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.