Results of a phase 1 multicentre investigation of dexmedetomidine bolus and infusion in corrective infant cardiac surgery.

BACKGROUND: Dexmedetomidine (DEX) is increasingly used intraoperatively in infants undergoing cardiac surgery. This phase 1 multicentre study sought to: (i) determine the safety of DEX for cardiac surgery with cardiopulmonary bypass; (ii) determine the pharmacokinetics (PK) of DEX; (iii) create a PK model and dosing for steady-state DEX plasma levels; and (iv) validate the PK model and dosing. METHODS: We included 122 neonates and infants (0-180 days) with D-transposition of the great arteries, ventricular septal defect, or tetralogy of Fallot. Dose escalation was used to generate NONMEM® PK modelling, and then validation was performed to achieve low (200-300 pg ml-1), medium (400-500 pg ml-1), and high (600-700 pg ml-1) DEX plasma concentrations. RESULTS: Five of 122 subjects had adverse safety outcomes (4.1%; 95% confidence interval [CI], 1.8-9.2%). Two had junctional rhythm, two had second-/third-degree atrioventricular block, and one had hypotension. Clearance (CL) immediately postoperative and CL on CPB were reduced by approximately 50% and 95%, respectively, compared with pre-CPB CL. DEX clearance after CPB was 1240 ml min-1 70 kg-1. Age at 50% maximum clearance was approximately 2 days, and that at 90% maximum clearance was 18 days. Overall, 96.1% of measured DEX concentrations fell within the 5th-95th percentile prediction intervals in the PK model validation. Dosing strategies are recommended for steady-state DEX plasma levels ranging from 200 to 1000 pg ml-1. CONCLUSIONS: When used with a careful dosing strategy, DEX results in low incidence and severity of adverse safety events in infants undergoing cardiac surgery with cardiopulmonary bypass. This validated PK model should assist clinicians in selecting appropriate dosing. The results of this phase 1 trial provide preliminary data for a phase 3 trial of DEX neuroprotection. CLINICAL TRIALS REGISTRATION: NCT01915277.

Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide.

Molecules that block nitric oxide's (NO) biosynthesis are of significant interest. For example, nitric oxide synthase (NOS) inhibitors have been suggested as antitumor therapeutics, as have inhibitors of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catabolizes endogenous NOS inhibitors. Dual-targeted inhibitors hold promise as more effective reagents to block NO biosynthesis than single-targeted compounds. In this study, a small set of known NOS inhibitors are surveyed as inhibitors of recombinant human DDAH-1. From these, an alkylamidine scaffold is selected for homologation. Stepwise lengthening of one substituent converts an NOS-selective inhibitor into a dual-targeted NOS/DDAH-1 inhibitor and then into a DDAH-1 selective inhibitor, as seen in the inhibition constants of N5-(1-iminoethyl)-, N5-(1-iminopropyl)-, N5-(1-iminopentyl)- and N(5)-(1-iminohexyl)-l-ornithine for neuronal NOS (1.7, 3, 20, >1,900 microM, respectively) and DDAH-1 (990, 52, 7.5, 110 microM, respectively). A 1.9 A X-ray crystal structure of the N5-(1-iminopropyl)-L-ornithine:DDAH-1 complex indicates covalent bond formation between the inhibitor's amidino carbon and the active-site Cys274, and solution studies show reversible competitive inhibition, consistent with a reversible covalent mode of DDAH inhibition by alkylamidine inhibitors. These represent a versatile scaffold for the development of a targeted polypharmacological approach to control NO biosynthesis.

Electron-transfer function of NAD+-immobilized alginic acid.

Polymerized NAD+ (Alg-NAD+) was prepared and its electrochemical properties were investigated. NAD+ has been covalently immobilized at the carboxyl group of alginic acid using water soluble carbodiimide (EDC) and then Alg-NAD+s of various NAD+ density were obtainable depending on NAD+ concentration in the reaction mixture. Absorbance of 260 nm of Alg-NAD+s showed that 3.4 to 17.6% of carboxyl groups of alginic acid were coupled with NAD+. The coenzyme activity of immobilized NAD+ has reached 80 to 90% on each Alg-NAD+. A cathodic peak in the cyclic voltammogram of Alg-NAD+ appeared at -1.2 V (vs. SCE) corresponding to the reduction wave of free NAD+. The anodic wave of NAD dimer was not observed in the presence of 2.0 mM methyl viologen and 5 units of diaphorase and NAD+ immobilized on the composite electrode could be reduced to the normal NADH. The ratio of apparent diffusion coefficient (Dapp.) of Alg-NAD+ and free NAD+ was evaluated from the variation of ipc with the square root of sweep rate (v 1/2). Despite the high molecular weight of Alg-NAD+, Dapp. Alg-NAD+/Dapp. free NAD+ are larger than that expected. These results indicate that electron transfer occurred effectively between each NAD+ molecule immobilized onto the polymer chain. It is also confirmed by a conjugated redox enzyme reaction with Alg-NAD+.

How does the increasing filling of the vacuum source diminish the suction in modern portable drainage systems?

Nine different brands representing the four main types of modern portable drainage systems (expanding suction balls, suction bellows, spring-loaded systems and high vacuum systems) were examined with respect to the relationship between the degree of filling of the vacuum source and the resulting vacuum. The results are presented first graphically and second numerically with five figures according to a system suggested by the authors. It is further concluded that the vacuum-volume curves, except for the high vacuum systems, presented by the manufacturers are not always in full accordance with the findings in this study. When a surgeon chooses to use a drain in a certain situation it is of great importance, on the one hand, that he has a knowledge of the degree of vacuum required for that particular situation and, on the other hand, which drains will fulfill these requirements. These problems are discussed in detail. This article provides baseline data for the different kinds of portable drains currently available and thus gives a background for rational decision making.

Strength of knots in surgery in relation to type of knot, type of suture material and dimension of suture thread.

The 12 commonest types of suture material in dimensions 7/0, 5/0, 000, 0 and 2 (USP, 1965) were tested in 16 types of knot with regard to tensile strength of knot using the loop method. The results are given in tabular form as the strength of the loop for alltypes of knot tested, and as the mean knoe efficiency for certain groups of knots. The knot efficiencies are compared with regard to the different types of knot, the various types of suture material, and the different dimensions of thread using statistical methods including variance analysis. The strength of unknotted thread within a given dimension showed considerable variations for different suture materials: a given material could be more than twice as strong as the weakest material of the same dimension. With very few exceptions, the knot was the weakest point in a suture loop subjected to disrupting forces. The knot efficiency depended very largely on the type of knot and the strength of different types of knots varied from 3% to 99% of the corresponding unknotted thread. With the exception of two types of steel thread and both types of catgut, the efficiency was low for most simple crossed knots and for many simple parallel knots, and here considerable variations were recorded. Knot efficiency was clearly highest and showed least fluctuation with complex and particularly complex knots, and was closely similar for these. The dependency of knot efficiency on the type of suture material (mean for 16 knots) varied from 44% (polyethylene) to 90% (multifil steel). The variations in dependency on material were greatest with simple knots and with certain materials, and decreased with increasing knot complexity. The dependency of knot efficiency on the dimension of any particular suture material was apparently of much less importance than the type of knot and type of material.

Tissue holding power to a single suture in different parts of the alimentary tract.

Figures for tissue strength are reported from an investigation on the tissue holding power to a single suture in 8 parts of the gut between oesophagus and rectum in 71 preparations from 44 individuals. 1749 experiments were done. Three layers were tested in each part of the gut. The mean holding power of sutures in the mucosa was 0.26-0.83 kp, for those in the seromuscular coat 1.03-2.24 kp, and for through-and-through sutures, 1.02-2.54 kp. Appreciable differences in tissue strength appear to exist between different parts of the alimentary tract. The lowest values were noted in the oesophagus and sigmoid, and the highest in the stomach and colon. Sutures through the whole gut wall were hardly any stronger than sutures in the sero-muscular coat. There was a significant difference in holding power in cancer compared with non-cancer cases. The holding power was considerably reduced in subjects with cancer in the alimentary tract. Knowledge of tissue strength in the gut may help to explain why anastomoses break down, and will provide a firmer basis for the choice of sufficiently strong suture material and knots with a view to preventing this complication.

Tissue strength of structures involved in musculo-aponeurotic layer sutures in laparotomy incisions.

Tissue strength to breaking point against the pulling forces of a suture was investigated in the musculo-aponeurotic layer of the six laparotomy incisions most commonly used in surgery, namely 1) mid-line incision, 2) paramedial incision, 3) pararectal incision, 4) transverse incision, 5) right oblique subcostal incision, and 6) McBurney's incision. When the suture length was 5 mm and the interval between sutures 10 mm, the mean tissue holding power was 1.9 kp for peritoneum and transversalis fascia together; 5.6 and 3.2 kp for longitudinal incisions through andinary sutures; and 22.9 kp for linea alba with sutures placed lateral to the transition between linea alba and rectus sheath. In comparison with these longitudinal incisions the tissue-holding power in corresponding tissues in transverse incisions was greater (c. 40% greater in the linea alba and anterior rectus sheath and c. 60% greater in the posterior rectus sheath). When regard was paid to the total closure strength of the musculo-aponeurotic layer, e.g. in paramedian incisions the sum of the figures for the anterior and posterior rectal sheaths, the paramedian incision was found to give the weakest closure, followed by the only slightly stronger pararectal incision. The strongest closure was obtained with the midline incision through the linea alba when the sutures were placed laterally to the transition between the linea alba and the rectus sheath. The values for holding power recorded for the musculo-aponeurotic layer may provide a rational basis for the choice of thread dimension and knot type in order to create a suture loop that will be at least as strong as the tissue.

Tensile strengths of twelve types of knot employed in surgery, using different suture materials.

When knotted loops of suture material were subjected to increasing tensile stress it was the knot that gave way in 710 of 720 experiments. The knot is thus the weakest point in the loop. A new code for describing knots useful in surgery has been worked out. The tensile strength of 12 different knots using twelve different suture materials with the dimension 3/0 (USP) was examined systematically. It was found that the efficiency of the knots varied depending upon the tensile strength of the material, 5% for the weakest and 99% for the strongest knot-material combination. Monofil and multifil steel threads were superior to other materials examined with regard to the knot strength. Chromic and plain catgut showed at least 50% of the tensile strength of the corresponding thread, irrespective of the type of knot. Silk was among the materials which gave the weakest knots. In principle, the more turns and throws the stronger the knot.

Mortality after laparotomy. A 10-year series.

The Department of Surgery at the University Hospital, Linköping has 133 beds and serves a population of 130000. During the 10-year period 1962-1971 35039 in-patient operations were performed, of which 16719 (48%) were laparotomies. If fracture surgery and urological operations are excluded (during the relevant period these specialties were included under General Surgery) the proportion of laparotomies becomes 67%. Of patients subjected to this procedure 431 (2.58%) died. The mortality for appendicectomy was 0.2%, for gall-bladder surgery 1.3%, for gastric surgery 8.1%, for colon surgery 11.9% for small-gut surgery (including ileus) 15.2%, and for pancreatic surgery 22.2%. Over and above the target organ, malignancy and age exceeding 50 years appear to have contributed greatly to a lethal outcome.

The strength of suture knots after one week in vivo.

The strength of knotted thread for 12 different types of suture knot in combination with 11 types of suture material used in surgery was investigated one week after insertion in subcutaneous tissue in rabbits. The results were compared with similar investigations on knot strength carried out with 'dry knots'. The thread dimension used in both experiments was 000 (USP). As in vitro, the weakest point of a suture loop subjected to traction was the knot. The incidence of thread rupture within the loop but outside the knot was 1.4% in vitro and 5.9% in vivo, and was commonest with plain catgut. With one exception, however, thread breakage occurred at greater strain than the average required to produce knot failure with the material in question. A greater proportion of knots slipped in vivo then in vitro (72% and 35% respectively), with reduction of the strength of the suture loop as result. There was also greater scatter of measured values under in vivo conditions (standard deviation: 11% in vitro, 23% in vivo). For 7 of 11 suture materials the results indicated a reduction in knot-holding power after one week in situ in the living animal compared with in vivo conditions. This was naturally enough most marked with the two types of catgut (chrome 48%, plain 57%). In contrast, Dexon apparently remained unchanged after one week in vivo. The non-absorbable materials tested showed an estimated average fall in knot-holding power from 100% to 88% (range 109-65%), viz, an average of 12% units. The loss of holding power in vivo was, however, apparently never greater than 1/3 compared with 'dry knots' and calculated on average for all types of knot with non-absorbable materials.

The strength of tissue against individual sutures in structures involved in the repair of inguinal hernia.

The strength of tissue against individual sutures in structures used in the repair of inguinal hernia was tested in situ in 19 cadavers. Altogether 465 measurements were made. Three different layers were investigated, and the mean tissue strength to a single suture was recorded as the mean of all means for each preparation and aspect as follows. (1) The superficial layer (external oblique aponeurosis). Superior aspect 5.3 kp, inferior aspect 5.5 kp. (2) Middle layer. Superior aspect (internal abdominal oblique), 5.9 kp; inferior aspect (inferior border of the inguinal ligament), 6.8 kp. (3) Deep layer. Superior aspect (transversalis fascia), 5.3 kp; inferior aspect (ilio-pubic tract), 6.9 kp. In Cooper's ligament the mean holding power of the tissue against a single suture was found to be 9.1 kp. The site of the most medial of the sutures in the superior aspect of the middle layer corresponds to the conjoined tendon, and the mean tissue strength to this suture was 11.0 kp. The findings thus suggest that the strengths of the tissues of the anterior and posterior walls of the inguinal canal are roughly equal. The structures making up the conjoined tendon and Cooper's ligament were strongest, however, and showed tissue strengths nearly twice those of other structures.

Relaparotomy. A ten-year series.

A review of the literature covering c. 158,000 laparotomies shows that acute relaparotomy has an incidence of 1.0% and a mortality rate of 43%. Over and above this, rupture of the abdominal wound, which illogically is often considered separately, occurs in 0.6% of all laparotomies and carries a mortality of 34% in the 179,000 laparotomies reviewed in this article. Our own series of 121 relaparotomies in 16,719 cases of laparotomy (an incidence of 0.72%, including burst abdomen) with a 28.1% mortality is discussed. Indications for relaparotomy have included haemorrhage (19%), ileus (25%), peritonitis (32%), wound rupture (22%), and other causes (2%).