Context: Patients who present with problems with definitive dialysis access (arteriovenous fistula (AVF) or arteriovenous graft (AVG)) become catheter dependent (temporary access), a condition that often carries a higher risk of infections, central venous occlusions and recurrent hospitalisations. For AVG, primary patency rates are reported to be 30% to 90% in patients undergoing thrombectomy or thrombolysis. According to the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines, surgery is preferred when the cause of the thrombosis is a stenosis at the site of the anastomosis in thrombosed AVF. The European Best Practice Guidelines (EBPG) reported that thrombosed AVF may be preferably treated with endovascular techniques, but when the cause of thrombosis is in the anastomosis, surgery provides better results with re-anastomosis. Therefore, there is a need to carry out a systematic review to determine the effectiveness and safety of the intervention for thrombosed fistulae.

This review aims to establish the efficacy and safety of interventions for failed AVF and AVG in patients receiving haemodialysis (HD).

The review included randomised controlled trials (RCTs) and quasi-RCTs in people undergoing HD treatment using AVF or AVG presenting with clinical or haemodynamic evidence of thrombosis. Patients had to have used an AVF or AVG at least once.

Comparison of the angiojet rheolytic catheter to surgical thrombectomy for the treatment of thrombosed hemodialysis grafts. Peripheral AngioJet Clinical Trial.

Abstract:
To compare the clinical effectiveness of the AngioJet F105 rheolytic catheter to that of surgical thrombectomy for the treatment of thrombosed hemodialysis grafts.

This was a multicenter, prospective, randomized trial comparing technical success, primary patency, and complication rates. A total of 153 patients were enrolled: 82 patients in the AngioJet group and 71 patients in the surgical thrombectomy group. Patient follow-up was performed 24-48 hours, 1 month, and 6 months after the procedures.

Technical success, as defined by the patient's ability to undergo hemodialysis treatment, was 73.2% for the AngioJet group and 78.8% for the surgical thrombectomy group (P = .41). The primary patency rates of the AngioJet group were 32%, 21%, and 15% at 1, 2, and 3 months, respectively. The primary patency rates for the surgical group were 41%, 32%, and 26% at 1, 2, and 3 months, respectively. This difference approached statistical significance (P = .053). The groups had similar complication rates-14.6% in the AngioJet group and 14.1% in the surgery group-although the surgery group had more major complications (11.3%). In the AngioJet group, there was a transient increase in plasma-free hemoglobin, which normalized within 24-48 hours.

The AngioJet F105 catheter provides similar clinical results when compared to surgical thrombectomy for the treatment of thrombosed hemodialysis grafts. The difference in patency rates between these two techniques approached statistical significance. In addition, results of both thrombectomy methods were inferior to those suggested by the Dialysis Outcomes Quality Initiative guidelines.

Synthetic dialysis shunts: thrombolysis with the Cragg thrombolytic brush catheter.

Abstract:
To evaluate the effectiveness of the Cragg thrombolytic brush catheter for declotting of synthetic arteriovenous dialysis shunts.

In this randomized controlled trial, 77 patients with synthetic forearm loop shunts that were thrombosed were randomly assigned to undergo pharmacomechanical thrombolysis with a pulsed spray (n = 34) or a thrombolytic brush catheter (n = 43). The following findings were evaluated: declotting time, urokinase dose, procedure time, complications, and shunt patency at the first dialysis session and at 3 months. All data were collected prospectively in an unblinded manner.

The total amount of urokinase used, including secondary interventions, was 243,657 IU with the catheter versus 476,563 IU with the pulsed spray (P = .001). At 15 minutes, clot lysis was successful in 66% of the patients with the catheter versus in 19% with the pulsed spray (P = .001). At 30 minutes, clot lysis was successful in 98% with the catheter versus 47% with the pulsed spray (P = .001). Procedure complication rates and patency at 3 months were similar for the catheter and the pulsed-spray groups.

Use of the Cragg catheter with urokinase offered faster and more complete clot lysis than did use of the pulsed spray with urokinase. The amount of urokinase used with the catheter was half that used with the pulsed spray. Shunt patency at 3 months was similar for the two treatment methods.

Endovascular versus surgical treatment for thrombosed hemodialysis grafts: A prospective, randomized study.

Abstract:
The objective of this study was to compare clinical outcome and costs for two widely used treatment strategies for hemodialysis graft thrombosis.

During a 4-year period, 80 patients with thrombosed dialysis grafts were randomly assigned to surgical thrombectomy with or without graft revision (SURG) or thrombolytic therapy with urokinase with the pulse-spray technique (ENDO), with adjunctive percutaneous transluminal angioplasty as indicated. All the procedures were performed in an endovascular operating suite with fistulography. The clinical and cost data were tabulated, and the outcome was analyzed with the life-table method.

Fifty-six women and 24 men ranged in age from 33 to 90 years (mean, 63.7 years). The patients had undergone a mean of 2.8 prior access procedures in the ipsilateral extremity. All the grafts were upper extremity expanded polytetrafluoroethylene grafts. Lesions that were presumed to be the primary cause of graft thrombosis were identified in 73 of 80 grafts, and 60 of these were at the venous anastomosis. The procedure time averaged 99 minutes for the patients in the SURG group and 113 minutes for the patients in the ENDO group (P =.12). Eleven patients in the ENDO group crossed over to surgical revision as compared with two patients in the SURG group who required adjunctive percutaneous transluminal angioplasty (P =.005). The mean cost of treatment (including room and supply costs but not professional fees) was significantly higher for the ENDO group than for the SURG group ($2945 vs $1512; P <.001). There were no procedure-related complications in either group. At a median follow-up time of 24 months, there was no difference in primary or assisted primary patency between groups, which averaged 6 and 7 months, respectively.

Although thrombolytic therapy combined with endovascular treatment can extend the life of dialysis grafts with results similar to surgical revision, there is a high rate of technical failure necessitating surgery and a substantially higher cost for thrombolysis.

Regarding "Endovascular versus surgical treatment for thrombosed hemodialysis: a prospective, randomized study".

Hydrodynamic thrombectomy system versus pulse-spray thrombolysis for thrombosed hemodialysis grafts: a multicenter prospective randomized comparison.

Abstract:
To evaluate the safety and efficacy of a hydrodynamic thrombectomy system in a prospective, multicenter randomized comparison with pulse-spray thrombolysis in hemodialysis grafts.

Nine centers enrolled 120 adult patients with recently (</=14 days) thrombosed hemodialysis grafts. Graft venography was used to confirm occlusion in 62 patients randomly assigned to thrombectomy and 58 to thrombolysis. For thrombolysis, a mixture of 5,000 U of heparin and 250,000 U of urokinase was distributed throughout the thrombus, first to the venous then to the arterial graft end. For thrombectomy, the catheter was passed in the same sequence. Technical success was removal of 80% or more of thrombus. Clinical success was technical success plus the ability to dialyze. Also assessed were total procedure time, thrombus treatment time, procedure-related blood loss, other complications, and 30- and 90-day outcomes.

Patient demographics were comparable. Technical success rates were 95% (59 of 62) for thrombectomy and 90% (52 of 58) for thrombolysis (P: =.31). Clinical success rates were 89% (55 of 62) and 81% (47 of 58), respectively (P: =.24). At 30 days, 69% (43 of 62) and 66% (38 of 58), respectively, could be dialyzed through the graft (P: =.70); at 90 days, the rates were 40% (25 of 62) and 41% (24 of 58), respectively (P: =.91). None of these differences or those for procedure-related blood loss and early and late complications were statistically significant. Thrombus treatment times of 16.8 minutes for thrombectomy and 23.4 minutes for thrombolysis were significantly different (P: <.01).

The hydrodynamic thrombectomy system is at least as efficacious and safe as pulse-spray thrombolysis but shortens thrombus treatment time.

Gianturco self-expanding stent in the treatment of stenosis in dialysis access grafts.

Abstract: This study evaluated the effectiveness of the Gianturco endovascular stent in preserving graft patency following percutaneous transvenous angioplasty (PTVA) of stenotic lesions occurring at the graft-vein anastomosis in hemodialysis patients with polytetrafluoroethylene grafts. Fifty-eight patients having 50% or greater stenosis were randomly divided into a treatment group (N = 28) and a concurrent control group (N = 30) following PTVA. In the treatment group, a stent was placed following dilatation. Graft thrombosis, the need for surgical revision, or the need for a repeat PTVA were used as end point events. The period of time from the PTVA/stent procedure to the end point event was referred to as the duration of efficacy (DE). By life table analysis, the DE for the treatment group was 100% at 30 days, 91% at 60 days, 85% at 90 days, 72% at 180 days, and 17% at 360 days. Comparison of the characteristics and results obtained in the treatment group and that of the concurrent control group revealed no significant difference in any parameter prior to treatment, in the response to PTVA, or in the DE of the procedure performed. It was concluded that the stent offered no advantage in the treatment of the graft-vein anastomosis stenotic lesion affecting PTFE dialysis access grafts.

Pulmonary embolism from pulse-spray pharmacomechanical thrombolysis of clotted hemodialysis grafts: urokinase versus heparinized saline.

Abstract:
To compare the frequency and extent of pulmonary embolism (PE) occurring during pulse-spray pharmacomechanical thrombolysis (PSPMT) of clotted hemodialysis grafts with use of either urokinase (UK) or heparinized saline (HS). Postintervention primary patency and complication rates were compared for each method of thrombolysis.

Twenty-seven patients were enrolled in this prospective, randomized, double-blind study evaluating PE with two PSPMT agents. The doses of heparin were similar between groups. The only variable was that one group of patients received UK and the other received HS. In two cases, the venous anastomosis could not be crossed. Eleven patients were treated with UK and 14 with HS. Nuclear medicine perfusion lung scans were performed before treatment and after graft declotting procedures. Lung perfusion was quantified to 10% of a pulmonary segment (0 = normal perfusion, 1 = segmental perfusion defect), with nine segments counted for each lung.

Baseline nuclear medicine perfusion lung scan results were abnormal (> or = 20% segmental perfusion defect) in 19 patients (70.4%). New PE (one or more pulmonary segments) occurred in two patients treated with UK (18.2%) and nine patients treated with HS (64.3%; P = .04). All cases of PE were asymptomatic. Quantitative global pulmonary perfusion analyses revealed that treatment with UK improved flow to 0.2 +/- 2.0 pulmonary segments, whereas treatment with HS decreased perfusion to 1.0 +/- 1.7 segments (P = .16, NS). Although postintervention primary patency rates were similar according to life-table analysis (P = .76, NS), complication rates were higher with use of HS (n = 4, 28.6%) than with use of UK (n = 2, 18.2%) (P = .6, NS).

All PE were asymptomatic during PSPMT, but treatment with UK reduced the rate of PE and tended to result in smaller defects in lung scan results. Most patients undergoing hemodialysis have abnormal baseline perfusion scan results, but PSPMT with UK improved many of them. The postintervention primary patency rates were similar between groups, but complications were more frequent after treatment with HS.

Thrombosed hemodialysis grafts: percutaneous mechanical balloon declotting versus thrombolysis.

Abstract:
To compare a technique of mechanical balloon declotting of thrombosed hemodialysis grafts with conventional pulsed-spray thrombolysis.

Forty patients had 53 episodes of graft thrombosis over a 19-month period. Twenty-nine grafts were randomly treated with thrombolysis with urokinase and 24 grafts with mechanical declotting by placement of crossed balloon catheters within the graft. Patency was determined by retrospective review of hemodialysis records.

Successful hemodialysis for 1 week after the procedure was achieved in 21 (88%) of the 24 grafts treated mechanically and 26 (90%) of 29 grafts treated with thrombolysis. Continuous pulse oximetry showed no change in oxygen saturation in either group, and no clinical signs or symptoms of pulmonary embolism were noted. Average total procedure times were 2.2 hours for mechanical declotting and 3.5 hours for thrombolysis (P < .05). Probability of patency (mechanical vs thrombolysis) was 42% vs 45% at 3 months, 36% vs 25% at 6 months, and 8% vs 4% at 12 months. One major complication of ulnar artery embolization occurred in the thrombolysis group.

Mechanical declotting of hemodialysis grafts is faster and as effective as thrombolysis.

Clinical and Economic Benefits of Stent Grafts in Dysfunctional and Thrombosed Hemodialysis Access Graft Circuits in the REVISE Randomized Trial.

Abstract:
To compare reinterventions and associated costs to maintain arteriovenous graft hemodialysis access circuits after rescue with percutaneous transluminal angioplasty (PTA), with or without concurrent Viabahn stent grafts, over 24 months.

This multicenter (n = 30 sites) study evaluated reintervention number, type, and cost in 269 patients randomized to undergo placement of stent grafts or PTA alone. Outcomes were 24-month average cumulative number of reinterventions, associated costs, and total costs for all patients and in 4 groups based on index treatment and clinical presentation (thrombosed or dysfunctional).

Over 24 months, the patients in the stent graft arm had a 27% significant reduction in the average number of reinterventions within the circuit compared to the PTA arm (3.7 stent graft vs 5.1 PTA; P = .005) and similar total costs ($27,483 vs $28,664; P = .49). In thrombosed grafts, stent grafts significantly reduced the number of reinterventions (3.7 stent graft vs 6.2 PTA; P = .022) and had significantly lower total costs compared to the PTA arm ($30,329 vs $37,206; P = .027). In dysfunctional grafts, no statistical difference was observed in the number of reinterventions or total costs (3.7 stent graft vs 4.4 PTA; P = .12, and $25,421 stent graft and $22,610 PTA; P = .14).

Over 24 months, the use of stent grafts significantly reduced the number of reinterventions for all patients, driven by patients presenting with thrombosed grafts. Compared to PTA, stent grafts reduced overall treatment costs for patients presenting with thrombosed grafts and had similar costs for stenotic grafts.

Balloon angioplasty versus Viabahn stent graft for treatment of failing or thrombosed prosthetic hemodialysis grafts.

Abstract:
To compare the results of stent graft placement to balloon angioplasty for the treatment of stenosis at the venous anastomosis of failing and thrombosed prosthetic hemodialysis grafts.

This prospective, multicenter trial included 293 patients randomized (1:1) to the stent graft (n = 145) or balloon angioplasty (n = 148) group for treatment of stenosis at the venous anastomosis of dysfunctional (n = 164) or thrombosed (n = 129) hemodialysis grafts. The primary study end point was target lesion primary patency at 6 months; participants were followed for up to 24 months. Primary patency of the access circuit was a secondary end point. Statistical analysis of effectiveness was performed using both the intent-to-treat population and the effectiveness-per-protocol (EPP) populations for primary patency end points. Statistical analysis of additional effectiveness end points was performed using the EPP population.

The 6-month target lesion primary patency was statistically greater in the stent graft group than the balloon angioplasty group (intent-to-treat, 51.6% vs 34.2% [P = .006]; EPP, 52.9% vs 35.5% [P = .008]). Compared with the angioplasty group, the stent graft group increased the median time from the index procedure to the next intervention on the target lesion by 95 days (203 vs 108 days). Patients with dysfunctional (stenotic) grafts had higher target lesion primary patency compared with patients with thrombosed grafts regardless of treatment (EPP, stent graft, 64.6% vs 36.1% and balloon angioplasty, 45.8% vs 23.5%). When compared with angioplasty, using a stent graft for treatment of a venous anastomotic stenosis of a thrombosed graft increased the 6-month target lesion primary patency by 53.6% (EPP, 36.1% vs 23.5%).

When compared with balloon angioplasty, a stent graft provided superior target lesion primary patency at 6 months for treatment of venous anastomotic stenoses of dysfunctional and thrombosed prosthetic hemodialysis grafts.


Context: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) causes progressive or relapsing weakness and numbness of the limbs, which lasts for at least two months. Uncontrolled studies have suggested that intravenous immunoglobulin (IVIg) could help to reduce symptoms. This is an update of a review first published in 2002 and last updated in 2013.

To assess the efficacy and safety of intravenous immunoglobulin in people with chronic inflammatory demyelinating polyradiculoneuropathy.

We selected randomised controlled trials (RCTs) and quasi-RCTs that tested any dose of IVIg versus placebo, plasma exchange, or corticosteroids in people with definite or probable CIDP.

Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy.

Abstract:
To determine the efficacy of IV immunoglobulin (IVIg) given patients with untreated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

A randomized, double-blind, multicenter, investigator-initiated study compared IVIg (Aventis Behring LLC, King of Prussia, PA) with placebo (5% albumin). On days 1, 2, and 21, IVIg (1 g/kg) or placebo was given. The primary outcome measure was the change in muscle strength from baseline to day 42, using the average muscle score (AMS). Secondary outcome measures included change from baseline AMS at days 10 and 21, the Hughes' functional disability scale, forced vital capacity (FVC), and nerve conduction studies (NCS) of four motor nerves (median, ulnar, peroneal, and tibial).

The patients (n = 33) were randomized. Of these, 30 (14 women, 16 men, aged 54 +/- 20 years, range 13 to 82) received IVIg and 23 were given placebo (12 women, 11 men, aged 50 +/- 18 years, range 23 to 73). Baseline AMS values of the groups were similar (IVIg 7.06 +/- 1.31 versus placebo 7.28 +/- 1.18, p = 0.53). There were two dropouts in placebo group and one in the IVIg group. Mean AMS improved at day 42 comparing IVIg with placebo (0.63 versus -0.1, p = 0.006). Improved strength was seen by day 10. The placebo group lost strength over this same interval. In the IVIg, 11 subjects improved by the functional disability scale; none worsened. This differed (p = 0.019) from those in the placebo-treated group (two improved, two got worse, remainder unchanged). Forced vital capacity did not improve with IVIg treatment. IVIg improved ulnar motor distal latency (p = 0.005), tibial distal compound muscle amplitude (p = 0.003), and peroneal nerve conduction velocity (p = 0.03).

IVIg improves strength in patients with untreated CIDP by day 10 with continued benefit through day 42; more than one third improve by at least a functional grade on a disability scale. This study provides data supporting IVIg as the initial treatment for CIDP.

Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy.

Abstract: This multicenter, randomized, double-blind, crossover trial compared a six week course of oral prednisolone tapering from 60 mg to 10 mg daily with intravenous immunoglobulin (IVIg) 2.0 g/kg given over one to two days for treating chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Twenty-four of the thirty-two randomized patients completed both treatment periods. Both treatments produced significant improvements in the primary outcome measure, change in an 11-point disability scale two weeks after randomization. There was slightly, but not significantly, more improvement after IVIg than with prednisolone, the mean difference between the groups in change in disability grade being 0.16 (95% CI = -0.35 to 0.66). There were also slightly, but not significantly, greater improvements favoring IVIg in the secondary outcome measures: time to walk 10 meters after two weeks and improvement in disability grade after six weeks. Results may have been biased against IVIg by the eight patients who did not complete the second arm of the trial. A serious adverse event (psychosis) attributable to treatment occurred in one patient while on prednisolone and in none with IVIg.

Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial.

Abstract:
Short-term studies suggest that intravenous immunoglobulin might reduce disability caused by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but long-term effects have not been shown. We aimed to establish whether 10% caprylate-chromatography purified immune globulin intravenous (IGIV-C) has short-term and long-term benefit in patients with CIDP.

117 patients with CIDP who met specific neurophysiological inflammatory neuropathy cause and treatment (INCAT) criteria participated in a randomised, double-blind, placebo-controlled, response-conditional crossover trial. IGIV-C (Gamunex) or placebo was given every 3 weeks for up to 24 weeks in an initial treatment period, and patients who did not show an improvement in INCAT disability score of 1 point or more received the alternate treatment in a crossover period. The primary outcome was the percentage of patients who had maintained an improvement from baseline in adjusted INCAT disability score of 1 point or more through to week 24. Patients who showed an improvement and completed 24 weeks of treatment were eligible to be randomly re-assigned in a blinded 24-week extension phase. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00220740.

During the first period, 32 of 59 (54%) patients treated with IGIV-C and 12 of 58 (21%) patients who received placebo had an improvement in adjusted INCAT disability score that was maintained through to week 24 (treatment difference 33.5%, 95% CI 15.4-51.7; p=0.0002). Improvements from baseline to endpoint were also recorded for grip strength in the dominant hand (treatment difference 10.9 kPa, 4.6-17.2; p=0.0008) and the non-dominant hand (8.6 kPa, 2.6-14.6; p=0.005). Results were similar during the crossover period. During the extension phase, participants who continued to receive IGIV-C had a longer time to relapse than did patients treated with placebo (p=0.011). The incidence of serious adverse events per infusion was 0.8% (9/1096) with IGIV-C versus 1.9% (11/575) with placebo. The most common adverse events with IGIV-C were headache, pyrexia, and hypertension.

This study, the largest reported trial of any CIDP treatment, shows the short-term and long-term efficacy and safety of IGIV-C and supports use of IGIV-C as a therapy for CIDP.

Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial.

Abstract:
Intravenous immunoglobulin (IVIg) and corticosteroids are effective as initial treatment in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but little is known about the comparative risk-benefit profile of their long-term use in this disease. We compared the efficacy and tolerability of 6-month therapy with IVIg versus that with intravenous methylprednisolone.

We did a multicentre, randomised, double-blind, placebo controlled, parallel-group study in patients with CIDP. We assessed efficacy and tolerability of IVIg (0·5 g/kg per day for 4 consecutive days) and intravenous methylprednisolone (0·5 g in 250 mL sodium chloride solution per day for 4 consecutive days) given every month for 6 months. Eligible patients had to be in an active or stationary phase of the disease. Allocation to treatment was centrally managed with a computer-generated, 1:1 randomisation scheme with a sequential block size of four. All patients and assessors were unaware of the treatment assignment. After therapy discontinuation, patients were followed up for 6 months to assess relapses. The primary outcome was the difference in the number of patients discontinuing either therapy owing to inefficacy or intolerance. Secondary endpoints included the difference in the proportion of patients experiencing adverse events or worsening after therapy discontinuation. This study is registered with EUDRACT, number 2005-001136-76.

45 patients (24 IVIg, 21 intravenous methylprednisolone) completed the study; one was excluded for inappropriate inclusion. More patients stopped methylprednisolone (11 [52%] of 21) than IVIg (three [13%] of 24; relative risk 0·54, 95% CI 0·34-0·87; p=0·0085). When adjusted for sex, age, disease duration, comorbidity, modified Rankin scale and ONLS scores at enrolment, and previous treatment with IVIg and steroids, the difference between the two groups remained significant (odds ratio 7·7, 95% CI 1·7-33·9; p=0·0070). Reasons for discontinuation were lack of efficacy (eight in the methylprednisolone group vs three in the IVIg group), adverse events (one in the methylprednisolone group), or voluntary withdrawal (two in the methylprednisolone group). Two patients on IVIg died during follow-up after the 6-month assessment. The proportion of patients with adverse events did not differ between the intravenous methylprednisolone group (14 [67%] of 21) and the IVIg group (11 [46%] of 24; p=0·1606). After therapy discontinuation, more patients on IVIg worsened and required further therapy (eight [38%] of 21) than did those on methylprednisolone (none of ten; p=0·0317).

Treatment of CIDP with IVIg for 6 months was less frequently discontinued because of inefficacy, adverse events, or intolerance than was treatment with intravenous methylprednisolone. The longer-term effects of these treatments on the course of CIDP need to be addressed in future studies.

Kedrion.

A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy.

Abstract: Chronic inflammatory demyelinating polyradiculoneuropathy is a paralytic syndrome, causing considerable disability and even death. In controlled clinical trials, plasma exchange prevented or ameliorated neurological deficits, but the efficacy of immune globulin infusion remains unproved. Also unknown is whether immune globulin infusion is as effective, or more effective, than plasma exchange and what dosages and frequencies are best. In this observer-blinded study, using some objective end points not subject to bias (e.g., summated compound muscle action potential), 20 patients with progressive or static polyneuropathy were randomly assigned to receive either of the two treatments for 6 weeks, followed by a washout period, and then were assigned to receive the other treatment. Plasma exchange (twice a week for 3 weeks then once a week for 3 weeks) and immune globulin infusion (0.4 gm/kg once a week for 3 weeks, then 0.2 gm/kg once a week for the next 3 weeks) were used. End points assessed before and after treatment schedules were neurological disability score; muscle weakness of the neurological disability score; summated compound muscle action potentials of ulnar, median, and peroneal nerves; summated sensory nerve action potentials of ulnar and sural nerves; and vibratory detection threshold of the great toe using CASE IV. Observers were masked as to treatment used. Of 20 patients, 13 received both treatments whereas 4 did not worsen sufficiently to receive the second treatment--1 patient left the study during and 2 after the first treatment to receive unscheduled treatment elsewhere.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: a double blind, placebo controlled study.

Abstract: Patients with a clinical diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) were randomised in a double-blind, placebo-controlled multicentre trial to investigate whether high-dose intravenous immunoglobulin treatment (IVIg) for 5 consecutive days has a beneficial effect. Fifteen patients were randomised to IVIg and 13 to placebo. In the IVIg treatment group 4 patients improved and 3 patients in the placebo group. The degree of improvement of the patients in the IVIg treatment group was no different from the patients in the placebo group. Electrophysiological studies did not show significant differences between the groups. Since a previously performed cross-over trial showed that a selected group of CIDP patients responded better to IVIg than to placebo, it is concluded that we need better criteria to select CIDP patients for treatment with IVIg.

Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study.

Abstract: Thirty patients with definite or probable chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) of chronic progressive (16 patients) or relapsing (14 patients) course were randomly assigned to receive intravenous immunoglobulin (IvIg) 0.4 g per kg body weight or a placebo treatment on 5 consecutive days in a double-blind, cross-over trial. Neurological function was monitored by serial quantitative assessments [neurological disability score (NDS); clinical grade (CG) and grip strength (GS) measurements] and by electrophysiological studies before and after each treatment period. Twenty-five patients completed both treatment periods. A comparison of the observed changes in clinical outcome measures revealed statistically significant differences in favour of IvIg, with (mean +/- SD) improvements in NDS by 24.4 +/- 5.4 points (P < 0.002) in CG by 1 +/- 0.3 points (P < 0.001) in GS by +6.3 +/- 1.7 kg (P < 0.005), whereas scores were unchanged or worse with placebo. A secondary two-groups analysis of the first trial period included all 30 patients; 16 patients had been randomly assigned to IvIg and 14 to placebo treatments. Again significant differences in favour of IvIg were observed in all the clinical end-points: improvement in NDS was 35.6 +/- 25 points (P < 0.0001), in CG it was 1.3 +/- 1.9 points (P < 0.002) and in GS +9.8 +/- 7.7 kg (P < 0.001), whereas all scores worsened with placebo. Of the 30 patients, 19 (63%) improved with IvIg treatments; nine out of 16 patients (56%) with chronic progressive CIDP, and 10 out of 14 patients (71%) with relapsing CIDP (differences were not statistically significant). A placebo response was seen in five patients. Comparison of paired electrophysiological measurements before and 4 weeks after IvIg treatments revealed statistically significant improvements in the summed motor conduction velocities (sigma MCV; P < -0.0001) and in the summed compound muscle action potentials (CMAP) evoked with proximal stimulation (sigma proximal CMAP, P < 0.03) of median, ulnar, peroneal and tibial nerves. Eight of nine IvIg responders with chronic progressive CIDP improved gradually to normal function with a single 5 day course of IvIg; in five of these, small doses of prednisone were prescribed during follow-up. In 10 IvIg responders with relapsing CIDP, improvements lasted a median 6 weeks (range 3-22 weeks) and was reproducible with open label treatments. All 10 patients have been maintained and stabilized with IvIg pulse therapy of 1 g per kg body weight or less, given as a single infusion prior to the expected relapse. A beneficial response to IvIg was found to be most likely in patients with acute relapse or with disease of one year or less. Patients with predominantly sensory signs did not improve.

[The clinical usefulness of high-dose intravenous immunoglobulin therapy for chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy].

Abstract: To explore the optimum dose of intravenous immunoglobulin (i.v.Ig) for treating patients with chronic inflammatory demyelinating polyrneuropathy and multifocal motor neuropathy, we compared the usefulness of i.v.Ig among 3 treatment doses. Fifty-nine patients were randomly divided into three treatment dosage groups: 20 patients for Group I using 50 mg/kg/day x 5 days, 19 patients Group II using 200 mg/kg/day x 5 days, and 20 patients Group III using 400 mg/kg/day x 5 days. We assessed clinically and electrophysiologically the effectiveness of the treatment at 5 weeks after the initial infusion. For patients in Group I and II who had not improved (or worsened) with the first treatment, we gave a one-step larger dose in the second treatment (i.e. 200 mg/kg/day x 5 days for those who had been given 50 mg/kg/day x 5 days, 400 mg/kg/day x 5 days for those who had been given 200 mg/kg/day x 5 days) after more than 9 weeks. We found that 15% of the patients in Group I, 21% in Group II and 60% in Group III improved dose-dependently with the first intravenous immunoglobulin treatment. Seven (47%) of 16 patients in Group I and 4 (40%) of 11 patients in Group II improved after the second treatment with larger doses. Adverse reactions including chill sensation, fever, skin eruption and increase in blood GOT and GPT levels were transient and mild. One patient in Group III developed left hemiparesis showing the small infarction in the right thalamus during the course of the treatment, but the symptom was mild. In conclusion, the high-dose intravenous immunoglobulin therapy (400 mg/kg/day x 5 days) is useful for treating patients with CIDP and MMN, although care must be taken of the risk of causing cerebral infarctions.

A pilot study to compare the use of the Excorim staphylococcal protein immunoadsorption system and IVIG in chronic inflammatory demyelinating polyneuropathy.

Abstract: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune mediated neuropathy responding to immunomodulation with IVIG or plasma exchange (PE). We tested the efficacy and safety of selective immunoglobulin removal by Excorim immunoadsorption (IA) in a pilot trial in CIDP patients randomized to monthly IA or IVIG treatments for 6 months. Response rates at 2 and 6 months were greater with IA due to longer disease duration and greater disability at baseline in the patients receiving IVIG. IA appears to be a safe and efficacious therapy for patients with CIDP, but an appropriately powered clinical trial with stratification for disease duration is required.

Efficacy and safety of Privigen(®) in patients with chronic inflammatory demyelinating polyneuropathy: results of a prospective, single-arm, open-label Phase III study (the PRIMA study).

Abstract: This prospective, multicenter, single-arm, open-label Phase III study aimed to evaluate the efficacy and safety of Privigen(®) (10% liquid human intravenous immunoglobulin [IVIG], stabilized with L-proline) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Patients received one induction dose of Privigen (2 g/kg body weight [bw]) and up to seven maintenance doses (1 g/kg bw) at 3-week intervals. The primary efficacy endpoint was the responder rate at completion, defined as improvement of ≥1 point on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. The preset success criterion was the responder rate being ≥35%. Of the 31 screened patients, 28 patients were enrolled including 13 (46.4%) IVIG-pretreated patients. The overall responder rate at completion was 60.7% (95% confidence interval [CI]: 42.41%-76.43%). IVIG-pretreated patients demonstrated a higher responder rate than IVIG-naïve patients (76.9% vs. 46.7%). The median (25%-75% quantile) INCAT score improved from 3.5 (3.0-4.5) points at baseline to 2.5 (1.0-3.0) points at completion, as did the mean (standard deviation [SD]) maximum grip strength (66.7 [37.24] kPa vs. 80.9 [31.06] kPa) and the median Medical Research Council sum score (67.0 [61.5-72.0] points vs. 75.5 [71.5-79.5] points). Of 108 adverse events (AEs; 0.417 AEs per infusion), 95 AEs (88.0%) were mild or moderate in intensity and resolved by the end of study. Two serious AEs of hemolysis were reported that resolved after discontinuation of treatment. Thus, Privigen provided efficacious and well-tolerated induction and maintenance treatment in patients with CIDP.


Context: Variation in blood pressure levels display circadian rhythms. Complete 24-hour blood pressure control is the primary goal of antihypertensive treatment and reducing adverse cardiovascular outcomes is the ultimate aim. This is an update of the review first published in 2011.

To evaluate the effectiveness of administration-time-related effects of once-daily evening versus conventional morning dosing antihypertensive drug therapy regimens on all-cause mortality, cardiovascular mortality and morbidity, total adverse events, withdrawals from treatment due to adverse effects, and reduction of systolic and diastolic blood pressure in people with primary hypertension.

We included randomised controlled trials (RCTs) comparing the administration-time-related effects of evening with morning dosing monotherapy regimens in people with primary hypertension. We excluded people with known secondary hypertension, shift workers or people with white coat hypertension.

Morning versus evening amlodipine treatment: effect on circadian blood pressure profile in essential hypertensive patients.

Abstract: OBJECTIVE: To determine the antihypertensive efficacy and the potential impact on circadian blood pressure pattern of morning versus evening administration of amlodipine to essential hypertensive patients. METHODS: Twelve mild-to-moderate essential hypertensives were investigated in this open, randomized cross-over study. Blood pressure and heart rate were measured by use of ambulatory blood pressure monitoring after a wash-out period of 1 week and after treatment schedules with 5 mg amlodipine once a day either at 0800 h or at 2000 h for 3 weeks. Effects were evaluated by linear and rhythm analysis using the ABPM-FIT program. RESULTS: Both morning and evening administrations of amlodipine significantly (P < 0.01) reduced the elevated systolic and diastolic blood pressures during daytime. However, due to baseline values being lower during night-time, a significant (P < 0.05) reduction was observed only in systolic, not in diastolic, blood pressure. Maximal blood pressure values were significantly (P </= 0.01) decreased by both treatment regimens, whereas nightly minimum values remained unchanged. The early morning rise in blood pressure was decreaseed after morning and slightly more pronounced aftger evening dosing of amlodipine. Though both amlodipine treatments more effectively reduced daytime blood pressure levels, the circadian profile was not greatly affected. Amlodipine treatment had no effect on heart rate. CONCLUSION: The results demonstrate that, independently from the dosing time, the long-acting calcium antagonist amlodipine sufficiently reduced blood pressure in essential hypertensive patients without increasing the nightly drop. The drug-induced decrase in the early morning rise in blood pressure may be advantageous in reducing the early morning cardiovascular risk.

Differential effects of morning and evening dosing of nisoldipine ER on circadian blood pressure and heart rate.

Abstract: The time of administration of once-daily antihypertensive agents may have a significant impact on blood pressure control during awake and sleep periods. Using 24-h ambulatory monitoring, we compared the effects of morning and evening dosing of the long-acting dihydropyridine calcium channel blocker, nisoldipine extended-release (ER), on circadian blood pressure (BP) and heart rate in patients with mild-to-moderate hypertension. After completing a 3-week placebo run-in period, 85 patients were randomized to morning versus evening nisoldipine ER treatment at a fixed 20-mg dose. Patients were treated for 4 weeks, followed by crossover to the alternate dosing regimen for 4 additional weeks. Twenty-four-hour ambulatory monitoring was performed at baseline and at 4 and 8 weeks after randomization. Awake and sleep times were determined by electronic activity recorders (Actigraphy). Similar least-squares (+/-SE) mean changes from baseline in 24-h BP (systolic BP/diastolic BP: -11.9/-7.4 +/- 0.6/0.5 v -11.6/-6.5 +/- 0.6/0.5 mm Hg) and heart rate (1.0/1.7 +/- 0.4/0.4 beats/min) occurred with morning and evening administration, respectively. A significantly greater effect on awake diastolic BP (systolic BP/diastolic BP: -12.6/-8.1 +/- 0.7/0.4 v -11.3/-6.4 +/- 0.7/0.4 mm Hg; P = .16/.01) was observed with morning dosing compared with evening dosing. In addition, small increases in sleep and early morning heart rate were seen with evening compared with morning administration of nisoldipine (sleep, 3.1 +/- 0.4 v 0.4 +/- 0.4 beats/min; P < .001; early morning, 3.5 +/- 0.7 v 0.5 +/- 0.7 beats/min; P = .002). These differential effects on awake BP and sleep heart rate were also observed in patients who had normal (dippers) and elevated (nondippers) BP values during sleep. Appropriate evaluation of the efficacy and safety of long-acting antihypertensive agents is essential when evening administration is being considered. In the present study, the timing of nisoldipine ER administration had no effect on mean changes in BP and heart rate over a 24-h period. However, nisoldipine ER had some differential effects during sleep and awake periods with morning relative to evening dosing.

Efficacy and safety of a once daily graded-release diltiazem formulation in essential hypertension.

Abstract:
The efficacy and safety of a chronotherapeutic, graded-release diltiazem HCl extended-release (GRD) 120-, 240-, 360- and 540-mg dose administered once-daily at bedtime (10 PM) were evaluated in a 7-week randomized, double-blind comparison to placebo and to GRD 360 mg administered once-daily at 8 AM in 478 patients with moderate-to-severe essential hypertension.

We assessed the change from baseline to end point in trough diastolic blood pressure (DBP) at 6 PM to 10 PM and in mean DBP from 6 AM to 12 noon between GRD 360 mg PM and GRD 360 mg AM, measured by ambulatory BP monitoring (ABPM).

Bedtime doses of GRD showed dose-related mean reductions in trough DBP that were significant for GRD doses of 240 mg and higher. Bedtime GRD 360 mg was associated with a significantly greater reduction in mean DBP between 6 AM and 12 noon compared to morning GRD 360 mg with a least squares mean for treatment difference of -3.3 mm Hg (P =.0004). Similar dose-related and significant reductions in systolic BP (SBP) and heart rate (HR) were obtained. Incidence of adverse events (AEs) for all GRD groups (44.5%) was less than that obtained for the placebo group (49.3%). The 540-mg group showed an incidence of AEs (43.5%) similar to that observed for the 240-mg group (42.6%).

The GRD dose-dependently significantly reduces BP and HR over the 24-h interval after once-daily bedtime dosing. Further greater reductions were obtained between 6 AM and 12 noon, when circadian BP is highest, compared to morning administration of the same dose. The 540-mg GRD was safe, well tolerated, and offers further therapeutic option for patients with severe hypertension who required additional BP control.

[Preventive chronotherapy with capoten in hypertensive outpatients].

Abstract: The study was made of effectiveness of preventive chronotherapy (PC) and comparative benefit of preventive CT vs conventional therapy (CT) in 47 patients with essential hypertension (EH) stage I, II and III. The group on PC consisted of 25 patients. Capoten was given in a single dose from 12.5 to 50 mg 24 hours before the acrophase of blood pressure (BP). BP was measured 4-5 times a day for 4 days according to N. S. Korotkov's technique before the treatment and for the first 4 days of capoten treatment. A course of preventive CT was to continue for 30 days.

[Time-dependent effects of ramipril in patients with hypertension of 2 stage].

Abstract: Time-related effects of ramipril were studied in 30 patients with essential hypertension stage II. Central hemodynamics, chronostructure of circadian rhythms of systolic, diastolic and mean arterial pressure, heart rate, double product were assessed before and after ramipril intake throughout 24 hours. The patients were randomized into 3 equal groups by time of ramipril administration: morning, afternoon and evening. Ramipril was given in dose 5 mg at 8 a.m., 14.00 or 17.00 and 20.00 p.m. Some hemodynamic parameters were measured each 4 hours. The data were analyzed using variation statistics and cosinor-analysis. Hypotensive effect of ramipril appeared approximately the same. Hemodynamics responded better after the evening intake of the drug.

Baseline Characteristics and Early Blood Pressure Control in the CONVINCE Trial.

Abstract: -Blood pressure (BP) control rates around the world are suboptimal. Part 2 of the National Health and Nutrition Educational Survey (NHANES) III indicates that only 27.4% of hypertensive Americans aged 18 to 74 years have a BP of <140/90 mm Hg. We wanted to assess BP control during the first 2 years and to describe the baseline characteristics of patients enrolled in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Study, an international clinical trial that compares outcomes in hypertensive patients randomized to initial treatment with either controlled-onset extended-release verapamil or the investigator's choice of atenolol or hydrochlorothiazide. At randomization, BP was <140/90 mm Hg in only 20.3% of the 16 602 subjects (average+/-SD age 65.6+/-7.4 years; 56% women, 84% white/7% black/7% Hispanic). The average BP at enrollment was 148/85 mm Hg for patients taking BP medications (n=13 879) and 161/94 mm Hg for previously untreated patients (n=2723). After medication titration, with a transtelephonic computer that recommended an increase in the dose or number of antihypertensive agents whenever the BP was 140/90 mm Hg, 84.8% of the subjects attained the goal BP. During 2 years of treatment, BP control was maintained in 67% to 69% of the subjects (69% to 71% for systolic BP of <140 mm Hg and 90% for diastolic BP of <90 mm Hg). These data suggest that the control of systolic BP is more difficult than the control of diastolic BP. The US national goal of having 50% of hypertensives with a BP of <140/90 mm Hg may be achievable if a forced titration strategy is used. Interested investigators, free care and medications, and well-educated subjects may make the attainment of such a goal easier in the CONVINCE study than in the general population.

Management of antihypertensive treatment with Lisinopril: a chronotherapeutic approach.

Abstract: Risk for cardiovascular events seems to be higher in the early morning, also as consequence of a rise in blood pressure (BP) values due to the characteristic circadian pattern of BP variability. Therefore, a suitable therapeutic BP control should be tightest during the early morning. On the basis of the ambulatory blood pressure monitoring (ABPM) studies, it has been previously demonstrated that the antihypertensive effect of once daily drug, generally administrated in the morning, decreases at the end of the dosing period. A chronotherapeutic approach to the management of hypertension (this field has been pourly investigated so far) would allow the assessment of the optimum timing of drug dosing, according to the circadian BP rhythm and to the chronorisk maps, in hypertensive patients affected by associated vascular pathologies. This would increase the therapeutic effects. The aim of this study was to assess BP changes due to ACE-inhibitor (Lisinopril 20 mg/die) once daily administration at three different times (8.00 AM, 4.00 PM, 10.00 PM), in order to optimise the dosing time. 40 subjects (mean age +/- SD: 45 +/- 10) affected by primary mild to moderate hypertension were submitted to ABPM for 24 hours, by means of Spacelabs 90207, before and after pharmacological treatment. Patients were randomised to take the drug at 8.00 AM, 4.00 PM or 10.00 PM, and they repeated ABPM every two months, by changing the dosing time. The chronobiological analysis showed: 1) a sensible decrease both in Systolic (S)BP and Diastolic (D)BP without affecting the circadian rhythm, in all evaluations; 2) a greater reduction of SBP and DBP from 6.00 AM to 11.00 AM, period in which cardiovascular risk is higher, after 10.00 PM dosing; 3) no other sensible reduction in SBP and DBP occurred after night administration as compared to that caused by other dosing times. Lisinopril administration at 10.00 PM. has been shown to be much more useful since, although BP circadian rhythm was unmodified, it protects hypertensive patients from both vascular chronorisk and Cruickshank effect (J-curve). Therefore, a chronobiologist antihypertensive treatment in order to increase the therapeutic effect already obtained with the traditional statistic methods.

[Controlled release diltiazem in monotherapy of hypertension--time of drug administration and circadian blood pressure pattern].

Abstract: 30 patients with primary mild to moderate hypertension (DBP 95-110 mm Hg) were treated with long acting diltiazem (120 or 240 mg) once daily in the morning (7.00-8.00 a.m.) for at least 3 weeks and after that the administration time was changed to evening dose (19.00-20.00 p.m.) for next 3 weeks. 24-hours ABPM was performed in all patients on the last day of each period. Obtained recordings were compared in different periods of time: total 24 hours, 6.00-23.00, 23.00-6.00, 4.30-8.00, 5.00-11.00, 20.00-2.00. Mean values of systolic and diastolic blood pressure, heart rate and pressure load (defined as percentage of records above 140/90 mm Hg in day and above 120/80 mm Hg at night) did not differ significantly between investigated dosage regimens. The evening administration of diltiazem did not produce greater decrease of BP at night than the morning dose. For this reason slow release formulation of diltiazem (oxycardil in doses of 120 to 240 mg) can be safely administered in the evening if needed.

[Advantages of capoten chronotherapy of patients with hypertension in an outpatient setting].

Abstract:
To compare the efficiency of a short course of preventive chronotherapy and traditional therapy with capoten in an outpatient setting.

Forty-two patients with stage II essential hypertension were divided into 2 groups: 20 controls were treated with capoten in a dose of 12.5-50 mg 3 times a day and 22 received capoten once a day in the same single dose 1.5-2 h before arterial pressure (AP) acrophase. Central hemodynamics was studied by echocardiography, regional hemodynamics by reheoencephalography before and at the end of therapy.

In the control group AP normalized after capoten therapy in 3 patients, decreased by at least 10% but did not normalize in 9, and did not change in 8 patients. The results in the chronotherapy group were as follows: AP normalized in 5, decreased by at least 15% in 13, and did not change in 4 patients. Normalization of daily profiles of hemodynamic values and more favorable shifts in the cerebral bloodflow were more often seen in patients who received chronotherapy.

Capoten chronotherapy of patients with essential hypertension, carried out in an outpatient setting, is obviously preferable to traditional treatment: no side effects were observed and a better hypotensive effect was attained with lower total dose.

Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial.

Abstract:
Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk, but the benefit compared with other drug classes is controversial.

To determine whether initial therapy with controlled-onset extended-release (COER) verapamil is equivalent to a physician's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease.

Double-blind, randomized clinical trial conducted at 661 centers in 15 countries. A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. After a mean of 3 years of follow-up, the sponsor closed the study before unblinding the results.

Initially, 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (eg, diuretic, beta-blocker, or an angiotensin-converting enzyme inhibitor) could be added in specified sequence if needed.

First occurrence of stroke, myocardial infarction, or cardiovascular disease-related death.

Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease-related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88-1.18; P =.77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease-related death, 1.09 (95% CI, 0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease-related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) (HR, 1.54 [95% CI, 1.16-2.04]; P =.003). More cardiovascular disease-related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53).

The CONVINCE trial did not demonstrate equivalence of a COER verapamil-based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or beta-blocker treatment.


Context: Infants born preterm are at increased risk of cognitive and motor impairments compared with infants born at term. Early developmental interventions for preterm infants are targeted at the infant or the parent-infant relationship, or both, and may focus on different aspects of early development. They aim to improve developmental outcomes for these infants, but the long-term benefits remain unclear. This is an update of a Cochrane review first published in 2007 and updated in 2012 and 2015.

Primary objective To assess the effect of early developmental interventions compared with standard care in prevention of motor or cognitive impairment for preterm infants in infancy (zero to < three years), preschool age (three to < five years), and school age (five to < 18 years). Secondary objective To assess the effect of early developmental interventions compared with standard care on motor or cognitive impairment for subgroups of preterm infants, including groups based on gestational age, birthweight, brain injury, timing or focus of intervention and study quality.

Studies included randomised, quasi-randomised controlled trials (RCTs) or cluster-randomised trials of early developmental intervention programmes that began within the first 12 months of life for infants born before 37 weeks' gestational age (GA). Interventions could commence as an inpatient but had to include a post discharge component for inclusion in this review. Outcome measures were not prespecified, other than that they had to assess cognitive outcomes, motor outcomes or both. The control groups in the studies could receive standard care that would normally be provided.

Neurodevelopment until the adjusted age of 2 years in extremely low birth weight infants after early intervention--a case-control study.

Abstract: A total of 104 infants with birth weights of less than 1000 grams were enrolled in this prospective case-control study in order to examine the effect of occupational therapy based on sensory integration (SI) and neurodevelopmental therapy (NDT) on neurological development. The children were grouped as matched pairs on the basis of a set of developmental risks assessed at the age of 3 months. The intervention children had a weekly session of 60 minutes of occupational therapy from the corrected age of 6 months up to 12 months. All the children were examined at the corrected age of 3, 6, 9, 12, 18 and 24 months. The neurodevelopment of the cases and the controls did not differ essentially and the only significant difference was found in the social development of the children at the age of 12 months to the advantage of the intervention group. It is concluded that this amount of occupational therapy in at-risk children does not have a relevant effect on neurological development.

One-year outcome of auditory-tactile-visual-vestibular intervention in the neonatal intensive care unit: effects of severe prematurity and central nervous system injury.

Abstract: Thirty-seven infants with severe central nervous system injury or extreme prematurity were randomly assigned to a multisensory (auditory-tactile-visual-vestibular) intervention or control group. Intervention began in the hospital at 33 weeks' postconceptional age and continued twice daily in the home until 2 months' corrected age. Mother-infant interactions during feedings were videotaped, and the Bayley Scales of Infant Development were administered. Control mothers stimulated their infants more during feeding, but these significant differences dissipated by 4 months. The presence of periventricular leukomalacia was associated with significantly poorer mental development, regardless of group assignment. Experimental infants tended to exhibit better motor and mental performance and had 23% fewer cerebral palsy diagnoses at 1 year, but these trends were not statistically significant. The type of brain injury was more important in determining 1-year developmental outcome than type of postnatal experience, suggesting that periventricular leukomalacia presents a major challenge for infant development.

Cognitive performance and attachment patterns at four years of age in extremely low birth weight infants after early intervention.

Abstract: This study aims at assessing the effects of an early occupational therapy intervention on the cognitive development and the development of attachment patterns in ELBW infants. The intervention, given weekly at home from six months to 12 months, aimed at supporting parent-child interaction and enhancing motor control and coordination. The study population consisted of 100 ELBW infants matched in pairs in accordance to their pre-perinatal risk scores and allocated successively to intervention or non-intervention groups. Cognitive development was assessed with the Bayley Scales at age two and with the WPPSI at age four. Attachment to primary caregiver was assessed with the Preschool Assessment of Attachment (PAA). Cognitive performance was within age norms in both groups at both ages. Intervention did not show any effect on cognitive performance at the age of two years. At the age of four years, cognitive level was overall, and most notably for verbal performance, higher in the intervention group than in the control group. There was an over-representation of the so-called atypical attachment patterns (those not fitting the normative A, B, or C categories) in the control group. The results are discussed in terms of finding more global ways to support the development of at risk pre-term children.

Effect of a developmental program on motor performance in infants born preterm.

Abstract: A randomised controlled trial was conducted to evaluate the effect of a motor developmental program in improving motor performance in Thai infants born preterm. Eighty-four preterm born infants were randomly assigned to either a control or intervention group. Additionally, 27 low-risk preterm infants were included forming a comparative group for this study. From term equivalent age to four months adjusted age, all infants had their motor performance assessed monthly with the Test of Infant Motor Performance by one of the physiotherapist research assistants blind to group assignment and infants' adjusted age. In addition, the intervention infants received a developmental program at each monthly visit. Motor performance for each group plotted against age revealed linear trends of progression. The intervention group showed the greatest improvement. Two-way repeated measures ANOVA revealed significant differences across age and among groups. Scheffé comparisons indicated that the mean differences between each pair of the three groups were significant and supported the finding of greater improvement of the intervention infants over the control group. Thus the results suggest that the intervention program is likely to have beneficial effects when offered to a similar population of preterm born infants.

Early intervention promotes intellectual development of premature infants: a preliminary report. Early Intervention of Premature Infants Cooperative Research Group.

Abstract:
To evaluate the effect of early intervention on the intellectual development of the premature infants.

Premature infants at gestational age of 28-36.9 weeks were randomly divided into two groups: intervention and conventional care groups. Normal newborn infants during the same period were included in the control group (routine care). Up to March 1996, 156 cases were over the age 1.5-2 years (corrected age), 52 in the intervention group, 51 in the conventional care group and 53 in the normal control group. Parents were taught to carry out the 0-2 year intervention program, which included motor, cognitive, speech development and social behavior. Every three months, height, weight and head circumference were measured. At the age of one and a half and two years, all infants in the three groups received infant development tests of Child Development Center of China (CDCC) scale. The examiner did not know which infant had received intervention.

There was no significant difference in biological factors among the two premature groups and in cultural and social factors among the three groups. Intelligence tests at the age of one and a half and two years showed that the average mental development index (MDI) in the intervention group was 13.8 and 14.6 higher than those in the conventional care group and the differences were significant. The psychomotor development index (PDI) was 5.2 and 4.7 higher but the differences were not significant. The MDI and PDI in the intervention group and normal control were quite close, but at two years, the MDI and PDI in the intervention group were 5.7 and 7.3 higher than those in the normal control and the differences were significant (P < 0.05). Compared with the normal control, the MDI in conventional care group at one and a half and two years of age were 11.5 and 8.9 lower. The difference was very significant. There were four cases of mental retardation, whose mental development index (MDI) was less then 70 in the conventional care group, but none in the intervention group.

Early intervention can promote intellectual development of the premature infants and may be beneficial to the prevention of mental retardation. Early and intensive intervention can produce better results. Bringing parent's initiative into full play through deepening their understanding of the importance of early intervention is the key to success.

Improving cognitive development of low-birth-weight premature infants with the COPE program: a pilot study of the benefit of early NICU intervention with mothers.

Abstract: The purpose of this pilot study was to evaluate the effectiveness of a parent-focused intervention program (COPE) on infant cognitive development and maternal coping. A randomized clinical trial was conducted with 42 mothers of low-birth-weight (LBW) premature infants hospitalized in a neonatal intensive care unit (NICU), with follow-up at 3 months' and 6 months' corrected ages. COPE mothers received the four-phase educational-behavioral program that began 2-4 days postbirth and continued through 1 week following discharge from the NICU. Comparison mothers received audiotaped information during the same four time frames. Results indicated that COPE infants had significantly higher mental development scores at a 3 months' corrected age (M = 100.3) than did the comparison infants (M = 93.9), and this difference widened at 6 months' corrected age, with COPE infants scoring 14 points higher. COPE mothers were significantly less stressed by the NICU sights and sounds and had significantly stronger beliefs about what behaviors and characteristics to expect from their premature infants. Findings from this study support the need for further testing of early NICU interventions with parents to determine their effectiveness on parental coping and infant developmental outcomes.

Early physiotherapy intervention in premature infants.

Abstract: Preterm infants are more likely to have disabling cerebral palsy (CP) than term infants. It has been reported that early therapeutic approaches may be appropriate for infants at risk of neuromotor dysfunction, to minimize the degree of future handicaps. Two hundred and twenty-nine infants born at less than 34 weeks' gestation, with birth weight < or = 2,000 g, cared for in the neonatal intensive care unit of Hacettepe University Hospital between January 1997-June 1999 were included in this study. Of the 229 infants initially included, 39 (17%) were dropped from the study within the first 12 months' assessment, due to lack of participation from the families. Thirty of the remaining 190 infants were found to have perinatal hypoxia or abnormal neurosonography, and were taken as the group at risk of development of CP, thus receiving early intervention therapy; these are listed as "premature at risk". The study group consisted of 160 infants not considered at risk. These were randomly paired into two groups of 80 infants, one that was given early interventional therapy, and the control group that received no program. Eleven of the 30 infants at risk, 2 of the 80 infants from the intervention group, and 4 of the 80 from the control group were diagnosed as having CP within the first six months of life. There was no difference in the age of loss or acquisition of reflexes and general abilities between the intervention and control groups. There was no difference in the prevalence of CP between the intervention and control groups. In conclusion this study showed no effect of early intervention in premature babies without risk of CP other than prematurity.

Is early occupational therapy in extremely preterm infants of benefit in the long run?

Abstract: A total of 126 infants with extremely low birth weight (ELBW; <1000 g) were enrolled in a prospective case-control study in order to examine the effect of occupational therapy based on sensory integration (SI) and neurodevelopmental therapy (NDT) on neurological development. The children were grouped as matched pairs on the basis of determined developmental risk scores assessed at the age of 3 months. The intervention children had a 6-month period of weekly occupational therapy from the corrected age of 6-12 months. The follow-up showed that the social development of the intervention children was significantly better at the age of 12 months, but at the age of 2 years the groups had equal developmental scores in neurological, neuropsychological and speech therapy assessments. The Miller assessment for pre-schoolers (MAP) performed in a total of 96 (92%) of the study children at the age of 4 years failed to demonstrate any significant differences between the groups. It is concluded that this amount of occupational therapy in ELBW infants does not have any detectable effect on long-term neurological development.

Effects of early intervention on cognitive function of low birth weight preterm infants.

Abstract: The Infant Health and Development Program is a randomized clinical trial to test the efficacy of educational and family support services and pediatric follow-up, offered during the first 3 years of life, in reducing the incidence of developmental delay in low birth weight preterm infants at eight clinical sites (N = 985). It was hypothesized that larger intervention effects would be found for the domains in which low birth weight preterm infants are known to have problems, specifically visual-motor and spatial skills and receptive language skills. These analyses explore the effects of the Infant Health and Development Program on different domains of cognitive functioning. Cognitive domains are identified by means of factor analysis of the intelligence tests used at 12, 24, and 36 months (Bayley Scales of Infant Development (including the Mental and Motor scales) at 12 and 24 months; the Stanford-Binet, Peabody Picture Vocabulary Test, and Beery Test of Visual Motor Intergration at 36 months). Our results reveal that, although intervention benefits accrue across cognitive domains at 24 and 36 months, gains are most pronounced for receptive language and visual-motor and spatial skills.

Effect of an early intervention programme on low birthweight infants with cerebral injuries.

Abstract:
To determine the effect of an early intervention programme (EIP) on low birthweight infants with cerebral injuries.

Subjects were 23 high-risk low birthweight infants (periventricular leukomalacia 15, intraventricular haemorrhage 5, both 3) receiving care in the neonatal intensive care unit (NICU) at Nagasaki University Hospital. Subjects were randomly assigned to the EIP group (n = 12) or the control group (n = 11). Participants in the EIP group received a Neonatal Behavioral Assessment scale (NBAS)-based intervention combined with developmental support designed to enhance the infants' development and the quality of the parent-infant relationship. The control group received routine medical nursing care without the EIP. The EIP began prior to discharge from the NICU and lasted until 6 months of corrected age. All children were examined on the NBAS preintervention and again at 44 weeks postconceptional age. Maternal anxiety status (STAI) and maternal feelings of confidence in dealing with her baby (LCC) were measured pre and postintervention. Mental and motor development was assessed postintervention using the Bayley Scale of Infant Development.

Orientation and State Regulation of infant behavioural profiles, the STAI and LCC scores significantly improved in the EIP group (mean difference (95% CI): Orientation 0.7 (0.4, 1.1), State Regulation 0.9 (0.3, 1.5), STAI -5.5 (- 9.1, -1.9, LCC 5.3 (4.2, 6.5)), but not in the control group. Bayley mental developmental index (MDI) score in the EIP group was higher than in the control group, but there was no significant difference between the two groups (mean difference (95% CI): MDI 8.5 (- 0.8, 17.8), PDI 6.7 (- 1.9, 15.4)).

The EIP has beneficial effects on neonatal neurobehavioural development and maternal mental health of low birthweight infants with cerebral injuries. This evidence suggests that short-term changes in maternal mental health and infant neurobehaviour promoted by an EIP may serve to initiate a positive interaction between parents and infants.


Context: Abortions prior to 14 weeks are among the most common outpatient surgical procedures performed on people capable of becoming pregnant. Various methods have been used to control pain; however, many people still experience pain with the procedure.

To evaluate the benefits and harms of local anaesthesia given for pain control during surgical abortion at less than 14 weeks' gestation.

We selected effectiveness and comparative effectiveness randomized controlled trials that studied local anaesthesia with common local anaesthetics and administration routes given for pain control in surgical abortion at less than 14 weeks' gestation using uterine aspiration. Outcomes included intraoperative pain, patient satisfaction, and adverse events.

Paracetamol 1 g given rectally at the end of minor gynaecological surgery is not efficacious in reducing postoperative pain.

Abstract:
We studied the analgesic effects of 1 g paracetamol given rectally at the end of surgery in a prospective, randomised, double-blind study.

One hundred and forty ASA I-II women scheduled for elective termination of pregnancy under general anaesthesia were randomly allocated to receive paracetamol or placebo. All patients had standardised anaesthesia with propofol, fentanyl and oxygen in nitrous oxide. Postoperative pain was assessed by VAS score.

We could find no difference regarding postoperative pain, need for analgesics or time to discharge between the groups.

The routine use of 1 g paracetamol given rectally at the end of surgery after termination of pregnancy seems not to be justified.

Analgesia for termination of pregnancy.

Omission of nitrous oxide from a propofol-based anesthetic does not affect the recovery of women undergoing outpatient gynecologic surgery.

Abstract:
Although nitrous oxide (N2O) is used commonly during anesthesia, clinically relevant advantages-disadvantages of using this agent are not well established in the ambulatory setting. This study in women undergoing ambulatory gynecologic surgery compares outcomes in patients administered total intravenous anesthesia with propofol versus the propofol plus N2O. The primary outcome was the time to home readiness. Secondary outcomes included the incidence of postanesthetic adverse events.

Women presenting for elective ambulatory termination of pregnancy or gynecologic laparoscopy were induced with an intravenous sleep dose of propofol and fentanyl. After induction, subjects were randomly allocated to maintenance anesthesia with propofol alone or propofol plus 65% N2O. Patients were assessed by a blinded observer in the postanesthetic care unit at 20-min intervals to determine home readiness. Postoperative pain and nausea were measured with visual analog scales. Postoperative analgesics and antiemetics were recorded. The incidence of adverse events occurring after hospital discharge was assessed by a telephone interview 24 h postoperatively.

A total of 740 patients received propofol alone, and 750 patients received propofol plus N2O. Mean home readiness times were not significantly different between treatment groups. There were no significant differences between groups in pain scores, nausea scores, analgesia administration, or antiemetic administration before discharge. There were no significant differences in the frequency of adverse events for 24 h after discharge from hospital.

Omission of N2O from a propofol-based anesthetic for ambulatory gynecologic surgery does not affect time to home readiness or the incidence of postoperative adverse events up to 24 h after discharge from hospital. (Key words: Awareness; outpatient surgery; total intravenous anesthesia.)

No effect of preoperative paracetamol and codeine suppositories for pain after termination of pregnancies in general anaesthesia.

Abstract: Outpatient surgery demands rapid recovery and satisfied patients. The purpose of the study was to investigate whether rectal premedication with paracetamol and codeine would reduce the need of rescue analgesics, reduce the postoperative pain experience and result in faster eligibility for discharge. Ninety pregnant patients scheduled for day-case surgery with evacuation of the uterine cavity were randomly assigned into two groups. The paracetamol and codeine group was given a suppository with 60 mg of codeine and 800 mg of paracetamol together with standard premedication of intramuscular midazolam 0.08 mg/kg. The placebo group was given a placebo suppository and midazolam. All patients underwent the surgical procedure under general anaesthesia with alfentanil 15 microg/kg and propofol 1.5-2 mg/kg. There were no statistically significant differences between the groups in the postoperative pain experience as judged by Visual Analogue Scale (VAS-scale), verbal scale or the need for rescue analgesic medication with ketobemidone. Most of the patients experienced little postoperative pain with more than 70% scoring less than 20 mm on a VAS-scale from 0-100 mm at any time during the postoperative period. The paracetamol and codeine patients were significantly more sleepy at 30 min postoperatively. There were no differences between the groups in postoperative nausea or vomiting and no difference in discharge eligibility. The use of pre-operative suppository with paracetamol 800 mg and codeine 60 mg is unnecessary in this group of patients.

Diazepam as a sedative in induced abortion.

Abstract:
In 136 patients, who underwent induced abortion by the vacuum curettage method under local anaesthesia (paracervical block), the effect of 10 mg diazepam intravenously as preoperative sedative was investigated for its ability to abolish the subjective experience of pain. The trial was carried out as a paired sample, random, allocation, double-blind, fixed dose trial, and the statistical method was sequential analysis. Thirty-six pairs showed no difference and were excluded. After 32 pairs (24 A preferences and 8 O preferences), diazepam showed a significant superiority to placebo (p less than 0.05) (Fig. 1.) Amnesia for the procedure was reported by about one-quarter of the diazepam-treated patients, and in practically all cases the sedative effect had subsided 1-3 hours after the operation.

Diazepam has been reported to reduce pain and discomfort and in many cases to produce a total amnesia.  The drug was tested with 136 patients undergoing vacuum curettage for abortion.  About 1/2 hour before the pro cedure, patients received premedication with 50 mg pethidine sc.  At the beginning of the procedure, half the patients received 10 mg diazepam iv , and the other half a placebo.  Paracervical block was then used with 1 % carbocaine.  After 3 minutes, the cervix was dilated with a Hegar dila tor, the uterine contents were removed by the suction curette, and .2 mg methyl-ergometrine maleate (Methergin) was given iv.  At 1-3 hours posto peratively, patients were asked if the operation had been painful.  In 36 instances no preference was shown between results.  In 32 instances w here a preference was shown diazepam was considered superior to the plac ebo in reducing pain and discomfort in 24 patients.  In 18 of the 68 pat ients treated with diazepam, there was total amnesia for the procedure.  However, 2 patients receiving the placebo also had amnesia.  At 1-3 hours after the procedure, 4 patients in the diazepam group and 3 in the placebo group were slightly somnolent.  With the dose used, the procedure can be done on an outpatient basis.

Paracervical block with etidocaine for out-patient abortion.

Abstract: Paracervical block using etidocaine 0.5 % and 1.0 % without adrenaline proved to be an effective anaesthetic procedure for first trimester abortion performed by surgical dilatation of the cervix and subsequent vacuum suction. Three blocks out of 24 were inadequate, probably due to inaccurate deposition of the local anaesthetic. There were two adverse reactions, possibly as a result of inadvertant intravascular injection. The need for long-acting agents for the present indication is questioned.

Auxiliary pain relief during suction curettage.

Is pain prophylaxis in minor gynaecological surgery of clinical value? a double-blind placebo controlled study of paracetamol 1 g versus lornoxicam 8 mg given orally.

Abstract: Methods: In a prospective randomised placebo controlled double-blind study 210 ASA I-II women scheduled for elective termination of pregnancy received 1 g paracetamol, 8 mg lornoxicam or placebo orally 60 min before anaesthesia which was standardised with propofol, fentanyl and oxygen in nitrous oxide 1:2. Postoperative pain was assessed by VAS-score at 30 and 60 min after end of surgery and at discharge as primary endpoints. Need for rescue medication and time to discharge were secondary endpoints. Results: All patients had an uncomplicated course. Overall pain intensity was low, however, the patients pretreated with lornoxicam had significantly less pain after surgery, no difference could however, be seen in need for rescue medication or time to discharge between the three groups. Conclusion: General pain prophylaxis may be argued in minor gynaecological surgical procedures where postoperative pain is of low intensity. If general prophylaxis is to be given in minor gynaecological surgery, a non steroidal anti-inflammatory (NSAID) such as lornoxicam, seems more efficacious as compared to a standard dose of 1 g paracetamol.

A randomized controlled trial of fentanyl for abortion pain.

Abstract:
Our aim was to find out whether intravenous fentanyl was effective in reducing the pain of first-trimester abortion.

This randomized controlled trial included 825 women attending a nonhospital abortion facility. Some women chose standard care. Women who did not choose standard care were randomly assigned to receive either 50 to 100 microg of fentanyl, a placebo, or no intervention. With SAS software and a mixed effects analysis of variance model with covariates, we compared mean pain scores of the fentanyl and placebo groups to detect a difference of at least 1 point on an 11-point pain scale.

The mean pain score of the fentanyl group was 1.0 point less than that of the placebo group (95% confidence interval, 3.7-4.3) and 0.9 point less than that of the observational group (95% confidence interval, 4.7-5.1). This pain reduction was statistically significant, but the women who were studied wanted a 2-point reduction from fentanyl.

Fentanyl, when compared with the placebo, reduced abortion pain by 1.0 point on an 11-point scale. This reduction was of questionable clinical significance and was less than desired by the women included in the study.

A randomized, double blind, placebo-controlled study to investigate the use of conscious sedation in conjunction with paracervical block for reducing pain in termination of first trimester pregnancy by suction evacuation.

Abstract:
This study evaluated the role of conscious sedation in pain relief during termination of first trimester pregnancy by suction evacuation (SE) under local anaesthesia.

A hundred women undergoing SE before 12 weeks gestation were randomized by computer using the sealed envelope method to receive placebo (saline) or conscious sedation (2 mg midazolam and 25 microg fentanyl) i.v. 5 min before cervical dilatation. Paracervical block was given to all patients, 2 min later. Pain scores during and after SE, post-operative side-effects and satisfaction level were compared.

No statistically significant differences in pain scores were found between the two groups. Post-operative side-effects such as dizziness (P = 0.015) and drowsiness (P < 0.001) were significantly more severe in the conscious sedation group. However, patients in the conscious sedation group reported better satisfaction levels than the control group (P = 0.003).

The use of conscious sedation significantly improved patient satisfaction during termination of first trimester pregnancy by SE under local anaesthesia, despite a lack of improvement in pain relief and the presence of increased severe dizziness/drowsiness in the post-operative period.


Context: Pressure ulcers are localized injuries to the skin or the underlying tissue, or both, and are common in older and immobile people, people with diabetes, vascular disease, or malnutrition, as well as those who require intensive or palliative care. People with pressure ulcers often suffer from severe pain and exhibit social avoidance behaviours. The prevention and treatment of pressure ulcers involves strategies to optimize hydration, circulation, and nutrition. Adequate nutrient intake can reduce the risk factor of malnutrition and promote wound healing in existing pressure ulcers. However, it is unclear which nutrients help prevent and treat pressure ulcers. This is an update of an earlier Cochrane Review.

To evaluate the benefits and harms of nutritional interventions (special diets, supplements) for preventing and treating pressure ulcers in people with or without existing pressure ulcers compared to standard diet or other nutritional interventions.

We included randomized controlled trials (RCTs) in people with or without existing pressure ulcers, that compared nutritional interventions aimed at preventing or treating pressure ulcers with standard diet or other types of nutritional interventions.

Pressure sores and tube feeding in patients with a fracture of the hip: a randomized clinical trial.

Abstract: Pressure sores are a frequent problem, especially in elderly patients. Nutritional status may influence the incidence, progression and severity of pressure sores, data, however, are contradictory (1). The purpose of this study was to determine the effect of supplemental feeding on the nutritional status and the development and severity of pressure sores. The effect of supplemental feeding overnight (tube +) on patients with a fracture of the hip and a high pressure-sore risk score, was studied in a randomized clinical trial. The control group (tube -) had no supplemental feeding. After informed consent, 140 patients were randomized, and 129 of these took part in the trial (62 tube +, and 67 tube -). Protein and energy intake, haemoglobin, serum albumin, total serum protein and pressure-sore grade were measured at admission and after 1 and 2 weeks. Of the 62 patients randomized for tube feeding (tube +), only 25 tolerated their tube for more than 1 week and 16 for 2 weeks. Nevertheless, energy and protein intake was significantly higher in the tube + group (P < 0.001). This, however, did not significantly influence total serum protein, serum albumin and development and severity of pressure sores after 1 and 2 weeks. Comparison of the actually tube fed group (n=25 at 1 week, n = 16 at 2 weeks) and the control group showed a 2-3 times higher protein and energy intake (P < 0.0001), and a significantly higher total serum protein and serum albumin after 1 and 2 weeks in the actually tube fed group (all P < 0.001). Pressure-sore development and severity were not significantly influenced in the actually tube fed group. We conclude that we were not able to show a significant decrease in development and severity of pressure sores, because the nasogastric tube for supplemental feeding was not well tolerated in this patient group. Nevertheless, tube feeding overnight does result in a significant higher protein and energy intake, and has a significant effect on nutritional status in the actually tube-fed group. Other means of supplemental feeding will have to be used in order to answer the question of whether supplemental feeding can decrease development and severity of pressure sores.

A multi-center trial of the effects of oral nutritional supplementation in critically ill older inpatients. GAGE Group. Groupe Aquitain Geriatrique d'Evaluation.

Abstract: The purpose of this study was to assess the effect of nutritional supplementation on dietary intake and on pressure ulcer development in critically ill older patients. The multi-center trial involved 19 wards stratified according to specialty and recruitment for critically ill older patients; 9 wards were randomly selected for nutritional intervention (nutritional intervention group), consisting of the daily distribution of two oral supplements, with each supplement containg 200 kcal, for 15 d. Pressure ulcer incidence was prospectively recorded for grades I (erythema), II (superficial broken skin), and III (subcutaneous lesion) for 15 d. Nutritional intake was monitored by using estimates in units of quarters validated by comparison with weight measurement. There were 672 subjects older than 65 y, and 295 were in the nutritional intervention group versus 377 in the control group. The patients were similar for age, sex ratio, and C-reactive protein. In comparison with the control group, the nutritional intervention group included more patients with stroke, heart failure, and dyspnea and fewer with antecedent falls, delirium, lower limb fractures, and digestive disease. The nutritional intervention group had a lower risk of pressure ulcers according to the Norton score but was less dependent (Kuntzman score) and had a lower serum albumin level. During the trial, energy and protein intakes were higher in the nutritional intervention group (day 2: 1081 +/- 595 kcal versus 957 +/- 530 kcal, P = 0.006; 45.9 +/- 27.8 g protein versus 38.3 +/- 23.8 g protein in the control group, P < 0.001). At 15 d, the cumulative incidence of pressure ulcers was 40.6% in the nutritional intervention group versus 47.2% in the control group. The proportion of grade I cases relative to the total number of cases was 90%. Multivariate analysis, taking into account all diagnoses, potential risk factors, and the intra-ward correlation, indicated that the independent risk factors of developing a pressure ulcer during this period were: serum albumin level at baseline, for 1 g/L decrease: 1.05 (95% confidence interval: 1.02 to 1.07, P < 0.001); Kuntzmann score at baseline, for 1-point increase: 1.22 (0.32 to 4.58, P = 0.003); lower limb fracture: 2.68 (1.75 to 4.11, P < 0.001); Norton score < 10 versus > 14: 1.28 (1.01 to 1.62, P = 0.04); and belonging to the control group: 1.57 (1.03 to 2.38, P = 0.04). In conclusion, it was possible to increase the dietary intake of critically ill elderly subjects by systematic use of oral supplements. This intervention was associated with a decreased risk of pressure ulcer incidence.

Impact on pressure ulcer healing of an arginine-enriched nutritional solution in patients with severe cognitive impairment.

A randomised, double-blind assessment of the effect of nutritional supplementation on the prevention of pressure ulcers in hip-fracture patients.

Abstract:
Malnutrition is a risk factor for development of pressure ulcers (PU). Nutritional supplementation may thus reduce the incidence of PU. We investigated the effect of nutritional supplementation on incidence of PU in hip-fracture patients at risk of developing PU.

Hip-fracture patients (n=103) were included in this double-blind, randomised, placebo-controlled trial. They received 400 ml daily of a supplement enriched with protein, arginine, zinc and antioxidants (n=51) or a non-caloric, water-based placebo supplement (n=52). Presence and stage of PU were assessed daily for 28 days or until discharge (median: 10 days during supplementation).

Incidence of PU was not different between supplement (55%) and placebo (59%), but incidence of PU stage II showed a 9% difference (difference: 0.091; 95% CI: 0.07-0.25) between supplement (18%) and placebo (28%). Of patients developing PU 57% developed it by the second day. Time of onset (days) showed a trend (P=0.090) towards later onset of PU with supplement (3.6+/-0.9) than placebo (1.6+/-0.9).

Hip-fracture patients develop PU at an early stage. Nutritional supplementation may not prevent PU at this stage, but contributes possibly to a delayed onset and progression of PU. Nutritional supplementation may be more effective if initiated earlier.

Arginine supplementation is well tolerated but does not enhance mitogen-induced lymphocyte proliferation in elderly nursing home residents with pressure ulcers.

Abstract:
Immune function declines with age, increasing risk for infection and delaying wound healing. Arginine enhances immune function and healing of standardized wounds in healthy elderly persons. The purpose of this study was to determine what level of arginine supplementation was orally and metabolically tolerated and effective in enhancing immune function in elderly persons with pressure ulcers.

Residents with one or more pressure ulcers were recruited from two local nursing homes. Subjects were randomized to receive 0 g (n = 10; age, 82 +/- 3 years), 8.5 g (n = 11; 81 +/- 3 years), or 17 g (n = 11; 87 +/- 2 years) of supplemental arginine each day for 4 weeks. Oral tolerance, ie, absence of nausea, vomiting, abdominal distention, or diarrhea, was assessed daily. Metabolic tolerance was assessed weekly by evaluating serum electrolytes. Lymphocyte proliferation to phytohemagglutinin and interleukin 2 production were measured at baseline and after 4 weeks of supplementation as indicators of immune function.

Supplemental arginine significantly increased plasma arginine levels and was orally and metabolically tolerated with no complaints of abdominal distress or no clinically relevant changes in electrolyte levels among groups. Lymphocyte proliferation and interleukin 2 production were significantly different between nursing homes. When data from nursing homes were considered individually, arginine supplementation did not enhance the proliferative response. In subjects from nursing home 2 only, there was a 38% and 75% decrease (p < .05) in lymphocyte proliferation with 8.5 and 17 g of supplemental arginine, respectively. Interleukin 2 production was no different among supplementation groups.

Pharmacologic doses of arginine were well tolerated but did not enhance lymphocyte proliferation or interleukin 2 production in nursing home residents with pressure ulcers. CLINICAL RELEVANCY: Enteral formulas supplemented with pharmacologic levels of arginine are frequently administered to elderly persons. This study demonstrates that the very old can tolerate these nitrogen loads if baseline renal function is normal and fluid intake is encouraged. Further research needs to be completed investigating the effect of arginine supplementation on immune function in this population before recommending arginine use.

Vitamin C and pressure ulcers.

Does vitamin C supplementation promote pressure ulcer healing?

Zinc supplementation: yea or nay?

Does oral supplementation with vitamins A or E promote healing of chronic wounds?