination of low PaO2 and nonpulmonary factors) and patients with PortoPH (based on pulmonary hemodynamics) were frequently denied OLT because of pre‐OLT test results and comorbidities. For patients who subsequently underwent OLT, transplant hospitalization mortality remained significant for both those with HPS (16%) and PortoPH (36%). (Liver Transpl 2004;182:10.)

Dexmedetomidine as a total intravenous anesthetic agent.

DEXMEDETOMIDINE is a highly selective α 2 adrenoceptor agonist that has sedative and analgesic properties with associated reduction in opioid and anesthetic requirements. 1-11 One significant advantage of dexmedetomidine is that in the clinical dose range there is no respiratory depression. 12-14 The agonistic action on the α 2 adrenoceptors in the sympathetic ganglia modulates the release of catecholamines, resulting in a sympatholytic effect and reports of bradycardia and hypotension. 15-19 As the dose of dexmedetomidine is increased, there is a direct action on the blood vessels causing vasoconstriction and a possible increase in blood pressure. 3,18 This report describes three patients who presented for surgery with potential airway management challenges. Dexmedetomidine was administered to these patients in increasing doses until general anesthesia was attained. The effects of these high doses of dexmedetomidine on respiratory function and hemodynamics are described. The rate of dexmedetomidine infusion was administered based on actual patient body weights.

Neoadjuvant chemotherapy and liver transplantation for hepatocellular carcinoma: A pilot study in 20 patients

BACKGROUND Liver transplantation for unresectable hepatocellular carcinoma yields disappointing results. Most cases recur within 2 years, often in the transplanted liver. METHODS A combination of neoadjuvant doxorubicin and orthotopic liver transplantation was used in 20 patients with unresectable hepatocellular carcinoma confined to the liver. Seventeen patients had tumors > 5 cm in greatest diameter, and 11 cases were stage IVA by the TNM classification. Doxorubicin was administered preoperatively, intraoperatively, and postoperatively at a dose of 10 mg/m2 weekly, totaling 200 mg/m2. RESULTS Chemotherapy was well tolerated although leukopenia was observed in 70% of patients. Eight patients died, five of recurrent tumor and three of hepatitis B. Three others remain alive 8-22 months after tumor recurrence. One patient had initial tumor recurrence in the allograft. Actuarial survival is 59% and tumor-free survival is 54% at 3 years. For the 17 patients with tumors > 5 cm, overall survival is 63% and tumor-free survival is 49% at 3 years. CONCLUSION The results of this pilot study suggest that neoadjuvant doxorubicin chemotherapy favorably alters the post-transplant survival of patients with hepatocellular carcinoma.

Evaluating and monitoring analgesia and sedation in the intensive care unit

Management of analgesia and sedation in the intensive care unit requires evaluation and monitoring of key parameters in order to detect and quantify pain and agitation, and to quantify sedation. The routine use of subjective scales for pain, agitation, and sedation promotes more effective management, including patient-focused titration of medications to specific end-points. The need for frequent measurement reflects the dynamic nature of pain, agitation, and sedation, which change constantly in critically ill patients. Further, close monitoring promotes repeated evaluation of response to therapy, thus helping to avoid over-sedation and to eliminate pain and agitation. Pain assessment tools include self-report (often using a numeric pain scale) for communicative patients and pain scales that incorporate observed behaviors and physiologic measures for noncommunicative patients. Some of these tools have undergone validity testing but more work is needed. Sedation-agitation scales can be used to identify and quantify agitation, and to grade the depth of sedation. Some scales incorporate a step-wise assessment of response to increasingly noxious stimuli and a brief assessment of cognition to define levels of consciousness; these tools can often be quickly performed and easily recalled. Many of the sedation-agitation scales have been extensively tested for inter-rater reliability and validated against a variety of parameters. Objective measurement of indicators of consciousness and brain function, such as with processed electroencephalography signals, holds considerable promise, but has not achieved widespread implementation. Further clarification of the roles of these tools, particularly within the context of patient safety, is needed, as is further technology development to eliminate artifacts and investigation to demonstrate added value.

Effect of intraoperative low-dose dopamine on renal function in liver transplant recipients

Patients undergoing orthotopic liver transplantation frequently receive dopamine infusions to preserve renal function. To test the benefit of such infusions on renal function, 48 nonanuric patients presenting for OLT were entered into a randomized double-blind protocol. After exclusion of 1 patient for intraoperative nephrectomy, 22 patients received dopamine at a rate of 3 micrograms.kg-1.min-1 during surgery and the first postoperative 48 h, and a control group of 25 patients received saline. Venovenous bypass was used in 45 of 47 patients. During the hepatic vascular anastomoses, the donor liver was flushed with cold saline. In 7 patients, the flush contained mannitol (50 g) as part of a surgical protocol to investigate its role as a potential free radical scavenger. Initially, it appeared that there was an increase in urine output during the neohepatic phase in those patients receiving dopamine versus controls (4.20 +/- 3.3 vs 2.10 +/- 1.3 ml.kg-1.h-1, respectively). Upon further statistical analysis, this increase was associated with inclusion of mannitol in the liver flush of 5 patients in the dopamine group. After excluding all patients receiving flush containing mannitol, there was no significant difference in urine output during the neohepatic phase between the dopamine group and controls (2.94 +/- 0.45 and 2.10 +/- 0.28 ml.kg-1.h-1, respectively). The glomerular filtration rates at 1 month after surgery were similar and decreased approximately 40% in each group. Although a beneficial effect of dopamine in all situations cannot be ruled out the authors conclude that routine perioperative use of dopamine is of little value in nonanuric patients presenting for orthotopic liver transplantation.

Continuous Small-dose Aprotinin Controls Fibrinolysis During Orthotopic Liver Transplantation

Large doses of aprotinin (1,000,000-2,000,000 kallikrein inhibitor units [KIU] initial dose and a 500,000 KIU/h infusion) have been used during orthotopic liver transplantation (OLT) to reduce the incidence and severity of fibrinolysis. This double-blinded study was designed to investigate whether a small-dose infusion of aprotinin (200,000 KIU/h) would control fibrinolysis. A controlled study was undertaken to compare small-dose aprotinin with a placebo in patients undergoing OLT with veno-venous bypass. Forty-four patients were randomized either to the aprotinin group (n = 21), which received an intravenous infusion of 200,000 KIU/h without an initial dose, or to a control group (n = 23), which received normal saline. Coagulation variables, thrombelastograms, and postoperative blood drainage were measured. Blood levels of fibrin degradation products (FDP) were significantly higher in the control group (95% > 20 micro gram/mL) at the end of surgery compared to the aprotinin group (53% > 20 micro gram/mL, P < 0.01). The transfusion of cryoprecipitate units was more in the control group versus the aprotinin (12.6 +/- 12.8 vs 5.7 +/- 7.5; P < 0.04), as was the number of fresh frozen plasma units (6.6 +/- 3.5 vs 3.6 +/- 6.1; P < 0.05). We conclude that an infusion of a small dose of aprotinin can safely control fibrinolysis during liver transplantation with a concomitant reduction in transfusion of blood products. (Anesth Analg 1996;82:1122-5)

Continuous Small-Dose Tranexamic Acid Reduces Fibrinolysis but not Transfusion Requirements During Orthotopic liver Transplantation

Tranexamic acid (TA) is a synthetic drug that inhibits fibrinolysis.It has been administered to decrease the use of blood products during cardiac surgery and orthotopic liver transplantation when infused in larger doses. A small-dose infusion of aprotinin causes a reduction in fibrinolysis and blood product requirement during orthotopic liver transplantation without apparent risk of intravascular thrombosis. This prospective study was designed to investigate whether a small-dose infusion of TA would be equally effective in reducing fibrinolysis and blood product transfusions during orthotopic liver transplantation. A double-blind, controlled study was undertaken to compare the efficacy of a small-dose TA infusion with that of a placebo. Thirty-two consecutive patients were randomized either to the TA group (n = 16), which received an intravenous infusion of 2 mg [center dot] kg-1 [center dot] h-1, or to the control group (n = 16), which received an identical volume of normal saline. Coagulation values were measured, a field rating was made by the surgeon, and a thrombelastogram was produced at four predetermined intervals throughout the case-before TA infusion was started, after portal vein ligation, 10 min after reperfusion, and at the end of surgery. Intraoperative transfusion requirements were recorded during the procedure and for the first 24 h postoperatively. A record was kept of any intraoperative epsilon-aminocaproic acid administered for uncontrolled fibrinolysis. The thrombelastogram clot lysis index was significant for lysis in the control group during both the anhepatic and the neohepatic phases (P < 0.01 and P < 0.05, respectively) when compared with the TA group. Fibrin degradation products were significantly increased (>20 micro g/mL) in the control group at reperfusion (P < 0.03) and at the end of surgery (P < 0.01). D-dimers were also significantly increased (>1 mg/L) in the control group at the end of surgery (P < 0.04). Nine of the 16 control patients versus 3 of the 16 TA patients required epsilon-aminocaproic acid rescue for fibrinolysis. There were no other significant differences between groups. Transfusion requirements during surgery and for the first 24 h postoperatively did not differ significantly between the two groups. We conclude that the use of small-dose TA reduces fibrinolysis but not transfusion requirements during orthotopic liver transplantation. (Anesth Analg 1997;85:281-5)

Early Experience with the Nuss Minimally Invasive Correction of Pectus Excavatum in Adults

Nuss described a minimally invasive technique for correcting pectus excavatum in children. A curved stainless-steel bar is inserted behind the sternum through the chest cavity with the convex surface face down, then rotated 180 degrees to elevate the sternum and correct the deformity. The procedure gained wide acceptance in children. The purpose of this study was to determine if the procedure is effective in adults. Only patients with symptoms limiting lifestyle, chest wall indices higher than 3.25, and demonstrable cardiac compression on echocardiography were accepted. Between April 1998 and January 2001, 14 adults aged 19 to 46 underwent assessment for the Nuss minimally invasive technique for correction of pectus excavatum. Eight patients, 19 to 32 years of age, met the stated criteria for acceptance. The comorbidities were 2 asymmetrical deformities, 2 scolioses, 1 previous pectus repair, and 1 previous breast augmentation. The patients were informed of the benefits and disadvantages of both the Ravitch and the Nuss procedures. All patients except the first had talked to one or more adults who previously had the procedure. Follow-up was 7 to 37 months (mean 22.1 months). Four patients have had their bars removed and maintained correction. Success of the operation was based on relief of cardiac compression, alleviation of symptoms, and adequate pain control. Operating time was 1 to 2:05 hours (mean 1:32 hours). Complications were pneumothorax in one patient, urinary retention in 2, and left lower lobe atelectasis in 5. Complications did not prolong hospitalization. Postoperative epidural analgesia was discontinued after 2 to 4 days (mean 2.8 days). Average daily pain scores were between 1.6 and 3.7 on a scale of 0 to 10. Hospital stay was 3 to 5 days (mean 4 days). Relief of symptoms and increase in activity were obtained in all patients. Relief of cardiac compression was demonstrated in the 6 patients who have had postoperative echocardiograms. Patients returned to normal activity 2 to 4 weeks postoperatively (mean 2.3 weeks). Duration of pain medicine was 2 to 4 weeks in 6 patients and 2 and 4 months for the other 2 (mean 5.5 weeks). There were 2 late complications related to the bar, but without loss of correction. The early experience with the Nuss minimally invasive pectus excavatum repair in adults is encouraging. The procedure is effective for correcting pectus excavatum in selected patients. Early results are dependent upon adequate bar stabilization and pain control. The long-term results in adults are unknown.

Inhaled nitric oxide after left ventricular assist device implantation: A prospective, randomized, double-blind, multicenter, placebo-controlled trial

BACKGROUND Used frequently for right ventricular dysfunction (RVD), the clinical benefit of inhaled nitric oxide (iNO) is still unclear. We conducted a randomized, double-blind, controlled trial to determine the effect of iNO on post-operative outcomes in the setting of left ventricular assist device (LVAD) placement. METHODS Included were 150 patients undergoing LVAD placement with pulmonary vascular resistance ≥ 200 dyne/sec/cm(-5). Patients received iNO (40 ppm) or placebo (an equivalent concentration of nitrogen) until 48 hours after separation from cardiopulmonary bypass, extubation, or upon meeting study-defined RVD. For ethical reasons, crossover to open-label iNO was allowed during the 48-hour treatment period if RVD criteria were met. RESULTS RVD criteria were met by 7 of 73 patients (9.6%; 95% confidence interval, 2.8-16.3) in the iNO group compared with 12 of 77 (15.6%; 95% confidence interval, 7.5-23.7) who received placebo (p = 0.330). Time on mechanical ventilation decreased in the iNO group (median days, 2.0 vs 3.0; p = 0.077), and fewer patients in the iNO group required an RVAD (5.6% vs 10%; p = 0.468); however, these trends did not meet statistical boundaries of significance. Hospital stay, intensive care unit stay, and 28-day mortality rates were similar between groups, as were adverse events. Thirty-five patients crossed over to open-label iNO (iNO, n = 15; placebo, n = 20). Eighteen patients (iNO, n = 9; placebo, n = 9) crossed over before RVD criteria were met. CONCLUSIONS Use of iNO at 40 ppm in the perioperative phase of LVAD implantation did not achieve significance for the primary end point of reduction in RVD. Similarly, secondary end points of time on mechanical ventilation, hospital or intensive care unit stay, and the need for RVAD support after LVAD placement were not significantly improved.