Glutamine supplementation of parenteral nutrition in critically ill patients

The role of glutamine in critically ill patients is debatable. Canadian CPGs 2009 recommended that when TPN is prescribed to critically ill patients, parenteral nutrition supplemented with glutamine where available is strongly recommended. However, in a recent update (2013), the committee downgraded the recommendation for IV glutamine to "should be considered". They also strongly recommend that glutamine NOT be used in critically ill patients with multi-organ failure. There are also insufficient data to generate recommendations for intravenous glutamine in critically ill patients receiving enteral nutrition. Below is the 2013 discussion:
 

It was noted that with the addition of 11 new trials (Tian 2006, Zhang 2007  Ozgultekin 2008, Yang 2008, Eroglu 2009, Perez-Barcena 2010, Andrews 2011, Cekman 2011, Grau 2011, Wernerman 2011 & Ziegler 2012), there were weaker signals for a reduction in overall mortality and  infectious complications and yet a strong treatment effect of IV supplemented glutamine on hospital mortality and ICU and hospital length of stay remained. It was further noted that a few large scale multicenter randomized trials of IV glutamine had failed to demonstrate a convincing positive effect (Andrews 2011, Wernerman 2011, Ziegler 2012).

 

Recent important paper: REDOXs study by the Canadian Critical Care Trials Group. New Engl J Med, 2013, 368:1489-1497.

A Randomized Trial of Glutamine and Antioxidants in Critically Ill Patients. 

Background

Critically ill patients have considerable oxidative stress. Glutamine and antioxidant supplementation may offer therapeutic benefit, although current data are conflicting.

Methods

In this blinded 2-by-2 factorial trial, we randomly assigned 1223 critically ill adults in 40 intensive care units (ICUs) in Canada, the United States, and Europe who had multiorgan failure and were receiving mechanical ventilation to receive supplements of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and enterally. The primary outcome was 28-day mortality. Because of the interim-analysis plan, a P value of less than 0.044 at the final analysis was considered to indicate statistical significance.

Results

There was a trend toward increased mortality at 28 days among patients who received glutamine as compared with those who did not receive glutamine (32.4% vs. 27.2%; adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P=0.05). In-hospital mortality and mortality at 6 months were significantly higher among those who received glutamine than among those who did not. Glutamine had no effect on rates of organ failure or infectious complications. Antioxidants had no effect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P=0.83).

Conclusions

Early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality among critically ill patients with multiorgan failure.

 

 Comment: Possible reasons for the different results to previous studies offered by the authors include;

 

1. In this study, combined  enteral and parenteral high doses of glutamine were used in critically ill patients with multi-organ failure. Other studies excluded this group of patients.

2. However, it was felt that the results of this 1223 patient multicentre trial, which suggested a significant safety concern, could not be ignored.

3. Previous studies were smaller and less methodologically robust.

4. The treatment was initiated within 24-hours ICU admission, while other studies used it later.

5. Most patients in this study were enterally fed, other studies they were mainly parenteral nutrition.

 

In summary it appears in ventilated patients with shock/multi-organ dysfunction, the use of early antioxidants is of no benefit, and glutamine may be harmful. Is that enough to close the book on this?

I totally agree with this, since in managing our ICU patients, most of our patients will have more than 2 organ failure and  those with MOF are the ones who carry high mortality. I am not keen to supplement my patients with glutamine either enterally or parenterally.

 

                                                                      xoxoxoxoxoxoxo

 

The earlier study of interest was published in BMJ in 2011 by Andrews et al i.e. SIGNET trial (Scottish Intensive care Glutamine or seleNium Evaluative Trial).

Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients

 

Objective To determine whether inclusion of glutamine, selenium, or both in a standard isonitrogenous, isocaloric preparation of parenteral nutrition influenced new infections and mortality among critically ill patients.

 

Design Randomised, double blinded, factorial, controlled trial.

Setting Level 2 and 3 (or combined) critical care units in Scotland. All 22 units were invited, and 10 participated.

Participants 502 adults in intensive care units and high dependency units for ≥48 hours, with gastrointestinal failure and requiring parenteral nutrition.

Interventions Parenteral glutamine (20.2 g/day) or selenium (500 μg/day), or both, for up to seven days.

Main outcome measures Primary outcomes were participants with new infections in the first 14 days and mortality. An intention to treat analysis and a prespecified analysis of patients who received ≥5 days of the trial intervention are presented. Secondary outcomes included critical care unit and acute hospital lengths of stay, days of antibiotic use, and modified SOFA (Sepsis-related Organ Failure Assessment) score.

Results Selenium supplementation did not significantly affect patients developing a new infection (126/251 v 139/251, odds ratio 0.81 (95% CI 0.57 to 1.15)), except for those who had received ≥5 days of supplementation (odds ratio 0.53 (0.30 to 0.93)). There was no overall effect of glutamine on new infections (134/250 v 131/252, odds ratio 1.07 (0.75 to 1.53)), even if patients received ≥5 days of supplementation (odds ratio 0.99 (0.56 to 1.75)). Six month mortality was not significantly different for selenium (107/251 v 114/251, odds ratio 0.89 (0.62 to 1.29)) or glutamine (115/250 v 106/252, 1.18 (0.82 to 1.70)). Length of stay, days of antibiotic use, and modified SOFA score were not significantly affected by selenium or glutamine supplementation.

Conclusions The primary (intention to treat) analysis showed no effect on new infections or on mortality when parenteral nutrition was supplemented with glutamine or selenium. Patients who received parenteral nutrition supplemented with selenium for ≥5 days did show a reduction in new infections. This finding requires confirmation.

 

 

 

 

Glutamine and Arginine supplementation of enteral feeding in critically ill patients

A variety of enteral feeding formulations were developed for patients with critical illnesses. To the best of our knowledge, no such formulation demonstrated a beneficial effect on clinical outcomes. As a result, disease specific enteral formulation is not recommended over the traditional types of enteral nutrition. However, the enteral nutrition enriched with omega-3 fatty acids may be beneficial to patients with ARDS.

 

Glutamine

Glutamine is a precursor for nucleotide synthesis and an important fuel source for rapidly dividing cells that is rapidly depleted in hypercatabolic patients.

It is nonessential amino acid that can be synthesized from glutamate and glutamic acid by glutamate ammonia ligase. Glutamine is an important fuel source for the small intestine. It was proposed that glutamine is necessary for the maintenance of normal intestinal morphology and function in the absence of luminal nutritients. It was suggested that both glutamine supplemented parenteral and enteral nutrition may prevent bacterial translocation via preservation and augmentation of small bowel villus morphology, intestinal permeability and intestinal immune function. However, it is unclear whether clinically relevant bacterial translocation even occurs in humans, much less whether there is any value in the prevention of such occurrences.

 

Glutamine supplementation of enteral nutrition has been evaluated in more than 30 controlled trials with critically ill patients, most of which had significant methodologic problems or were too small to make definitive conclusions.

Meta-analyses of RCTs that compared enteral nutrition with and without glutamine, there was no difference in mortality or infectious complications. In a recent update (2013), the absence of mortality benefit persisted among patients who received glutamine enriched enteral nutrition (www.criticalcarenutrition.com).

 

Based on 2 level 1 and 7 level 2 studies, enteral glutamine should be considered in burn and trauma patients. There are insufficient data to support glutamine enriched enteral nutrition for routine use in most critically ill patients because clinical trials have not found consistent improvement in clinical outcomes.(Canadian Clinical Practice Guidelines 2013). Given the harm associated with glutamine in patients with multi-organ failure, it is considered unsafe to administer EN glutamine even in burns/trauma patients with MOF (REDOXs trial). There for the CPG strongly against any glutamine to be used in critically ill patients with multi-organ failure.

Glutamine is metabolized by the liver, kidneys and splanchnic tissue into glutamate and ammonia. Accumulation of glutamine and its byproducts may lead to adverse effects such as encephalopathy.

 

 

Arginine

Arginine is considered conditionally essential during critical illness because it is utilized more quickly. It is required for normal immune function and healing. It has improtant roles in nitrogen metabolism, ammonia metabolism and generation of NO. Despite this, aginine enriched enteral nurtition is NOT recommended for routine use in critically ill patients because clinical outcomes have been inconsistent.

Meta-analyses that compared arginine enriched enteral nurtition to standard enteral nutrition in crtically ill patients found no effect on mortality and no effect on infectious complications. These results persisted in the recent update www.criticalcarenutrition.com. Based on 4 level 1 studies and 22 level 2 studies, diet supplemented with arginine and other select nutrients are not recommended to be used for critically ill patients.
Some studies suggested that arginine enriched enteral nutrition was potentially harmful (JPEN 2001).

 

 

 

 

Platelet dysfunction in Uremia

In ICU, sometimes we have to refer our critically ill patients for surgical tracheostomy. The majority of these patients is suffering from MODS which include acute kidney injury. Very often, the level of urea varies from day to day, and also related to the frequency of dialysis in ICU. This is where we have a problem, since quite often the ENT surgeons request for a single digit of urea level. Their concern is bleeding associated with renal failure. Many times the procedure is delayed due to this request. This is what I read from uptodate.com:

The association between renal failure and bleeding was recognized more than 200 years ago. Impaired platelet function is one of the main determinants of uremic bleeding.

Clinical and Lab manifestations

1. Bleeding may involve the skin, oral and nasal mucosa, gingiva, gastrointestinal, urinary tracts and respiratory system. Excessive bleeding may also occur in response to injury or invasive procedures.

2. Although an association between bleeding time prolongation and uremia has long been suggested, there are no good studies demonstrating an increase risk of either spontaneous bleeding or bleeding with a procedure that is associated with prolonged bleeding time among patients with chronic kidney disease.

3. Degree of azotemia (elevation of BUN or creatinine) does not correlate with bleeding risk.

4. Patients may display increased sensitivity to aspirin. The platelet count is usually normal. Generally  levels of circulating coagulation factors are normal and there is no prolongation of the PT or APTT unless there is coexisting coagulopathy.

Pathogenesis - the cause of uremic bleeding is multifactorial.

Causes of platelet impairment include intrinsic platelet defects, abnormal platelet-endothelial interaction, uremic toxins and anemia.

1. The most important factor is platelet dysfunction which is due to decreased platelet aggregation and impaired platelet adhesiveness.Contributing factors extrinsic to platelets include the action of uremic toxins, anemia, increased NO production, von Willebrand factor abormalities, decreased platelet production and abnormal interaction between the platelet and the endothelium of the vessel wall.

2. Uremic toxins:

Consistent with this postulate is the observation that mixing uremic plasma with normal platelets impairs platelet function. However urea is not the major platelet toxin and there is no predictable correlation between the BUN and the bleeding time in patients with renal failure. The addition of urea, guanidinoacetic acid or creatinine to the plasma did not affect platelet function. High levels of guanidinosuccinic acid and methylguanidine have been suggested as potential contributors to uremic platelet dysfunction, likely through simulation of NO production.

3. Anemia

Is common in patients with CKD and is primarily due to decreased renal erythropoietin production. Correction of anemia with blood transfusions or erythopoietic stimulating agents often improves platelet dysfunction. It has been proposed that rheologic factors play an important role in the overall relationship between anemia and platelet function.

4. Nitric oxide

NO is an inhibitor of platelet aggregation that is produced by endothelial cells and platelets. Studies have shown that platelet NO synthesis is increased, may be due to elevated levels of guanidinosuccinic acid (uremic toxin).

Treatment:

No specific therapy is required in patients without bleeding even in the setting of severe azotemia. Correction of platelet dysfunction is warranted in patients who are actively bleeding or who are about to undergo a surgical procedure. It is important to identify any sources of bleeding.

 

A number of modalities to improve platelet function and reduce bleeding, which vary in their onset and duration of action.

 

1. Dialysis:

Hemodialysis can partially correct the bleeding in about two thirds of uremic patients. It should be done without systemic anticoagulation.

2. Desmopressin

It is the simplest and most rapidly acting of acute treatment for platelet dysfunction in uremic patient. dDAVP is effective in at least one-half of patients and appears to act by increasing the release of large factor VIII: von Willebrand factor multimers from endothelial cells. Other factors may include increases in platelet membrane glycoprotein expression. dDAVP can be given intravenously at a dose of 0.3 mcg/kg (in 50 ml of saline over 15 to 30 minutes if IV) or 3 mcg/kg if intranasally. The improvement in bleeding time begins within one hour and lasts 4 to 8 hours. Tachyphylaxis typically develops after the second dose, perhaps due to depletion of endothelial stores of the factor VIII: von Willebrand factor multimers. Reduced urine volume and hyponatremia may occur in patients who have urine output.

 

3. Correction of anemia

Raising the Hb to about 10g/dL or higher will reduce the bleeding time in many patients, occasionally to a normal level. This can be achieved by RC transfusions or via administration of recombinant erytrhopoietic stimulating agents (ESAs). The improvement in platelet function persists for as long as the Hb remains elevated. ESAs may also have a direct beneficial effect on platelet function.

4. Estrogen
Most chronic control of bleeding can be achieved in many uremic patients by the administration of conjugated estrogens. The long term use is limited by estrogen related side effects. The mechanism is not well understood but may be due to decreased generation of NO.

5. Cryoprecipitate
The infusion of cryoprecipitate (10 units intravenously every 12 - 24 hours) can shorten the bleeding time in many uremic patients. The improvement in BT begins within one hour and lasts 4-24 hours;  it is presumably mediated by the presence in cryoprecipitate of a substance that enhances platelet aggregation, such as factor VIII: von Willibrand factor multimers. The potential risk of infectious complications of this modality limit its use to patients with life threatening bleeding who are resistant to treatment with dDAVP and blood transfusions.

In my opinion, the surgeons (esp ENT surgeon in my case) should understand about the multifactoral causes of platelet dysfunction in uremia. There is no correlation in between the  value of BUN and the risk of bleeding. If the patient is on regular dialysis, have a good Hb and no evidence of spontaneous bleeding there are no reasons to postpone the tracheostomy. If intermittent HD is done, anticoagulation should be avoided especially after the procedure. I should do more PDT in my ICU to overcome this problem.

 

D-dimer in diagnosing of PE

There were five trauma cases this morning in the ICU. The ICU 2 was admitted during the weekend. Another polytrauma case (without TBI), who developed acute respiratory failure and required ventilatory support. The injuries are fracture  right ribs from 2nd to 5th, lung contusion, open book fracture and fracture femur. The C-spine was cleared clinically. There were bilateral pulmonary infiltrates on both sides of the lungs. He has moderate increased in A-a gradient. I start to go thru few differential diagnoses in my mind which include fat embolism syndrome, PE, aspiration pneumonia, worsening lung contusions and finally TRALI. Suddenly I was distracted by the MO's comment: Since the D-dimer was positive, this patient has been treated for pulmonary embolism and 'they' have started him on fondaparinux...I asked, what was the next plan? She said, the orthopedic team is planning for ILN once this patient is more 'stable'..Actually, I raised few issues, first of all the safety of fondaparinux in this pelvic injury and secondly since when D-dimer was used as a confirmatory test for PE??

"D-dimer assays for the diagnosis of PE have been extensively studied. They are best characterized as having good sensitivity and negative predictive value but poor specificity and positive predictive value."

Sensitivity: D-dimer levels are abnormal in about 95% of all patients with PE when measured by ELISA, quantitative rapid ELISA or semi-quantitative rapid ELISA. This falls to about 90% when measured by qualitative rapid ELISA or quantitative latex agglutination, 86% measured by semiquantitative latex agglutination and 82% measured by erythrocyte agglutination. Among patients who have subsegmental PE, d-dimer levels are abnormal in only 50% when measured by quantitative latex agglutination.

Specificity: D-dimer levels are normal in only 40-68% of patients without PE, regardless of the assay used. This is a consequence of abnormal D-dimer levels being common among hospitalized patients, especially those with malignancy or recent surgery. The specificity decreases even further in the setting of severe renal dysfunction and increased patient age.

NPV: The ability of a normal or negative D-dimer assay to exclude acute PE  depends on both the type of D-dimer assay and the clinical pretest probability that a patient has acute PE.

Taken together, the evidence indicates that a D-dimer level less than 500ng/ml by quantitative ELISA or semiquantitative latex agglutination is sufficient to exclude PE in patients with a low or moderate pretest probability of PE.
source: uptodate.com



 

BLUNT AORTIC INJURY

Today, during the morning handover, there was a polytrauma case. Very interesting, since he has thoracic aorta dissection,, open book fracture of pelvis, liver laceration and fracture femur. Another striking findings were rhabdomyolysis and acute kidney injury. This is a very interesting case since there are a few possible causes of acute kidney injury which include hypovolemia, contrast induced nephropathy, rhabdomyolisis, and trauma to the genitourinary tract.

I asked the MO, was the dissection due to blunt aortic injury?? Well, she didn't have a clue.

Blunt aortic injury usually occur at the junction between the mobile arch and the fixed descending aorta, just distal to the origin of the left subclavian artery, as a result of severe deceleration injury. Less frequently, the ascending aorta or arch vessels are injured by direct trauma.

It is divided into two:
1. Significant aortic injury: with disruption of the intima and full thickness of the media. There is a high risk of rupture

2. Minimal aortic injury: with laceration limited to the intima and inner media.  Radiologically this manifests as an intimal flap< 1 cm with minimal periaortic hematoma. There is a low risk of rupture

Clinical signs include unequal upper limb pulses, pseudocoarctation or interscapular murmur. The aortic injury should be suspected if the mechanism of injury is suggestive of rapid deceleration such as high speed (greater than 90 km/hr) motor vehicle or motorcycle crashes or a pedestrian hit by a vehicle.
CT and transesophageal echocardiography have been used for screening and diagnostic purposes.
Limitation of TOE : it provides high diagnostic accuracy for aortic injury and also allows examination for blunt cardiac injury. Imaging of distal aorta, proximal arch and major branches are limited.

Chest radiograph signs of blunt aortic injury:
1. Signs of periaortic hematoma:
-Widened mediastinum > 8 cm at the level of aortic knuckle
-Obscured aortic knuckle
-Opacification of aortopulmonary window
-Deviation of trachea, left main bronchus or nasogastric tube
-Thickened paratracheal stripe

2. Indirect signs:
-left haemothorax
-Left pleural cap
-Fractured first or second ribs


Significant aortic injury requires prompt surgical or endoluminal stent repair. Surgery should be deferred sometimes indefinitely if severe associated injuries or comorbidities make the operative risk unacceptably high.
Options for surgery: direct repair (clamp and sew), endoluminal stent repair.
Conservative management includes antihypertensive therapy (B-blockers +/- vasodilators) and serial imaging to assess for expanding pseudoaneurysm that will require intervention.

reference: Oh's intensive care manual 5th edition pg 794













 

Tumor Lysis Syndrome

It is caused by massive lysis of malignant cells and leads to release of large amounts of potassium, phosphate and uric acid into the systemic circulation with secondary hypocalcemia. Acute kidney injury can result from precipitation of uric acid and/or calcium phosphate in the renal tubules.

Most commonly encountered after initial chemotherapy for

a) High grade lymphomas (particularly Burkitt subtype)

b) Acute lymphoblastic leukemia (mature B cell acute lymphoblastic leukemia)

c) May occur spontaneously in high grade lymphoma or ALL

d) May occur in other tumor types with a high proliferative rate, large tumor burden or high sensitivity to cytotoxic therapy.

Diagnosis: Cairo-Bishop Definition of TLS

Laboratory tumor lysis syndrome is defined as any 2 or more of the following metablic abnormalities and presents within 3 days before or 7 days after instituting chemotherapy.

a) Uric acid > 476 micromol/L or 25% increase from baseline

b) Potassium > 6 mmol/L or 25% increase from baseline

c) Phosphate > 1.45 mmol/L in adults (> 2.1 in children) or 25% increase from baseline

d) Calcium < 1.75 mmol/L or 25% decrease from baseline

Clinical TLS: is defined as laboratory TLS plus one or more of the following that was not directly or probably attributable to a therapeutic agent

a) Increased serum creatinine > 1.5 from the upper limit normal

b) Cardiac arrythmias/sudden death

c) Seizure

Treatment

Best management is prevention
 

1. Key components are

a) Aggressive fluid hydration prior to therapy in all patients at intermediat or high risk for TLS. Children and adult should initally receive 2 to 3 L/m2 per day of IV fluid (or 200ml/kg per day in children weighing less than 10 kg). Urine output should be monitored closely and maintained within a range of 80 to 100 ml/m2 per hour (2 ml/kg for both children and adults, 4-6ml/kg in children less than 10 kg). Diuretics can be used to maintain the urine output, if necessary but should not be required in patients with relatively normal renal and cardiac function.
 

b) Diuresis
 

c) Administration of hypouricemic agents

Purine catabolism results in the production of hypoxanthine and xanthine which are metabolized to uric acid via the enzymatic action of xanthine oxidase. Allopurinol inhibits xanthine oxidase: blocking  hypoxanthine and xanthine to uric acid. After two to three days, allopurinol therapy results in increased excretion of both hypoxanthine which is more soluble than uric acid and xanthine which is less soluble than uric acid. A marked increase in xanthine excretion can occur when allopurinol is given for prevention of TLS and may lead to acute renal failure or xanthine stones. Allopurinol does not reduce the serum uric acid concentration before treatment is initiated. Thus for patients with pre-existing hyperuricemia, rasburicase is the preferred hypouricemic agent. Urate oxidase (which in not present in human) oxidizes preformed uric acid to allantoin which is 5 to 10 times more soluble than uric acidin acid urine. When exogenous urate oxidase (rasburicase) is administered, serum and urinary uric acid levels decrease markedly within approximtely four hours.

 

d) Urinary alkalinazion: generally not recommended. Benefit in increasing uric acid excretion is unproven. Potential harms, particularly in the setting of hyperphosphatemia.

e) Indications for dialysis are oliguria, persistent hyperuricemia, hyperphosphatemia and hypocalcemia.

Indications for renal replacement therapy include:

-Severe oliguria and anuria

-Persistent hyperkalemia

-Hyperphosphatemia induced symptomatic hypocalcemia

PERCUTANEOUS TRACHEOSTOMY

Important summary of my presentation:

Since Ciaglia et al. described the percutaneous dilatational tracheostomy (PDT) in 1985, PDT has gained popularity over surgical  tracheostomy in the intensive care setting. Percutaneous tracheostomy (PCT) requires less time to perform, it is less expensive and it is typically performed sooner (because an operating room does not have to be scheduled).  In a meta-analysis of 17 randomized control trials, PDT offers several advantages such as decreased wound infections, decreased bleeding and mortality compared to surgical technique. Indications for PCT are the same as those for standard open tracheostomy. Established contraindications against PCT are unstable fractures of cervical spine, severe local infection of anterior neck and uncontrolled coagulopathy. Relative contraindications are high PEEP or oxygen requirements, difficult anatomy, proximity to extensive burns or surgical wounds, elevated intracranial pressure, haemodynamic instability and previous radiotherapy to the neck.  In experienced hands, PDT seems to be a safe procedure. The number of relative contraindications to PDT declines with increasing operator experience. Overweight patients have a five times higher risk of perioperative complications with PDT than normal weight patients.

Percutaneous tracheostomy using the dilator (or Ciaglia) technique is superior to other percutaneous approaches including the single-forceps (Griggs) technique. Several commercial kits are available for PDT. Eventhough procedure differs slightly with choice of kit, the basic steps remain common. No strong evidence supports one specific kit or technique. To minimize complications, it is recommended that each institution chooses one kit and gain familiarity to appreciate its advantages and drawbacks. With bronchoscope guidance, the operator can ascertain correct tracheostomy site, intratracheal guidewire placement, intratracheal dilator placement without tracheal damage, proper partial withdrawal of the endotracheal tube and placement of tracheostomy tube. If ultrasound machine is available, a skilled operator can evaluate the anatomy of major vessels and the thyroid gland in relation to tracheostomy site. It helps in localize the level of tracheal rings and indentify midline puncture, depth etc. Following PDT, a routine chest radiograph is probably unnecessary, provided the procedure had been uncomplicated. In a retrospective review of 60 patients undergoing tracheostomy with bronchoscopic guidance, a post-procedure chest radiograph was only useful in detecting complications following procedures deemed difficult by and experienced operator.

 

Vancomycin in ICU

I am writing this today because someone is confused on prescribing vancomycin in critically ill patients. I hope this comment is useful, at least for my revision.

 

Vancomycin is a glycopeptide antibiotic, used for suspected or proven gram-positive infections.  Vancomycin's primary route of elimination is by renal excretion of unchanged drug. The rate of elimination is directly related to creatinine clearance.

 

The rate of killing depends primarily on time of concentration exceeding the organism's MIC (concentration dependent with time dependence). The ratio of area under the time concentration curve  during a 24 hour period to MIC(AUC0-24h/MIC ratio) is the best predictor of efficacy in this model.

Adverse effects:

1. Red man syndrome: is anaphylactoid reaction during or immediately following rapid infusion of large doses of vancomycin. Flushing usually involves face and neck, but can affect the whole body. It may be eliminated by avoiding massive doses and prolonging the infusion time e.g. no more than 500mg/hour or a maximum of 15 mg/min should prevent most infusion related reactions.

2. Nephrotoxicity: in monotherapy is not fully understood since early preparations were associated with nephrotoxicity. Only 20 cases reported in the medical literature in the years 1956-1984 despite the incessant use. Most of these cases were complicated by concomitant aminoglycoside therapy and pre-existing renal problems as well as investigator discrepancies in interpreting serum levels. Renal insufficiency due to vancomycin administered concomitantly with an aminoglycosides is well established. The incidence of acute renal failure in this setting may be as high as 20 to 30 percent.

3. Ototoxicity: has been described but it is the incidence is < 2%. Only approximately 40 cases of oto- and nephrotoxicity were reported in medical literature in the years 1956-1984.

Dosing

Vancomycin doses of 15 to 20 mg/kg should be administered q12h in patients with normal renal function, not to exceed 2g per dose. In settings where rapid clearance is anticipated, the intervals may be increased to q8h. For rapid achievement of target concentrations in seriously ill patients, a loading dose of 25 to 30 mg/kg may be administered. This may be appropriate for patients with critical illness in the setting of high anticipated Vd (e.g. burns, fluid overload).

 

Vancomycin dosing is based on actual BW (even in the setting of obesity), and doses are rounded to the nearest 250 mg. In general, the drug should b infused over 0.5 hours for each 500mg increment (e.g. 500mg over 0.5 hours, 1g over 1 hour etc). In the setting of the red man syndrome, the rate of infusion may be reduced to 500mg over 1 hour.

 

In recent RCT of continuous infusion regimens have not shown substantial improvement in patient outcomes compared with intermittent dosing.

 

In obesity, to avoid individual doses greater than 2g, the total daily dse can be divided into 3 administrations (q8h). In patients with renal insufficiency, doses in the range of 15-20mg/kg (based on target trough concentration) rounded to the nearest 250mg should be administered at frequencies based on estimations of creatinine clearance.

 

Serum concentration monitoring

Troughs versus peaks: Trough concentrations are useful as surrogate to AUC and are generally considered the most accurate and practical method to monitor vancomycin. Therefore, optimal dosing is guided by knowledge of both susceptibility and trough concentration.

There is little role for the routine monitoring of peak vancomycin concentrations, given the concentration independent pd properties and lack of data correlating peak concentrations with either efficacy or toxicity. IDSA 2005 guidelines for endocarditis endorsed target peak of 30-45 mcg/ml, the opinion was based on animal models and invitro susceptibility data rather than clinical evidence.

 

Target trough

At least 10 mcg/ml, may reduce emergence of isolates with elevated MIC. In the setting of invasive infections (e.g. bacteremia, endocarditis, osteomyelitis, prosthetic joint infections, HAP, infections of CNS) aim trough of 15-20 mcg/ml. Such concentrations generally achieve an AUC/MIC of > 400 for isolates with vancomycin MIC < 1. If MIC is > 2 mg/ml, alternate therapies should be considered.

 

Timing of levels: trough concentrations should be measured within 30 minutes prior to infusion of the fourth or fifth dose following the inital dose or dose adjustment. Trough concentration monitoring should be performed in patients receiving vancomycin therapy longer than 3 days. Once target concentrations are achieved, the trough should be monitored at least weekly for patients who receive longer therapy.

Serum creatinine concentration should be determined daily until stable,the weekly. More intensive monitoring may be considered if renal function unstable, if nephrotoxic drugs are administered concomitantly.

For patients on RRT via the newer, more permeable high flux membranes, repeat vancomycin is often required following each session. Many favour supplemental doses of at least 500 mg following each hemodialysis session.

Whenever practical, serum concentrations assessed immediately prior to hemodialysis may be used to guide subsequent dosing.

 

Pulmonary Disease in Chronic Liver Failure

Portal hypertension is responsible for:
1. Gastrointestinal bleeding
2. Ascites
3. Portosystemic encephalopathy
4. Hepato-renal syndrome
5. Pulmonary disease:
    a. Hepato-pulmonary syndrome
    b. Porto-pulmonary hypertension

A. Hepatopulmonary syndrome
It is characterized by:
i. Portal hypertension (with or without cirrhosis)
ii. Hypoxaemia (A-a gradient > 15 mmHg on room air)
iii. Evidence of pulmonary vascular dilatation

Diagnosis: Contrast enhanced echocardiography demonstrates delayed  visualization of microbubbles (more than 3 cardiac cycles) into the left heart of injected agitated saline bubbles intravenously. This suggests intrapulmonary shunt, whereas immediate visualization would suggest intracardiac shunting.

Treatment: Oxygen therapy, exclusion of other causes of hypoxaemia (shunt) and liver transplant

B. Portopulmonary hypertension

It is characterized by:
i. Portal hypertension
ii. PCWP < 15 mmHg
iii. Pulmonary hypertension (mPAP > 25 mmHg at rest)
iv. Pulmonary vascular resistance > 120 dynes per m-5 (3 Woods units)

Diagnosis: Right heart catheterization with measurement of PAP is the 'gold standard for diagnosis.

Treatment is a liver transplant (LT). In appropriately selected subjects, LT can effectively treat all the complacations of endstage CLD. LT can be determined by calculation of the model for end-stage liver disease (MELD) score. It is contraindicated in severe pulmonary hypertension (mPAP > 50 mmHg) but can be considered in those who respond to treatment with oral or IV vasodilator therapy.

Reference: Manual of Intensive Care by Irwin and Rippe.

Questions: Forty year old man with history of hepatitis C presents with dyspnoea. On examination he is jaundiced, with spider naevi and ascites. Chest X-Ray and spirometry are normal. Pulse oximetry is performed: Standing 88% and Supine 97%. (From data interpretation in critical care medicine)

1. What is the likely diagnosis?
     Answer: Hepatopulmonary syndrome in end-stage Hep C cirrhosis.

2. What is the postulated pathophysiological mechanisms?
     Answer: Intrapulmonary vasodilation with right to left shunting. The process affects mainly the bases. Changes in posture that increase basal pulmonary blood flow (upright position) worsen gas exchange.

Orthodeoxia is hypoxaemia accentuated in the upright position.
Platypnoea is increased dyspnoea in upright position, improved by assuming the recumbent position. Causes are: a. Intracardiac shunts (intra-atrial shunt) with or without lung disease and b. Pulmonary vascular shunts (pulmonary artery-pulmonary vein communications) either anatomical or parenchymal.

3. What further investigation is indicated?
     Answer: see above

4. Is liver transplantation likely to help?
    Answer: Yes, over 80% of patients with hepatopulmonary syndrome have resolution or marked improvement in intrapulmonary vasodilatation with LT. This contrasts with portopulmonary hypertension which is considered a contraindication (see comment above).




 

stroke- imaging

A 55 year old man presented to the department of emergency medicine after developing right sided weakness and inability to speak. He has a history of hypertension on ACEI.

Q1: List CT head abnormalities seen in an acute ischemic stroke.
A:
1. Hyperdensity within an intracranial vessel owing to intraluminal thrombus.
2. Parenchymal hypoattenuation owing to cytotoxic oedema. Hypoattenuation on CT is highly specific for irreversible ischemic brain damage.
 3. Obscuration of gray white matter contrast and effacement of sulci owing to edema
 4. Insular ribbon sign. Hypodensity and swelling of insular cortex. Located between the Sylvian fissure and the basal ganglia, it is supplied by small perforating branches of the MCA.
5. Obscuration of the lentiform nucleus. Also called blurred basal ganglia - early and frequent sign in MCA infarction.

Q2: List the abnormalities you might expect to see in an MRI done in a patient with an acute ischaemic stroke.
Answer:

1. Subtle low signal (hypointense) on T1 - often difficult to see at this stage
2. High signal (hyperintense) on T2 - comparable to hypodensity on CT
3. High intensity on DWI - the most sensitive sequence for stroke imaging. DWI sensitive to restriction of Brownian motion of extracellular water due to imbalance caused by cytotoxic edema.

Reduction in the ADC. DWI is sensitive to the microscopic random motion of the water molecule protons, a value known as the apparent diffusion coefficient (ADC), which is measured and captured by this type of imaging. ADC maps allow us to assess the extent of ischaemic disease. Measuring the ADC allows us to get an idea about the depth of ischemia in the penumbra itself and to obtain data regarding tissue viability.

MRI is commonly used method for assessment of the ischemic core and penumbra. The diffusion weight MRI (DWI) lesion is generally assumed to reflect the ischemic infarct, whereas the PWI perfusion weighted MRI (PWI) which uses gadolinium contrast lesion includes both infarct and penumbra hence the potential for perfusion mismatch.

DATA interpretation on coagulation

A 44 year old man presents with dyspnoea and is diagnosed as having multiple pulmonary emboli on CTPA. He is commenced on heparin 1000 units/hr after a 5000 unit bolus. During the night his heparin has increased to 1500 units/hr. The blood results are from the next morning:

PT 12, APTT 38.3
Fibrinogen 3.8g/L
D-dimer (latex immunoassay) > 20.0 mgh/ml (normal < 0.5)

1. Give two reasons for the low APTT despite heparin
2. List causes for an increased predisposition to venous thromboembolic disease?

Answer 1
Inadequate heparinisation, AT-III deficiency, increased heparin clearance, increased heparin binding proteins

Note: Heparin resistance is a term used to describe patients who require unusually high doses of heparin (>35,000u/day), and can be attributable to antithrombin deficiency, increased heparin clearance, elevation in heparin-binding proteins, elevation in factor VIII, and elevation of fibrinogen.
Heparin protocols are more effective in achieving goal in anticoagulation than ad hoc approach.

Heparin is a natural gycosaminoglycan that is extracted from procine intestinal mucosa. Intravenous administration results in immediate onset of action with t1/2 of 60secs-90 minutes. Liver and renal disease results in prolonged t1/2. When heparin combine with antithrombin III (heparin cofactor), thrombosis is blocked through inactivation of activated factor II, IX, X, XI and XII. Heparin also binds to platelets, both inhibiting and promoting their function.
Coagulation test findings: increased APTT, mildly increased PT, increased TCT, normal protamine corrected APTT test, normal reptilase time
TCT: thrombin clotting time -   test of the traditional final common pathway of the coagulation cascade which converts fibrinogen to fibrin.
Reptilase time - assist with the differentiation of causes of an increased TCT. Reptilase is a thrombin -like molecule that converts fibrinogen to fibrin but is not inhibited by antithrombin III.
Protamine corrected APTT: the APTT after protamin is added to the patient's blood.


Answer 2
1. anti-thrombin III deficiency
2. protein C and S deficiency
3. Factor V Leiden gene mutation
4. Lupus anticoagulation and anti-cardiolipin
5. malignancy
6. hyperhomocysteinemia

QUESTION 2

A 54 year old man post CABG is bleeding briskly into the chest drains
INR 1.4, PT 16, APTT 55, TT 17, fibrinogen 1.2 and Platelet 65

1. How would you correct this man's coagulation?
Answer: The TT is normal, so coagulopathy is not due to heparin. Consumptive or dilutional coagulopathy and needs platelets, FFP, and cryoprecipitate.

QUESTION 3

A 24 year old woman has the following haematology and coagulation profile post admission to ICU after post partum haemorrhage.
WCC 5.6, Hb 6g/dL, Platelts 30, PT 30.6, APTT > 150, fibrinogen 0.8, D-Dimer > 10 (normal < 0.4)
1. What is the likely cause of these abnormalities?
Answer: DIC
2. In this context list 3 likely causes of this coagulation profile
-preeclampsia, AF embolism, sepsis
-intrauterine fetal death
-massive or mismatched transfusion
3. What does an elevated D-dimer indicate?
Answer: Tests fibrinolysis (breakdown of the X linked fibrin)

QUESTION 4

A 54 year old woman presented to the ED after having been unwell for 4 days. Her FBC report is:
Hb 12.8 g/dL, WBC 56.5, Platelet 347, Hct 41.4%
Neutrophil 96.3%
Lymphocyte 2.8%
Mono 0.7%, Eosin 0.1%, Baso 0.1%
Moderate rouleaux. Marked neutrophilia. Dohle bodies present, toxic granulation present.
1. What likely hematological process is revealed by the abnormal white cell count?
Answer: Acute leukemoid reaction.
-> 50,000 cells, normal baso and eosinophil counts, Dohle bodies, toxic granulation

another DKA patient

Last week, I received a call from my specialist about a man who was admitted 24 hours ago with diabetic ketoacidosis. His metabolic acidosis was severe, pH 6.9 and given bicarbonate therapy. His ketoacidosis improved with insulin therapy but his amylase level was increased. Because of possible acute pancreatitis, I admitted him to ICU for observation.
I reviewed him later in the ICU and noticed that his ABG on admission still showed AG metabolic acidosis (and require insulin for ketoacidosis) but in general he was improving. His Ranson score for initial 24 hours was only 1 and within 48 hours score was less than one. No significant finding on US abdomen/hepatobiliary, but CT scan was not done. He was discharged well the following day.

Comment:
The most common precipitating causes for DKA and HHS are infection and discontinuation of or inadequate insulin therapy. Others are acute illnesses such as CVA, MI and acute pancreatitis. Sometimes I used the pneumonic I GET SMASHED to go through the possible precipitating events.

Serum amylase and lipase are the standard tests to diagnose acute pancreatitis, but are often elevated in patients with DKA who do not have pancreatitis. As a result, the diagnosis of pancreatitis in patients with DKA should be based upon clinical findings and CT scan.  The mechanisms for hyperamylasemia and hyperlipasemia in DKA are not well defined, but the following observations have been made:
1. In 100 consecutive cases of DKA, 11 had acute pancreatitis as confirmed by CT scan. The most common causes were hypertriglyceridemia and alcohol intake. 2 did not have abdominal pain. (Am J gastroenterol 2000)
2. In a review of 134 consecutive episodes of DKA in patients with no CT evidence of acute pancreatitis, elevations of serum amylase and lipase ( 3x or higher) were seen in 17 and 24% respectively. Abdominal pain was present in 19% of the series. (Am J of gastroenterol 2000)
3. The source of these nonspecific amylase elevations is most often salivary though may also be pancreatic. The source of nonspecific lipase elevations is not known.
4. The rise in amylase correlates with pH and plasma osmolality, while the rise in lipase correlates only with plasma osmolality. Peak values are seen within 24 hours of presentation.

Thrombotic Thrombocytopenia Purpura

General principle:
Acute presentation of severe to moderate thrombocytopenia. May present with fever, neurologic signs or symptoms and renal abnormalities. The complete pentad of signs/symptoms (i.e. thrombocytopenia, microangiopathic hemolytic anemia, fever and neurologic and renal abnormalities) is present in fewer than 25% of cases.

Etiology: 1. Autoimmune - may be HIV associated
              2. Congenital

Pathophysiology

1. Deficiency of von Willibrand factor-cleaving enzyme (ADAMTS 13) results in persistence of large multimeric forms and increased platelet adhesion.
a. autoimmune (i.e. idiopathic) TTP: autoantibody forms against ADAMTS 13
b. congenital TTP: Familial decrease in production of functional ADAMTS 13

2. Formation of platelet thrombi in microvasculature leads to tissue ischaemia and end organ disease
3. Intravascular hemolysis by increased shearing forces

Diagnosis
1. Laboratory
a. thrombocytopenia
b. red cell fragnments on peripheral blood film (shistocytes)
c. elevated LDH
d. Indirect bilirubin may be elevated
e. hemostasis parameters otherwise normal
f. creatinine may be increased, hematuria may be present
g. Usefullness of ADAMTS 13 level and antibody for diagnosis controversial

Treatment:
-Medical emergency: more than 90% mortality without treatment
-Institute immediate plasma exchange; replacement fluid must be plasma
-continue daily plasma exchange until LDH and platelet count have normalized for 2-3 days, then begin to taper frequently of plasma exchange
-transfuse FFP (4-6 units in an adult) if plasma exchange delayed
-corticosteroids - role unclear
-Patients with renal failure - hemodialysis
-refractory cases -splenectomy, vincristine, rituximab, immunosuppression

Prognosis
1. 90% mortality without rapid institution of therapy
2. Relapses after reduction/discontinuation of plasma exchange occur in a minority of patients

Hemolytic Uremic Syndrome
Pathophysiology:
1. deposition of platelet thrombi in small and medium sized vessels
2. no deficiency of ADAMTs 13
3. Especially in children, antecedent gastrointestinal illness and exposure to bacterial toxins may precede illness ("endemic HUS")

Treatment
1. Primarily supportive e.g. dialysis
2. Plasma exchange of value in some patients
3. Most cases resolve with supportive care

Data Interpretation

A previously well 54 year-old man presents with confusion. On examination a rash is noted. Temperature 37.1. The initial blood results are provided below.

Venous biochemistry
Na 135
K 3.8
Urea 18 mmol/l -*
Creatinine 177 micromol/l-*
Bilirubin 45 micromol/l -*

Hematology:
Hb 99 g/l
WBC 10.8 x 10(9)/L
Platelet 26 x 10(9)/L-*
Blood film: Schistocytes-*

Coagulation
PT 10 s
APTT 29 s
Fibrinogen 3.0 g/L

What is the most likely diagnosis?
Thrombotic thrombocytopenic purpura

What treatment needs to be instituted urgently?
Plasmapheresis

TTP shows a classic pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, and renal and neurological defects. This is thought to be related to an abnormal metalloproteinase (ADAMST 13). The condition is seen with certain infections, drugs (e.g. calcineurin antagonists, clopidogrel), pregnancy, systemic lupus erythematosus and graft versus host disease.
The labarotary findings in this condition are:
-low platelets
-reduced hemoglobin level with polychromasia, shictocytes and spherocytes
-increased reticulocytes
-reduced haptoglobin and increased lactate dehydrogenase levels
-unconjugated hyperbilirubinemia with urinary urobilinogen
-variable neutrophilia
-increased urea and creatinine levels (greater in hemolytic uremic syndrome)

Hematology question

Question 1

A man with fractured ribs following a fall has the following results:

Hb: 10.9 g/dL
PCV: 39%
MCHC: 30g/dL
WBC: 12.8 x 10 (9)/L
Neutrophils: 64%
Lymphocytes: 27%
Monocytes: 3%
Myelocytes: 2%
Metamyelocytes: 4%

Nucleated RBCs, slight poikilocytosis, slight anisocytosis

1. What is this type of blood picture?
A: Leukoerythroblastic picture
leukoerythroblastic picture on blood film can be the bone marrow response to any irritation including marrow infiltration (causing immature red cells). Marrow infiltrative disorders include myelomas, malignancy, myelofibrosis, Gaucher's disease etc. It can also occur as a response to severe critical illness such as trauma, sepsis, massive hemolysis or severe megaloblastic anemia. Leukoerythroblastic change refers to the presence of nucleated red blood cells and primitve white blood cells.

Peripheral blood smear showing the presence of nucleated red blood cells and immature white cells.

2. List four possible underlying causes?Marrow infiltration, overwhelming sepsis, major blood loss and marrow hypoxia

3. What is meant by the terms anisocytosis and poikilocytosis?
Anisocytosis is excessive inequality in the size of red blood cells
Poikilocytosis is increase in number of abnormally shaped red blood cells on film

Question 2

A 78 yr old man presented after a fall resulting in a bruised hip. His Full blood count is the following:

Hb 12.0 g/dL
WBC: 1.9 x 10 (9) --> low
Platelet: 28 x 10 (9) --low
RBC: 3.01 x 10 (9)--low
HCT: 0.358 --low
MCV: 118.9 fL --high
MCH: 39.9 pg --high
MCHC: 335 G/L --normal
Neutrophils 79.6%
Lymphocyte 17.3%
Monocytes 3.1%
Eosinophils 0.0%
Basophils 0.0%

Moderate anisocytosis, marked macrocytosis

List causes for the raised MCV?
Answer:
-B12 deficiency
-folate deficiency
- myeodysplastic syndrome
- therapy with cytotoxics or immunposuppressants
- alcohol
-hypothyroidism
- alcohol and hypothyroidism do not produce such high levels of MCV usually but anwers accepted.

Note: macrocytosis - describe erythrocyte that are larger than normal, typically reported as MCV greater than 100 fL. Because the amount of Hb in the cell increases proportionately with the increase in size, MCHC remains within normal limits.
Causes of macrocytosis are many and range from benign to malignant; thus a complete work up to determine etiology is essential. Macrocytosis can occur at any age, but it is more prevalent in older age groups because the causes of macrocytosis are more prevalent in older persons.

Use of Na bicarbonate in diabetic ketoacidosis

On Friday evening after my late afternoon rounds, a new patient arrived in ICU. That time was about 15 minutes to 6 pm. My medical officer told me the diagnosis is diabetic ketoacidosis. She is a young lady, known type 1 diabetes mellitus since she was twelve-year old. There was no appropriate handover since the intern who accompanied the patient only functioned as a  'medical' porter and didn't know what was going on except that his patient has a diagnosis of DKA. This place is very strange and the system is not right. I still not really impressed with the department of emergency in my hospital.
She has a pink cannula (20G) in her right arm. After scrutinizing the case notes (no attached intravenous fluid chart), we concluded that she received the appropriate IV fluid replacement therapy. From the ABG, she had a high AG metabolic acidosis, pH of 7.15. Urine ketone was positive, blood sugar level on admission was 41mmol/l, serum Na 125 and K 4.5. We also noted that IV NaHCO3 was given by medical medical officer to treat the acidosis. Ten units of IV insulin was given but the sliding scale has not been started.

The question is "Is Na bicarbonate therapy is indicated to treat high anion gap acidosis in DKA?"

Let me start with the major effects of metabolic acidosis on the body
Respiratory effects:
1. Hyperventilation (Kussmaul respirations) - as compensatory response
2. Shift of ODC to the right
3. Decreased 2,3 DPG in the red cells (shift the ODC back to the left)

Cardiovascular effects:
1. Depression of myocardial contractility
2. Sympathetic overactivity (include tachycardia, vasoconstriction, decreased arrythmia threshold)
3. Resistance to the effects of catecholamines
4. Peripheral arteriolar vasodilation
5. Venoconstriction of peripheral veins
6. Vasoconstriction of pulmonary arteries
7. Effects of hyperkalemia on heart

The cardiac stimulatory effects of sympathetic activity and release of cathecolamines usually counteract the direct myocardial depression while plasma pH remains above 7.2. At systemic pH values less than this the direct depression of contractility usually predominates. The direct vasodilation is offset by the indirect sympathetically mediated vasoconstriction and cardiac stimulation during a mild acidosis. The venoconstriction shifts blood centrally and this causes pulmonary congestion. Pulmonary artery pressure usually rises during acidosis.

Other effects:
1. Increased bone resorption (chronic acidosis only)
2. Shift of K out of cells causing hyperkalaemia

The effect on K level is variable and indirect effects due to the type of acidosis present are much more important. e.g. hyperkalaemia in renal failure is due to uraemic acidosis rather than the acidosis. In DKA, singnificant K loss due to osmotic diuresis, therefore the K level at presentation is variable although total body K stores are invariably depleted. Treatment with fluid and insulin can cause a prompt and marked fall in plasma K. Hypokalaemia may be than a problem.

Bicarbonate is an anion and cannot be given alone. Its therapeutic use is as a solution of Na bicarbonate. An 8.4% solution is a molar solution ( i.e. contains 1 mmol of HCO3 per ml). Thi solution is very hypertonic and its osmolality is 2,000 mOsm/kg.

The main goal of alkali therapy
1. to counteract the extracellular acidemia with the aim of reversing or avoiding the adverse clinical effects of the acidosis (esp adverse CVS effects).
2. Emergency management of hyperkalemia
3. To promote alkaline diuresis (e.g. to hasten salicylate excretion)

Undesirable effects of bicarbonate administration:
1. Hypernatremia
2. Hyperosmolality
3. Volume overload
4. Rebound or overshoot alkalosis
5. Hypokalaemia
6. Impaired oxygen unloading due to left shift of the ODC
7. Acceleration of lactate production by removal of acidotic inhibition of glycolysis
8. CSF acidosis
9. Hypercapnia

Important points about bicarbonate:
1. Ventilation must be adequate to eliminate the CO2 produced from bicarbonate. If hypercapnia occurs, CO2 crosses the cell membranes easily and intracellular pH may decrease even further with further deterioration of cellular function.
2. Bicarbonate may cause clinical deterioration if tissue hypoxia is present. This is due to increased lactate production (removal of acidotic inhibition of glycolysis) and the impairment of tissue oxygen unloading (left shift of ODC due to increased pH). This means that with lactic acidosis or cardiac arrest then bicarbonate therapy may be dangerous.
3. Bicarbonate is probably not useful in most cases of high anion gap acidosis.
4. The preferred management of metabolic acidosis is to correct the primary cause and to use specific treatment for any potentially dangerous complications.
5. Bicarbonate therapy may be useful for correction of acidemia due to non-organic or mineral acidosis (i.e. normal anion gap acidosis).

Diabetes Ketoacidosis - summary of events in pathophysiology of DKA:
1. A precipitating event occurs which results in insulin deficiency (absolute or relative) and usually an excess of stress hormones (particularly glucagon)
2. Hyperglycemia occurs due to decreased gluconse uptake in fat and muscle cells due to insulin deficiency
3. Lipolysis in fat cells now occurs promoted by the insulin deficiency releasing FFA into the blood
4. Elevated FFA levels provide substrate to the liver
5. A switch in hepatic lipid metabolism occurs due to the insulin deficiency and glucagon excess, so the excess FFA is metabolised resulting in excess production of acetyl CoA
6. The excess hepatic acetyl CoA is converted to acetoacetate which is released into the blood
7. Ketoacidosis and hyperglycemia both occur due to the lack of insulin and the increase in glucagon and most of the clinical effects follow from these two factors
8. Other acid-base and electrolyte disorders may develop as a consequence and complicate the clinical condition.

Oher acid base disorders may be present: Possible complicating acid base disorders are
1. Lactic acidosis due to hypoperfusion and anaerobic muscle metabolism
2. Metabolic alkalosis secondary to excessive vomiting
3. Respiratory alkalosis with sepsis
4. Respiratory acidosis due to pneumonia or mental obtundation
5. Renal tubular acidosis type 4 - the syndrome known as hyporeninemic hypoaldosteronism occurs in some elderly diabetics who have pre-existing moderate renal insufficiency by is not a common problem in acute DKA.


Correction of acidosis in DKA
This occurs more slowly than the correction of blood glucose but the use of bicarbonate in DKA remains controversial (Viallon CCM 1999) . In most studies the use of bicarbonate fails to provide any hemodynamic benefit that could not be attributed purely to osmotic load of sodium administered (Cooper ICM 1994). Therefore the evidence of benefits are lacking (Latif KA Diabetes care 2002). In a randomized trial of 24 DKA patients with admission arterial pH between 6.9 and 7.4 bicarbonate therapy did not change morbidity of mortality (Morris LR Ann inter med 1986). The study was small, limited to arterial pH 6.9 and above. There was no difference in the rate of rise in the arterial pH and serum bicarbonate and placebo groups. No prospective trial in DKA with pH values less than 6.9. Below pH 6.9 most authorities would recommend the use of bicarbonate to correct the pH partially.

There is no doubt that blood pH can be improved, but at the expense of worsening intracellular acidosis (Forsythe Chest 2000). Neurologic deterioration has been reported due to paradoxical fall in cerebral pH (Narins RG Ann Intern Med 1987). Other side effects of bicarbonate are listed above.

In the context of DKA, sodium bicarbonate also delays the clearance of ketones and may further enhance hepatic production even when insulin and glucose are being delivered (Okuda J Clin Endocrinol Metab 1996). This may slow the rate of recovery of the ketosis. At pH of > 7.0 insulin will block lipolysis and ketoacid production.

Selected patients who may benefit from cautious alkali therapy (Narins RG Ann Intern Med 1987):
1. Patients with an arterial pH of 7.0 in whom decreased cardiac contractality and vasodilation can further impair tissue perfusion. At an arterial pH above 7.00 most experts agree that bicarbonate thrapy is not necessary since insulin therapy alone will result in resolution of most of the metabolic acidosis.
2. Patiens with potentially life threatening hyperkalemia, since bicarbonate therapy in acidemic patients drives potassium into cells, thereby lowering the serum potassium concentration.

The conclusion is administering bicarbonate therapy is recommended if the pH is less than 6.9. Give 100mls of 8.4% of Na bicarbonate (can be added into 400mls of D5%)  together with 20mmol of KCl if the serum K is less than 5.3 mmol/l and administered over two hours.

"don't pour oil into fire"

I am not going to tell everything about what has happened to me recently. It is about a friend of mine, who I used to label him as my 'best friend forever' but unluckily he is also my colleague. There was a turning point where I have to make a radical changes for the betterment of the department. To cut the story short, because of misunderstanding the whole story was twisted and changed. From his view, I am the bad boy and he is always the good man who is being victimized. Anyway, I requested for not pouring oil into fire.If I bring myself down to his level the situation would turn from bad to worse. I don't think I could find someone who is capable of pouring oil on troubled water. I choose to mum the words, since that is the best solution to protect my self in term of psychological 'safety'.

I've found this article and I would like to share the points here. The title is "How to Not Let Criticism Affect your Self-Confidence".


There are two types of criticism:
(i). the kind that is meant to be constructive
(ii). the kind that is meant to be destructive.

Of course when someone gives you constructive criticism, you should listen to what they’re saying, determine whether or not what they’re saying is the truth and find ways to change it.

Constructive criticism is helpful because it helps you look at yourself as other people perceive you. It can help you change your direction in life to a path more beneficial.

Sometimes, however, we’re faced with criticism that is destructive. This type of criticism serves no other purpose but to tear you down and make you look worse than you really are.

Destructive criticism usually comes in these forms:

1. Derogatory names

2. Subtle put-downs in front of groups of people

3. Attacks against your character

4. Insults concerning your intelligence


The six reasons why people degrade you:

It can be a bewildering experience to be condemned by someone when you can’t think of a good reason why they’re acting that way. You probably never did anything to that person yet they’re saying such awful things about you all the sudden. There are a multitude of reasons why they act the way they do and none of them make sense. They include:

1. Bigotry – The people who condemn you probably think that all beliefs and cultures which differ from theirs are inferior. Many even have intense anger and hatred for people who are different enough from them. Though they may not admit it publicly, they will give you subtle hints every now and then that would make most people feel uncomfortable.

2. "Us vs. Them” Attitude – Since the dawn of time, people united together in groups simply because they shared a common enemy. Sometimes the hatred they felt served no logical purpose and what started off as small erupted into mindless sensationalism. This is an example of bigotry in a group setting.

3. Lack of Empathy – These people often have zero empathy for people who are different from them. This gives them the false impression that they can treat certain groups of people as cruelly and callously as they determine without consequences.

4. Grandiose Self-Worth – People who look down on others tend to think irrationally high of themselves. Self-confidence is an admirable quality but arrogance can be very dangerous to an individual. Arrogance, when left unchecked, will allow someone to become so blind to their own weaknesses that those flaws grow into something that not only hurts themselves but the people that they care about.

5. Failure to Accept Responsibility for Own Actions – Sometimes people hold themselves back from the finer things in life because of their own actions. But they refuse to admit this to themselves. Instead they think that everyone who goes far in life must have something morally wrong with them while they themselves are somehow “better people” because they never “sold out.” But if they were given a chance to switch places, they’d do it in a heart beat.

6. Envy – Some of these people love to be the center of attention. And they view other people’s success as an attack on their own self-esteem. When they see someone outshining them (who they don’t approve of) they’ll find any way possible to disparage that person. But if they’re not careful, that envy could grow into hate, and that hate could grow into insanity.

Don’t bring yourself down to their level

When you meet people who want to tear you down, do not give them attention.
If you respond in kind, you’re only playing into their hands.
They want you to play their games so that they’ll have more reasons to make you look like a bad person to others.

“Never argue with a fool, onlookers may not be able to tell the difference.” – Mark Twain

When someone acts like a fool, don’t bring yourself down to their level. Instead, try to lift them up to your level—as respectfully and sincerely as you can. If they don’t accept, at least you know that you tried to be a person of class and decency.

Stay focused on your goals

The best thing you can do when faced with unreasonable people is to stay focused on your goals and keep moving forward. Every second you spend wrestling in the mud with pigs holds you back from excellence–remember that. If you can take criticism without losing faith in yourself, it is you who has class.

People who enjoy disparaging people who mean no harm to anyone are small thinkers. But if you think big and focus on the great things you’ll be doing in the future, you’ll be the real winner of any confrontation you come across.

Hypothermia in Traumatic Brain Injury

An increased in temperature increased cerebral metabolism, oxygen requirements, CBF and ICP. Fever has been demonstrated to increase brain injury in animal models. In patients with raised ICP, a raised temperature should therefore treated aggressively (using cooling blankets, cool water, cool intravenous fluids, fans and antipyretic medications) and any evidence of infection identified early and treated with appropriate antibiotics. Fever can make an existing neurological dysfunction more apparent and may worsen an ongoing dysfunction.

It is postulated that fever may worsen ischaemia by following mechanisms:
1. Neurotransmitter and oxygen free radical production.
2. BBB failure.
3. Damaging depolarizations in the ischaemic penumbra.
4. Impaired recovery energy metabolism
5. Cytoskeletal proteolysis

Hypothermia has been known to offer protection for years. First reported as a treatment for brain injury in the 1950s. Currently therapeutic hypothermia is used in post cardiac arrest in particular VF/VT arrest and is supported by two randomized clinical trials  (in Europe and Australia).

In traumatic brain injury, the mechanism of ICP reduction in hypothermia is unknown but may be due to reduction in intracranial blood volume secondary in cerebral vasoconstriction or to alteration in metabolism. Induced hypothermia has been a proposed treatment fo TBI based upon its potential to reduce ICP as well as to provide neuroprotection and prevent secondary brain injury.

At present, there is no evidence that hypothermia  therapy should be used as primary neuroprotective strategy  in patients with severe traumatic brain injury.

1. A systemic review of 12 randomized controlled trials of mild to moderate hypothermia (32-33C) following TBI noted a small but significant decrease in the risk of death or poor neurologic outcome among more than 500 patients treated with hypothermia. Outcomes were influenced however by depth and duration of hypothermia as well as rate of rewarming after discontinuation of hypothermia. Nonetheless, the evidence is not yet sufficient to recommend routine use of therapeutic hypothermia for TBI outside of research settings.
JAMA 2003.

2. Lack of effect of induction of hypothermia after acute brain injury. NEJM 2001. Clifton GL et al. This study which evaluated the efficacy of hypothermia in head injuries was halted after the enrolment of 392 patients because the treatment was ineffective. Cooling patients to 33C within 8 hours after injury and maintaining hypothermia for 48h were not effective in improving the clinical outcome at 6 months and patients older than 45 years of age had a poorer outcome.

3. NABIS H II Trial - Very early hypothermia induction in patients with sever brain injury (the National Acute Brain Injury Study Hypothermia II): a randomized trial.
Prof Guy L Clifton et al. The Lancet Neurology, Volume 10, issue 2, February 2011.

Background: The inconsistent effect of hypothermia treatment on severe brain injury trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury.

Methods: It was a randomized multicentre clinical trial of patients with severe brain injury who were enrolled within 2-5 hours of injury at 6 sites in US and Canada. Patients with non-penetrating brain injury who were 16-45 years old and were not responsive to instructions were randomized to hypothermia (cooled to 35C) or normothermia. After trauma assessment was completed, the hypothermia group were cooled to 33C for 48h and then gradually rewarmed. Primary outcome was the Glasgow outcome scale score at 6 months.

Findings: Enrolment occurred over 4 years and the trial was terminated early due to suggestion of futility. Follow-up was from June 2006 to December 2009. 232 patients were intially randomized a mean of 1.6h after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia froup and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35C for the 52 patients in the hypothermia group was 2.6h and to 33C was 4.4h. Outcome was poor (severe disability, vegetative state or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (RR 1.08, 95% CI 0.76-1.53; p=0.67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1.30, 95% CI 0.58-2.52; p=0.52).

Interpretation
This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury.
Given the uncertainties surrounding its appropriate use, therapeutic hypothermia treatment should be limited to clinical trials or to patients with elevated ICP refractory to other therapies.

Decompressive Craniectomy in Diffuse Traumatic Brain Injury - DECRA trial

A must read paper published in New England Journal of Medicine, April 21, 2011.
The study was led by Prof DJ Cooper MD.
Funded by the National Health and Medical Research Council of Australia and others: DECRA Australian Clinical Trials.
DECRA - decompressive craniectomy for refractory intracranial hypertension in TBI.

Background: It is unclear whether decompressive craniectomy improves the functional outcome in patients with severe  TBI and refractory raised ICP.

Methods: In between December 2002 and April 2010, 155 adults with severe diffuse  TBI and intracranial hypertension that was refractory to first tier therapies were randomly assigned to undergo either bifrontotemporalparietal decompressive craniectomy or standard care.

The original primary outcome was unfavourable outcome (composite of death, vegetative state or severe disability) as evaluated on the GOS-E at 6 months after the injury.

The final primary outcome was the score on the GOS-E at 6 months.


Results:

Patients in the craniectomy group had less time with ICPs above the treatment threshold (p<0.001), fewer intervention for raised ICP and fewer days in ICU.

However patients undergoing craniectomy had worse scores on the GOS-E than those receiving standard care and greater risk of an unfavourable outcome.


Rates of death at 6 monts were similar in the craniectomy group (19%) and the standard care group (18%).


Conclusions:

In adults with severe diffuse TBI and refractory intracranial hypertension, early bifrontotemporoparietal decompressive craniectomy decreased intracranial pressure and length of stay in the ICU but was associated with more unfavourable outcomes.

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For many years Neurosurgeons and intensivists have speculated that decompressive craniectomy in patients with severe TBI and refractory intracranial hypertension my improve clinical outcomes eventhough there have been no well conducted randomised controlled trials in its favour. DECRA was conducted by ANZICS CTG and studied  155 patients over 7 years. 
This randomized trial revealed unexpected results that  showed early decompressive craniectomy reduced ICP and the length of stay in the ICU but it was also associated with a greater risk for unfavourable outcome at 6 months compared with standard care. Rates of death didn't differ between groups, but scores on the GOS-E were lower in the surgical group  and there was a significant increase in risk, more than double for an unfavourable outcome on that same scale.

The findings differ from those of most nonrandomized studies and are contrary to the hypothesis. This surgical strategy is increasingly used at neurotrauma centres internationally.

The original primary outcome was unfavourable outcome on the GOS-E, a composite of death, vegetative state or severe disability. However, after the interim analysis in 2007, the primary outcome was revised to be the functional outcome at 6 months after injury on the basis of proportional odds analysis  of the GOS-E.

The editorial points out that most neurosurgeons wouldn't consider this aggressive strategy in patients who have increased ICP  for such a short time, in this study ICP more than 20mmHg for 15 minutes. In addition,  in screening of 3478 patients, only 155 patients enrolled in the trial suggests a selected population excluding both patients with mass lesions  and those whose intracranial pressure was successfully brought under control. 

For reasons that are not clear decompressive craniectomy appeared to convert survivors from a favorable outcome to an unfavorable outcome. Among many possible explanations are variations in surgical technique and unintended changes in brain physiology - swollen brain expansion outside the skull causing axonal stretch and injury of changes in cerebral blood flow. Other issues that may explain the results include heavy enrolment from a single centre or baseline imbalances  between groups. Even considering these effects, craniectomy was not shown to be beneficial.

The main lesson from this study is that surgical reduction of ICP by the technique that was used by the investigators does not necessarily result in better outcomes for patients and indeed appears to worsen them in at least some circumstances. The procedures should not be abandoned on the basis of these results. Rather, the risks and benefits of the decompressive craniectomy must be weight carefully and must work to define appropriate clinical settings for this procedure. Caution should be applied in the routine use of this strategy.
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Further comments:
1. 3478 patients were screened over 7 years to enrol 155 patients. Shouldn't this trial have been stopped for futility?
2. Median ICP at randomization was 20 mmHg, did these patients even have intracranial hypertension?
3. ICP was managed for 15 minutes before surgery, is this clinical equipoise?
4. In this trial, decompressive craniectomy was performed at an average ICP of 22 mmHg for 30 minutes
5. There were 2.5x as many patients with bilateral fixed pupils in the surgical group. This between group difference was statistically significant (p=0.04).
6. After post-hoc adjustment for pupil reactivity at baseline, the between group differences were no longer significant for the score on the GOSE and for the risk of an unfavourable outcome.
7. the conclusion that decompressive craniectomy is associated with more unfavourable outcomes is highly misleading and not supported by the data.





 

Disorders of consciousness

-A normal level of consciousness depends on the interaction between the cerebral hemispheres and the rostral reticular activating system.
-Anatomical bilateral hemispheric lesions or brainstem lesions may result in an altered level of consciousness.
-Large unilateral hemispheric lesions may produce impairment of consciousness by compression of the upper brainstem.
-Metabolic processes may result in coma from interuption of energy substrate delivery or alteration of neuronal excitability.

Disorder of consciousness are characterized by an alteration of either the level or content of consciousness.

1. Consciousness - an awake individual demonstrates full awareness of self and environment.
2. Confusion - Inability to think with customary speed and clarity, associated with inattentiveness, reduced awareness and disorientation.
3. Delirium - Confusion with agitation and hallucination.
4. Stupor - Unresponsiveness with arousal only by deep and repeated stimuli.
5. Coma - unarousable unresponsiveness.
6. Locked in syndrome - total paralysis below third cranial nerve nuclei; normal or impaired mental function.
7. Persistant vegetative state - Prolonged coma > 1 month, some preservation of brainstem and motor reflexes.
8. Akinetic mutism - Prolonged coma with apparent alertness and flaccid motor tone.
9. Minimally conscious state - Preserved wakefulness, awareness and brainstem reflexes but poorly responsive.

Coma -like syndromes and related states:

1. Locked in syndrome
Features: alert and aware, vertical eye movements present, and able to blink. Quadriplegic, lower cranial nerve palsies (below CNIII nerve nuclei). No speech, facial or pharyngeal movements.
Site of lesion: bilateral anterior pontine lesion which transects all descending motor pathways bu spares ascending sensory and RAS.
Normal EEG. 90-100% of normal metabolism.
Similar state seen with severe polyneuropathies, MG and NMB.

2. PVS (apallic syndrome, neocortical death)
Features: Previously comatose, who now appear to be awake. Spontaneous limb movements, eye movements and yawning seen. However patient is inattentive, no speech, no awareness of environment and total inability to respond to commands.
Site of lesion: Extensive damage to both cerebral hemispheres with relative preservation of the brainstem.
EEG: polymorphic delta or theta waves, sometimes alpha. 40-60% of normal metabolism.
When vegetative state lasts longer than 4 weeks, it is termed persistent. PVS lasting for longer than 2 weeks implies a poor prognosis.

3. Akinetic mutism (coma vigile)
Features: Partially of fully awake patient, immobile and silent.
Site of lesion: Lesion is bilateral frontal lobes or hydrocephalus or third ventricular masses.
EEG: diffuse slowing. $0-80%  normal metabolism.
'Abulia' is the tern applied to milder forms of akinetic mutism.

4. Catatonia
Features: awake patients, sometimes a fixed posture, muteness with decreased motor activity.
Site: usually of psychiatric origin.
EEG: non specific EEG patterns associated with associated medical conditions. Variable metabolic changes in prefrontal cortex.
May be mimicked by frontal lobe disease and drugs.

5. Minimally conscious state
Features: Globally imparied responsiveness, limited but discernible evidence of self and environment.
Site: Global neuronal damage.
EEG: theta and alpha waves. 40-60%  normal metabolism.
Differs from PVS in that patients diagnosed with minimally conscious state have some level of awareness.