Neurocritical care topics covered in other sections of the book are shown in Table 2-1:
Table 2-1 Neurocritical care topics covered outside this chapter (followed by page number where the item may be found)
Intracranial pressure (ICP) monitoring - 868
Treatment of elevated ICP - 876
Adjuncts to ICP monitoring (jugular venous oxygen, brain tissue oxygenation, microdialysis…) - 874
Neurogenic stunned myocardium - 1054
Status epilepticus - 402
Vasospasm (including triple-H therapy) - 1045
2.1. Fluids and Electrolytes
2.1.1. Electrolyte abnormalities
• definition: serum [Na+] < 135 mEq/L
• minimum W/U: serum [Na+], serum osmolality, urine osmolality, clinical assessment of volume status. if volume status is high or low urinary [Na+]
SIADH: hypotonic hyponatremia (effective serum osmol < 275 mOsm/L) with inappropriately high urinary conentration (urine osmol > 100 mOsm/L) and euvolemia or hypervolemia
cerebral salt wasting (CSW): similar to SIADH but with extracellular fluid volume depletion due to renal sodium loss (urinary [Na} > 20 mEq/L)
• treatment: based on acuity, severity, symptoms & etiology (see SIADH (page 11) or CSW (page 14) as appropriate)
• risk of overy rapid correction: osmotic demyelination (including central pontine myelinolysis - CPM)
[Na+] < 135 mEq/L = mild, < 130 = moderate, < 125 = severe hyponatremia.
Hyponatremia in neurosurgical patients is chiefly seen in:
• syndrome of inappropriate antidiuretic hormone secretion (SIADH, see below): dilutional hyponatremia with normal or elevated intravascular volume. The most common cause of hyponatremia1. Usually treated with fluid restriction. May be associated with numerous intracranial abnormalities (see Table 2-2) and following transsphenoidal surgery
• cerebral salt wasting (CSW): inappropriate natriuresis with volume depletion. Treated with volume replacement (opposite to SIADH) and sodium (symptoms from derangements due to CSW may be exacerbated by fluid restriction2, see page 13). Etiology of 6% of cases of hyponatremia following aneurysmal SAH3
Other etiologies of hyponatremia
• renal failure
• volume overload (e.g. as in congestive heart failure)
• pseudohyponatremia: osmotically active solutes (e.g. glucose, mannitol, marked hyperlipidemia, or hyperproteinemia (which can occur in multiple myeloma)4) draw water from cells and also reduce the water fraction of plasma and produce artifactually low sodium values (an artifact of indirect lab techniques). For every 100 mg/dl increase of glucose, serum [Na] decreases by 1.6-2.4 mEq/L. It is necessary to measure serum osmolality to rule-out pseudohyponatremia
Figure 2-1 shows an algorithm for evaluating the etiology of hyponatremia5 which drives treatment decisions.
Figure 2-1 Evaluation of the etiology of hyponatremia
(adapted from Powers C, Friedman A H: Diagnosis and management of hyponatremia in neurosurgical patients. Contemp Neurosurg 29 (20): 1-5, 2007)
* effective serum osmolality = measured osmolality - [BUN]/2.8 (see Eq 2-1)
† volume status is usually assessed clinically, but this may be insensitive to volume depletion (see text)
§ SIADH may be associated with euvolemia or hypervolemia
Work-up requires assessment of:
1. serum sodium: must be < 135 mEq/L to qualify as hyponatremia
2. effective serum osmolality (AKA tonicity): the definition is shown in Eq 2-1, and should be used when the blood urea nitrogen (BUN) level is elevated (for a normal [BUN] of 7-18 mg/dl, just subtract 5 from the measured osmolality). Values < 275 mOsm/kg indicate hypotonic hyponatremia
3. urine osmolality: values > 100 mOsm/kg are inappropriately high if serum tonicity is < 275 mOsm/kg
4. volume status: differentiates SIADH from CSW
A. clinical assessment: better for hypervolemia (edema, upward trend in patient weights) but is insensitive in identifying extracellular fluid depletion as an etiology of hyponatremia6 (look for dry mucous membranes, loss of skin turgor, orthostatic hypotension)
B. normal saline infusion test used in uncertain cases. If base-line urine osmolality is < 500 mOsm/kg, it is usually safe to infuse 2 L of 0.9% saline over 24-48 hours. Correction of the hyponatremia suggests extracellular fluid volume depletion was the cause
C. central venous pressure (CVP) may be used: CVP < 5-6 cm H2O suggests hypovolemia in patients with normal cardiac function3, 5
5. check urinary [Na+] if volume status is high or low
6. determine duration of hyponatremia:
A. duration documented as < 48 hours is considered acute
B. hyponatremia of > 48 hours duration or of unknown duration is chronic
C. hyponatremia that occurs outside the hospital is usually chronic and asymptomatic except in marathoners and MDMA (“ecstasy”) drug users
Table 2-2 Etiologies of SIAD*
1. especially bronchogenic small-cell Ca
2. tumors of GI or GU tract
4. Ewing’s sarcome
B. meningitis: especially in peds
C. TB meningitis
E. brain abscess
2. head trauma: 4.6% prevalence
3. increased ICP: hydrocephalus, SDH…
5. brain tumors
6. cavernous sinus thrombosis
7. post craniotomy, especially following surgery for pituitary tumors, craniopharyngiomas, hypothalamic tumors
11. delerium tremens (DTs)
1. infection: pneumonia (bacterial & viral), abscess, TB, aspergillosis
3. respiratory failure associated with positive pressure respiration
1. drugs that release ADH or potentiate it
A. chlorpropramide (Diabinese®): increasies renal sensitivity to ADH
B. carbamazepine (Tegretol®), even more common with oxcarbazepine
C. HCTZ (see page 18)
D. SSRIs, TCAs
I. MDMA (“ecstasy”)
2. ADH analogues
B. oxytocin: ADH cross activity, may also be contaminated with ADH
1. adrenal insufficiency
2. stress, severe pain, nausea or hypotension (all can stimulate ADH release), postoperative state
3. acute intermittent porphyria (AIP)
* excerpted and modified1, 7
Due to slow compensatory mechanisms in the brain, a gradual decline in serum sodium is better tolerated than a rapid drop. Symptoms of mild ([Na] < 130 mEq/L) or gradual hyponatremia include: anorexia, headache, difficulty concentrating, irritability, dysgeusia and muscle weakness. Severe hyponatremia (< 125 mEq/L) or a rapid drop (> 0.5 mEq/hr) can cause neuromuscular excitability, cerebral edema, muscle twitching and cramps, nausea/vomiting, confusion, seizures, respiratory arrest and possibly permanent neurologic injury, coma or death.
SYNDROME OF INAPPROPRIATE ANTIDIURESIS (SIAD)
This term covers excess water retention in the face of hyponatremia, including cases due to inappropriate ADH secretion (SIADH, see below) as well as others without increased circulating levels of ADH (e.g. heightened response to ADH, certain drugs…). A partial list of etiologies is shown in Table 2-2 (see references1, 7 for details).
The diagnostic criteria of SIAD is shown in Table 2-3. It is critical to measure serum osmolality to rule-out pseudohyponatremia (see page 7) an artifact of indirect lab techniques.
Table 2-3 Diagnostic criteria for SIAD1
• decreased effective serum osmolality* (< 275 mOsm/kg of water)
• simulatneous urine osmolality > 100 mOsm/kg of water
• clinical euvolemia
A. no clinical signs of extracellular (EC) volume depletion (orthostatic hypotension, tachycardia, decreased skin turgor, dry mucous membranes…)
B. no clinical signs of excess EC volume (edema, ascites…)
• urinary [Na] > 40 mEq/L with normal dietary Na intake
• normal thyroid and adrenal function
• no recent diuretic use
• plasma [uric acid] < 4 mg/dl
• [BUN] < 10 mg/dl
• fractional Na excretion > 1%; fractional urea excretion > 55%
• NS infusion test: failure to correct hyponatremia with IV infusion of 2 L 0.9% saline over 24-48 hrs†
• correction of hyponatremia with fluid restriction
• abnormal result on water load test‡:
A. < 80% excretion of 20 ml of water/kg body weight over 5 hours, or
B. inadequate urinary dilution (< 100 mOsm/kg of water)
• elevated plasma [ADH]‡ with hyponatremia and euvolemia
* effective osmolality (AKA tonicity) = (measured osmolality) – [BUN]/2.8 with [BUN] measured in mg/dl
† this test is used n uncertain cases (corrects volume depletion), and is usually safe when baseline urine osmolality is < 500 mOsm/L
‡ water load test & [ADH] levels are rarely recommended (see text for details)
SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION (SIADH)
• definition: release of ADH in the absence of physiologic (osmotic) stimuli
• results in hyponatremia with hypervolemia (occasionally with euvolemia) with inappropriately high urine osmolality (> 100 mOsm/L)
• may be seen with certain malignancies and many intracranial abnormalities
• critical to distinguish from cerebral salt wasting which produces hypovolemia
• treatment: (initial guidelines in brief, see page 11 for details)
avoid rapid correction or overcorrection to reduce risk of osmotic demyelination (see page 11). Check serum [Na+] q 2-4 hours and do not exceed 1 mEq/L per hour, or 8 mEq/L in 24 hrs or 18 mEq/L in 48 hrs
severe ([Na+] < 125 mEq/L of < 48 hrs duration or with severe symptoms (coma, Sz): start 3% saline at 1-2 ml/kg body weight/hr + furosemide 20 mg IV qd
severe ([Na+] < 125 mEq/L of duration > 48 hours or unknown without severe symptoms: normal saline infusion @ 100 ml/hr + furosemide 20 mg IV qd
chronic or unknown duration and asymptomatic: fluid restriction (see Table 2-4) with dietary salt and protein, and, if necessary, adjuvant drugs (demeclocycline, conivaptan…)
SIADH, AKA Schwartz-Bartter syndrome, was first described with bronchogenic cancer which is one cause of SIAD. SIADH is the release of antidiuretic hormone (ADH) (AKA arginine vasopressin (AVP) - see page 111) in the absence of physiologic (osmotic) stimuli. Result: elevated urine osmolality, and expansion of the extracellular fluid volume leading to a dilutional hyponatremia which can produce fluid overload (hypervolemia), but SIADH may also occur with euvolemia. For unclear reasons, edema does not occur.
The hyponatremia of SIADH must be differentiated from that due to cerebral salt wasting (CSW) (see below) due to differences in treatment recommendations.
Etiologies: see Table 2-2.
DIAGNOSIS OF SIADH
In general, 3 diagnostic criteria are: hyponatremia, inappropriately concentrated urine, and no evidence of renal or adrenal dysfunction. In more detail:
1. low serum sodium (hyponatremia): usually < 134 mEq/L
2. low effective serum osmolality: < 275 mOsm/L
3. high urinary sodiumA (salt wasting): at least > 18 mEq/L, often 50-150
4. high ratio of urine:serum osmolality: often 1.5-2.5:1, but may be 1:1
5. normal renal function (check BUN & creatinine): BUN commonly < 10
6. normal adrenal function (no hypotension, no hyperkalemia)
7. no hypothyroidism
8. no signs of dehydration or overhydration (in many patients with acute brain disease, there is significant hypovolemia often due to CSW (see below) and as this is a stimulus for ADH secretion, the ADH release may be “appropriate”8). In uncertain cases, the NS infusion test may be used (see page 9)
A. there has not been an adequate explanation of the high urinary sodium in SIADH
If further testing is required, the following are options, but are rarely recommended:
1. measure serum or urinary levels of ADH. Rarely indicated since urine osmolality > 100 mOsm/kg is usually sufficient to indicate excessive ADH1. ADH is normally undetectable in etiologies of hyponatremia other than SIADH
2. water-load test: considered to be the definitive test9. The patient is asked to consume a water load of 20 ml/kg up to 1500 ml. In the absence of adrenal or renal insufficiency, the failure to excrete 65% of the water load in 4 hrs or 80% in 5 hrs indicates SIAD. ✖ CONTRAINDICATIONS: this test is dangerous if the starting serum [Na+] is ≤ 124 mEq/L or if the patient has symptoms of hyponatremia
Symptoms of SIADH
Symptoms are those of hyponatremia (see page 9) and possibly fluid overload. If mild, or if descent of [Na+] is gradual, it may be tolerated. [Na+] < 120-125 mEq/L is almost always symptomatic. These patients often have a paradoxical (inappropriate) thirst.
TREATMENT OF HYPONATREMIA WITH SIADH
Management is based on the severity and duration of hyponatremia, and the presence of symptoms. Two caveats:
1. ✖ be sure that hyponatremia is not due to CSW (see below) before restricting fluids
2. avoid too rapid correction or correction to normal or supranormal (overcorrection) sodium to reduce the risk of osmotic demyelination syndrome (see below)
Figure 2-2 Central pontine myelinolysis (arrowhead).
Axial FLAIR MRI
Osmotic demyelination syndrome: A complication associated with some cases of treatment for hyponatremia. While excessively slow correction of acute hyponatremia is associated with increased morbidity and mortality10, some cases of inordinately rapid treatment have been associated with osmotic demyelination syndrome (which includes central pontine myelinolysis (CPM) a rare disorder of pontine white matter11 (see Figure 2-2) and extrapontine myelinolysis (see Figure 2-3), as well as other areas of cerebral white matter). First described in alcoholics12, producing insidious flaccid quadriplegia, mental status changes, and cranial nerve abnormalities with a pseudobulbar palsy appearance. In one review13, no patient developed CPM when treated slowly as outlined below. And yet, the rate of correction correlates poorly with CPM; it may be that the magnitude is another critical variable14. Features common to patients who develop CPM are13:
• delay in the diagnosis of hyponatremia with resultant respiratory arrest or seizure with probable hypoxemic event
• rapid correction to normo- or hypernatremia (> 135 mEq/L) within 48 hours of initiating therapy
• increase of serum sodium by > 25 mEq/L within 48 hours of initiation of therapy
• over-correcting serum sodium in patients with hepatic encephalopathy
• NB: many patients developing CPM were victims of chronic debilitating disease, malnourishment, or alcoholism and never had hyponatremia. Many had an episode of hypoxia/anoxia15
• presence of hyponatremia > 24 hrs prior to treatment14
Treatment of underlying cause
The only definitive treatment
• if caused by anemia: usually responds to transfusion
• if caused by malignancy, may respond to antineoplastic therapy
• most drug related cases respond rapidly to discontinuation of the offending drug
Figure 2-3 Osmotic demyelination of pons (black arrowhead) & thalamus (white arrowhead). Coronal T2WI MRI
Figure 2-4 depicts an algorithm for selecting the correct SIADH treatment protocol.
Figure 2-4 Treatment protocol selection for hyponatremia in SIADH
Aggressive treatment protocol
Indications (also refer to Figure 2-4):
1. severe hyponatremia (serum [Na+] < 125 mEq/L)
2. AND either
A. duration known to be < 48 hours
B. or severe symptoms (coma, seizures)
1. transfer patient to ICU
A. 3% saline: start infusion 1-2 ml/kg body weight per hourA
B. and furosemideB (Lasix®) 20 mg IV q d
3. check serum [Na+] every 2-3 hours and adjust infusion rate of 3% saline
A. goal: raise serum sodium by 1-2 mEq/L/hr16 (use lower end of range for hyponatremia > 48 hours duration or unknown duration)
B. limits: do not exceed 8-10 mEq/L in 24 hrs and 18-25 mEq/L in 48 hrs1 (use lower end of these ranges for hyponatremia > 48 hours duration or unknown duration)
4. measure K+ lost in urine and replace accordingly
5. if symptoms of osmotic demyelination occur (early symptoms are lethargy and affective changes, usually after initial improvement): deficits may improve by stopping treatment and modestly relowering the serum sodium e.g. with DDAVP17, 18
A. infusion rate may be doubled to 2-4 ml/kg/hr for limited periods in patients with coma or seizures1
B. furosemide accelerates the increase in [Na+] and prevents volume overload with subsequent increase in atrial natriuretic factor and resultant urinary dumping of the extra Na+ being administered
Intermediate treatment protocol
Indications (also refer to Figure 2-4):
1. symptomatic nonsevere hyponatremia (serum [Na+] = 125-135 mEq/L), or
2. severe hyponatremia (serum [Na+] < 125 mEq/L), AND
A. duration > 48 hours or unknown AND
B. only moderate symptoms or nonspecific symptoms (e.g. H/A, or lethargy)
A. 0.9% saline (normal saline) infusion
B. and furosemide (Lasix®) 20 mg IV q d
C. consider conivaptan (see below) for refractory cases
2. check serum [Na+] every 4 hours and adjust infusion rate of normal saline
3. goals: [Na+] increase of 0.5-2 mEq/L/hr
4. limits: do not exceed 8-10 mEq/L in 24 hrs and 18-25 mEq/L in 48 hrs1
Routine treatment protocol and maintenance therapy
Indications (also refer to Figure 2-4):
1. asymptomatic nonsevere hyponatremia (serum [Na+] = 125-135 mEq/L), or
2. severe hyponatremia (serum [Na+] < 125 mEq/L) AND
A. duration > 48 hours or unknown AND
A. fluid restriction (see Table 2-4 for adults, for peds: 1 L/m2/day) while encouraging use of dietary salt and protein. Caution restricting fluids in hyponatremia following SAH (see page 1043)
B. for refractory cases, consider
1. demeclocycline: a tetracycline antibiotic that partially antagonizes the effects of ADH on the renal tubules19-21. Effects are variable, and nephrotoxicity may occur. Rx 300-600 mg PO BID
2. conivaptan (Vaprisol®): a nonpeptide antagonist of V1A & V2 vasopressin receptors. FDA approved for euvolemic and hypervolemic moderate-to-severe hyponatremia in hospitalized patients (NB: severe symptoms of seizures, coma, delerium… warrants aggressive treatment with hypertonic saline1). Use in the neuro-ICU has been described for treating elevated ICP when serum [Na] is not responding to traditional methods22 (off-label use - use with caution). Rx loading dose 20 mg IV over 30 minutes, followed by infusions of 20 mg over 24 hours x 3 days. If serum [Na+] are not rising as desired, the infusion may be increased to the maximal dose of 40 mg over 24 hours. Use is approved for up to 4 days total. Caution re drug interactions
3. lithium: not very effective and many side effects. Not recommended
Table 2-4 Fluid restriction recommendations1
Recommended fluid intake
< 500 ml/d
< 1 L/d
* solute ratio defined as:
CEREBRAL SALT WASTING
Cerebral salt wasting (CSW): renal loss of sodium as a result of intracranial disease, producing hyponatremia and a decrease in extracellular fluid volume9. CAUTION: patients with aneurysmal SAH may have CSW with hyponatremia which mimics SIADH, however there is usually also hypovolemia in CSW. In this setting, fluid restriction may exacerbate vasospasm induced ischemia9, 23-25.
The mechanism whereby the kidneys fail to conserve sodium in CSW is not known, and may be either a result of an as yet unidentified natriuretic factor or direct neural control mechanisms (see Hyponatremia following SAH, page 1043).
Laboratory tests (serum and urinary electrolytes and osmolalities) may be identical with SIADH and CSW26. Further-more, hypovolemia in CSW may stimulate ADH release. To differentiate: CVP, PCWP, and plasma volume (a nuclear medicine study) are low in hypovolemia (i.e. CSW). Table 2-5 compares some features of CSW and SIADH, the two most important differences being extracellular volume and salt balance. An elevated serum [K+] with hyponatremia is incompatible with the diagnosis of SIADH.
Table 2-5 Comparison of CSW and SIADH9*
↓ (< 35 ml/kg)
↑ or WNL
Signs & symptoms of dehydration
↑ or no Δ
↓ (< 8 mm Hg)
↑ or WNL
↓ (< 6 mm Hg)
↑ or WNL
↓ or no Δ
↑ or WNL†
Ratio of serum BUN]:[creatinine]
↑ or no Δ
↓ or no Δ
Serum [uric acid]
* abbreviations: ↓ = decreased, ↑ = increased, ↑↑ = significantly increased, WNL = within normal limits, no Δ = no change,  = concentration, + = present, ± = may or may not be present
† in reality, serum osmolality is usually ↓ in CSW
Treatment of CSW
Goals: volume replacement and positive salt balance.
Hydrate patient with 0.9% NS at 100-125 ml/hr. Do not give furosemide. For severe cases, 3% saline at 25-50 cc/hr is occasionally required. Salt may also be simultaneously replaced orally. Blood products may be needed if anemia is present.
Rapid correction of hyponatremia may be associated with osmotic demyelination (see page 11) and care should be taken to avoid overcorrection, as with SIADH (see page 11).
Fludrocortisone acetate acts directly on the renal tubule to increase sodium absorption. Benefits of giving 0.2 mg IV or PO q d in CSW have been reported27, but significant complications of pulmonary edema, hypokalemia and HTN may occur.
Urea: an alternative treatment using urea may be applicable to the hyponatremia of either SIADH or CSW, and therefore may be used before the cause has been ascertained: urea (Ureaphil®) 0.5 grams/kg (dissolve 40 gm in 100-150 ml NS) IV over 30-60 mins q 8 hrs28. Use NS + 20 mEq KCl/L at 2 ml/kg/hr as the main IV until the hyponatremia is corrected (unlike mannitol, urea does not increase ADH secretion). They supplemented with colloids (viz. 250 ml of 5% albumin IV q 8-12 hrs x 72 hrs).
Definition: serum sodium > 150 mEq/L. In neurosurgical patients, this is most often seen in the setting of diabetes insipidus (DI) (see below).
Since normal total body water (TBW) is ≈ 60% of the patient’s normal body weight, the patient’s current TBW may be estimated by Eq 2-2.
The free water deficit to be replaced is given by Eq 2-3. Correction must be made slowly to avoid exacerbating cerebral edema. One half the water deficit is replaced over 24 hours, and the remainder is given over 1-2 additional days. Judicious replacement of deficient ADH in cases of true DI must also be made (see below).
• due to low levels of ADH (or, rarely, renal insensitivity to ADH)
• high output of dilute urine (< 200 mOsmol/L or SG < 1.003) with normal or high serum osmolality and high serum sodium
• often accompanied by craving for water, especially ice-water
• danger of severe dehydration if not managed carefully
Diabetes insipidus (DI) is due to insufficient ADH, and results in the excessive renal loss of water and electrolytes. DI may be produced by two different etiologies:
• central or neurogenic DI: subnormal levels of ADH caused by hypothalamic-pituitary axis dysfunction. This is the type most often seen by neurosurgeons
• “nephrogenic DI”: due to relative resistance of the kidney to normal or supra-normal levels of ADH. Seen with some drugs (see below)
Etiologies of DI29:
1. (neurogenic) diabetes insipidus
A. familial (autosomal dominant)
C. posttraumatic (brain injury, including surgery)
D. tumor: craniopharyngioma, metastasis, lymphoma…
E. granuloma: neurosarcoidosis, histiocytosis
F. infectious: meningitis, encephalitis
H. vascular: aneurysm, Sheehan’s syndrome (rarely causes DI)
2. nephrogenic diabetes insipidus
A. familial (X-linked recessive)
D. Sjögren’s syndrome
E. drugs: lithium, demeclocycline, colchicine…
F. chronic renal disease: pyelonephritis, amyloidosis, sickle cell disease, polycystic kidney disease, sarcoidosis
85% of ADH secretory capacity must be lost before clinical DI ensues. Characteristic features: high urine output (polyuria) with low urine osmolality, and (in the conscious patient) craving for water (polydipsia), especially ice-water.
Differential diagnosis of DI:
1. (neurogenic) diabetes insipidus (true DI)
2. nephrogenic diabetes insipidus
A. idiopathic: from resetting of the osmostat
B. psychogenic polydipsia (excess free water intake)
4. osmotic diuresis: e.g. following mannitol, or with renal glucose spilling
5. diuretic use: furosemide, hydrochlorothiazide…
Central DI may be seen in the following situations:
1. following transsphenoidal surgery or removal of craniopharyngioma: (usually transient, therefore avoid long-acting agents until it can be determined if long-term replacement is required). Injury to the posterior pituitary or stalk usually causes one of three patterns of DI30:
A. transient DI: supra-normal urine output (UO) and polydipsia which typically normalizes ≈ 12-36 hrs post-op
B. “prolonged” DI: UO stays supra-normal for prolonged period (may be months) or even permanently: only about one third of these patients will not return to near-normal at one year post-op
C. “triphasic response”: least common
• phase 1: injury to pituitary reduces ADH levels for 4-5 days → DI (polyuria/polydipsia)
• phase 2: cell death liberates ADH for the next 4-5 days → transient normalization or even SIADH-like water retention (✖ NB: there is a danger of inadvertently continuing vasopressin therapy beyond the initial DI phase into this phase causing significant hemodilution)
• phase 3: reduced or absent ADH secretion → either transient DI (as in “A” above) or a “prolonged” DI (as in “B” above)
2. central herniation: shearing of pituitary stalk may occur (see page 285)
3. brain death: hypothalamic production of ADH ceases
4. with certain tumors:
A. pituitary adenomas: DI is rare even with very large macroadenomas. DI may occur with pituitary apoplexy (see page 635)
B. craniopharyngioma: DI usually only occurs postoperatively since damage to pituitary or lower stalk does not prevent production and release of ADH by hypothalamic nuclei
C. suprasellar germ cell tumors
D. rarely with a colloid cyst
E. hypothalamic tumors: eosinophilic granuloma
5. mass lesions pressing on hypothalamus: e.g. a-comm aneurysm
6. following head injury: primarily with basal (clival) skull fractures (see page 889)
7. with encephalitis or meningitis
8. drug induced:
A. ethanol and phenytoin can inhibit ADH release
B. exogenous steroids may seem to “bring out” DI because they may correct adrenal insufficiency (see Diagnosis below) and they inhibit ADH release
9. granulomatous diseases
A. Wegener’s granulomatosis: a vasculitis (see page 78)
B. neurosarcoidosis involving the hypothalamus (see page 71)
10. inflammatory: autoimmune hypophysitis31 (see page 1217) or lymphocytic infundibuloneurohypophysitis32 (distinct conditions)
The following are usually adequate to make the diagnosis of DI, especially in the appropriate clinical setting:
1. dilute urine:
A. urine osmolality < 200 mOsm/L (usually 50-150)A or specific gravity (SG) < 1.003 (may be 1.001 to 1.005)
B. or the inability to concentrate urine to > 300 mOsm/L in the presence of clinical dehydration
C. NB: large doses of mannitol as may be used in head trauma can mask this by producing a more concentrated urine
2. urine output (UO) > 250 cc/hr (peds: > 3 cc/kg/hr)
3. normal or above-normal serum sodium
4. normal adrenal function: DI cannot occur in primary adrenal insufficiency because a minimum of mineralocorticoid activity is needed for the kidney to make free water, steroids may reveal latent DI by correcting adrenal insufficiency
A. normally, urine osmolality averages between 500-800 mOsm/L (extreme range: 50-1400)
In uncertain cases, plot urine and simultaneous serum osmolality on the graph in Figure 2-5:
1. low serum osmolality: the patient has polydipsia
2. if the point falls in the “normal” range, a supervised water deprivation test is needed to determine if the patient can concentrate their urine with dehydration (caution: see below)
3. high serum osmolality: diagnosis of DI is established, and further testing is not needed (except to differentiate central from nephrogenic DI, if desired)
• to differentiate central from nephrogenic DI, give aqueous Pitressin® 5 U SQ: in central DI the urine osmolality should double within 1-2 hours
4. plotting more than one data point may help as some patients tend to “vacillate” around the border zones
Water deprivation test
If still unclear, the diagnosis of DI is confirmed by a water deprivation test (✖ CAUTION: perform only under close supervision as rapid and potentially fatal dehydration may ensue in DI). This test is rarely necessary if serum osmolality > 298 mOsm/LA. Stop IVs and make the patient NPO; check urine osmolality q hr.
1. continue the test until one of the following occurs:
A. normal response occurs: urine output decreases, and urine osmolality rises to 600-850 mOsm/L
B. 6-8 hours lapse
C. urine osmolality plateaus (i.e. changes < 30 mOsm in 3 consecutive hours)
D. patient loses 3% of body weight
2. if patient fails to demonstrate the normal response, then:
A. give exogenous ADH (5 U aqueous Pitressin® SQ), which normally increases urine osmolality to > 300 mOsm/L
B. check urine osmolality 30 and 60 minutes later
C. compare highest urine osmolality after Pitressin® to the osmolality just before Pitressin® according to Table 2-6
A. in compensated DI serum osmolality is more likely to be lower and to overlap with normals33
Figure 2-5 Interpretation of simultaneous serum vs. urine osmolality
(Provided by Arnold M. Moses, M.D., used with permission)
Table 2-6 Highest urinary osmolality after Pitressin in water deprivation test
Δ in urinary Osm
< 5% increase
partial ADH deficiency
> 67% increase
severe ADH deficiency
TREATMENT OF DI
See Table 2-7 and Table 2-8 for dosing forms and duration of action of vasopressin analogues.
Pitressin® is aqueous solution of 8-arginine vasopressin and should be used with caution in patients with vascular disease (especially coronary arteries). ✖ Caution in pre-scribing: sometime pitocin is confused with pitressin because of similarities of the name.
DDAVP (1-deamino-8-D-arginine vasopressin) AKA desmopressin. More potent and longer acting than vasopressin.
In conscious ambulatory patient
If DI is mild, and natural thirst mechanism is intact, instruct patient to drink only when thirsty and they usually “keep up” with losses and will not become overhydrated. If severe, patient may not be able to continue adequate intake of fluid (and constant trips to bathroom), in this case administer either:
1. desmopressin (DDAVP®)
A. PO: 0.1 mg PO BID, adjust up or down PRN urine output (typical dosage range: 0.1-0.;8 mg/d in divided doses)
B. nasal spray: 2.5 mcg (0.025 ml) by nasal insufflation BID, titrate up to 20 mcg BID as needed (the nasal spray may be used for doses that are multiples of 10 mcg)
2. ADH enhancing medications (works primarily in chronic partial ADH deficiency. Will not work in total absence of ADH)
A. clofibrate (Atromid S®) 500 mg PO QID
B. chlorpropramide: increases renal sensitivity to ADH
C. hydrochlorothiazide: thiazide diuretics may act by depleting Na+ which increases reabsorption in proximal tubules and shifting fluid away from distal tubules which is where ADH works. Rx: e.g. Dyazide® 1 PO q d (may increase up to 2 per day PRN)
In conscious ambulatory patient with impaired thirst mechanisms
If thirst mechanisms are not intact in conscious ambulatory patient, they run the risk of dehydration or fluid overload. For these patients:
1. have patient follow UO and daily weights, balance fluid intake and output using antidiuretic medication as needed to keep UO reasonable
2. check serial labs (approximately q weekly) including serum sodium, BUN
In non-ambulatory, comatose/stuporous, or brain-dead patient
(also see Management after brain death for organ donation, page 294)
1. follow I’s & O’s q 1 hr, with urine specific gravity (SG) q 4 hrs and whenever urine output (UO) > 250 ml/hr
2. labs: serum electrolytes with osmolality q 6 hrs
3. IV fluid management:
BASE IV: D5 1/2 NS + 20 mEq KCl/L at appropriate rate (75-100 ml/hr)
PLUS: replace UO above base IV rate ml for ml with 1/2 NS
NB: for post-op patients, if the patient received significant intraoperative fluids, then they may have an appropriate post-op diuresis, in this case use 1/2 NS to replace only ≈ 2/3 of UO that exceeds the basal IV rate
4. if unable to keep up with fluid loss with IV (or NG) replacement (usually with UO > 300 ml/hr), then EITHER
• 5 U arginine vasopressin (aqueous Pitressin®) IVP/IM/SQ q 4-6 hrs (avoid tannate oil suspension due to erratic absorption and variable duration)
• or vasopressin IV drip: start at 0.2 U/min & titrate (max: 0.9 U/min)
• or desmopressin injection SQ/IV titrated to UO, usual adult dose: 0.5-1 ml (2-4 mcg) daily in 2 divided doses
2.1.2. Serum osmolality
Clinical significance of various serum osmolarity values is shown in Table 2-9.
Table 2-9 Clinical correlates of serum osmolality
< 240 or > 321
risk of renal failure
risk of generalized seizures
Serum osmolality may be estimated using using Eq 2-4 (with [Na+] in mEq/L or mmol/L, and glucose and BUN in mg/dL).
NB: terms in square brackets  represent the serum concentrations (in mEq/L for electrolytes).
2.2. Blood pressure management
Table 2-10 shows some parenteral agents for acute control of hypertension grouped based on their effect on ICP34, 35.
Table 2-10 Effect of antihypertensives on ICP
Agents that may raise ICP (mostly vasodilators)
Agents that do not raise ICP
nitroprusside (NTP) (Nipride®)
nicardipine (Cardene®) DRUG INFO
Calcium channel blocker (CCB) that may be given IV. Unlike NTP, does not require arterial line, does not raise ICP, and no cyanide toxicity. Does not reduce heart rate, but may be used in conjunction with e.g. labetalol or esmolol if that is desired. SIDE EFFECTS: H/A 15%, nausea 5%, hypotension 5%, reflex tachycardia 3.5%.
Rx start at 5 mg/hr IV (off label: 10 mg/hr may be used in situations where urgent reduction is needed). Increase by 2.5 mg/hr every 5-15 minutes up to a maximum of 15 mg/hr. Decrease to 3 mg/hr once control is achieved. ✖Ampules contain 25 mg and must be diluted before administration.
✖ nitroprusside (NTP) (Nipride®) DRUG INFO
Use is diminishing because of side effects and effect on ICP. Raises ICP in patients with intracranial mass lesions36 due to direct vasodilatation, arterial > venous (small coronaries > large). May preferentially dilate peripheral vessels before cerebral vessels, thus producing a “cerebral steal” phenomenon. Acts in seconds, duration 3-5 min.
SIDE EFFECTS: thiocyanate and cyanide toxicity (may cause neurologic deterioration37 or hypotension) (follow thiocyanate levels if used > 24 hrs, at a rate ≥ 10 mcg/kg/min, or in renal failure; D/C if thiocyanate levels > 10 mg%), tachycardia, tachyphylaxis, hypotension which can extend an MI, “coronary steal”. Avoid in pregnancy.
Rx IV drip 0.25-8 mcg/kg/min (ave. = 3). To reduce risk of cyanide toxicity, start at very low rate of 0.3 mcg/kg/min, and do not give maximum rate of 10 mcg/kg/min for more than 10 minutes. To prepare: put 50 mg in 500 ml D5W (can only be mixed in D5W; solution can be double concentrated to reduce fluid or glucose load) = 100 mcg/ml; cover bottle with foil (light sensitive).
nitroglycerin (NTG)DRUG INFO
Raises ICP (less than with nitroprusside due to preferential venous action36). Vasodilator, venous > arterial (large coronaries > small). Result: decreases LV filling pressure (pre-load). Does not cause “coronary steal” (cf nitroprusside).
Rx 10-20 mcg/min IV drip (increase by 5-10 mcg/min q 5-10 min). For angina pectoris: 0.4 mg SL q 5 min x 3 doses, check BP before each dose.
labetalol (Normodyne®, Trandate®)DRUG INFO
Blocks α1 selective, ß non-selective (potency < propranolol). ICP reduces or no change38. Pulse rate: decreases or no change. Cardiac output does not change. Does not exacerbate coronary ischemia. May be used in controlled CHF, but not in overt CHF. Contraindicated in asthma. Renal failure: same dose. SIDE EFFECTS: fatigue, dizziness, orthostatic hypotension.
Onset 5 mins, peak 10 mins, duration 3-6 hrs.
Rx IV: patient supine; check BP q 5 min; give each dose slow IVP (over 2 min) q 10 minutes until desired BP achieved; dose sequence: 20, 40, 80, 80, then 80 mg (300 mg total). Once controlled, use ≈ same total dose IVP q 8 hrs.
Rx IV drip: add 40 ml (200 mg) to 160 ml of IVF (result: 1 mg/ml); run at 2 ml/min (2 mg/min) until desired BP (usual effective dose = 50-200 mg) or until 300 mg given; then titrate rate (bradycardia limits dose, increase slowly since effect takes 10-20 minutes).
Undergoes first pass liver degradation, therefore requires higher doses PO. PO onset: 2 hrs, peak: 4 hrs.
Rx PO: to convert IV → PO, start with 200 mg PO BID. To start with PO, give 100 mg BID, and increase 100 mg/dose q 2 day; max. = 2400 mg/day.
enalaprilat (Vasotec®)DRUG INFO
An angiotensin-converting enzyme (ACE) inhibitor. The active metabolite of the orally administered drug enalapril (see below). Acts within ≈ 15 mins of administration.
SIDE EFFECTS: hyperkalemia occurs in ≈ 1%. Do not use during pregnancy.
Rx IV: start with 1.25 mg slow IV over 5 mins, may increase up to 5 mg q 6 hrs PRN.
esmolol (Brevibloc®)DRUG INFO
Cardioselective short-acting beta blocker39. Being investigated for hypertensive emergencies. Metabolized by RBC esterase. Elimination half-life: 9 mins. Therapeutic response (> 20% decrease in heart rate, HR < 100, or conversion to sinus rhythm) in 72%. SIDE EFFECTS: dose related hypotension (in 20-50%), generally resolves within 30 mins of D/C. Bronchospasm less likely than other beta blockers. Avoid in CHF.
Rx 500 mcg/kg loading dose over 1 min, follow with 4 min infusion starting with 50 mcg/kg/min. Repeat loading dose and increment infusion rate by 50 mcg/kg/min q 5 mins. Rarely > 100 mcg/kg/min required. Doses > 200 mcg/kg/min add little.
fenoldopam (Corlopam®)DRUG INFO
Vasodilator. Onset of action < 5 minutes, duration 30 mins.
Rx IV infusion (no bolus doses): start with 0.1-0.3 mcg/kg/min, titrate by 0.1 mcg/kg/min q 15 min up to a maximum of 1.6 mcg/kg/min.
propranolol (Inderal®)DRUG INFO
Main use IV is to counteract tachycardia with vasodilators (usually doesn’t lower BP acutely when used alone).
Rx IV: load with 1-10 mg slow IVP, follow with 3 mg/hr. PO: 80-640 mg q d in divided doses.
For less urgent control of HTN (exception: sublingual nifedipine (see below)).
clonidine (Catapres®)DRUG INFO
Acts on cardiovascular control receptors in medulla oblongata, inhibits sympathetic outflow. Less confusion than Aldomet, but still sedating. Tachycardia rare. Onset: < 30 min.
SIDE EFFECTS: fluid retention (which may reduce effectiveness, counter with diuretic), dry mouth, sedation (minimize by slow dose increments), constipation, decreased CO & HR (by increased vagal tone), rebound HTN if withdrawn rapidly (caution in unreliable patients; treatment for rebound HTN: clonidine and labetalol, see page 20). Rebound is less likely and less severe with clonidine patches (Catapres TTS®), applied once per week.
Rx Rapid control: 0.2 mg PO, then 0.1 mg PO q 1 hr, stop at 0.8 mg total or if orthostatic. Maintenance dose: 0.1 mg PO BID or TID, increase slowly to max. 2.4 mg/day (usual 0.2-0.8 mg/day).
propranolol (Inderal®)DRUG INFO
Beta blocker. Use in HTN: blunts reflex tachycardia from vasodilators.
SIDE EFFECTS: CHF, symptomatic bradycardia, bronchospasm (avoid in asthmatics), rapid withdrawal → reflex tachycardia → exacerbates myocardial ischemia in CAD.
Rx 40 mg PO BID (usually with diuretic), titrate up to 640 mg/day in 2-3 divided doses. Or, Inderal-LA, 80 mg PO q d. SUPPLIED: 10, 20 40, 60 & 80 mg scored tabs. Inderal-LA (long acting) 60, 80, 120 & 160 mg capsules.
nifedipine (Procardia®, Adalat®)DRUG INFO
Short-acting calcium channel blocker (CCB). Decreases systemic vascular resistance. Increases cardiac index, CBF (by 10-20%), GFR, and Na excretion. Response some-what variable. Onset: 1-15 mins. Duration: 3-5 hrs.
SIDE EFFECTS: flushing H/A, palpitation, edema; reflex tachycardia, caution with beta blocker as negative inotropy may be additive. May cause severe hypotension in volume depleted patients (thus use with caution with mannitol or furosemide). May increase serum phenytoin (Dilantin®) levels. Use of short-acting CCBs may be associated with cardiac risk, thus long-acting agents should be used unless specific benefit outweighs the risk.
Rx 10-20 mg PO, faster onset with sublingual or buccal administration (puncture capsule), or if chewed (patient expels capsule after chewing). Note: the beneficial effects of the drug results from swallowing the capsule contents, the medication is not absorbed through the mucosa. If no response after 20-30 min, give additional 10 mg.
labetalol (Normodyne®, Trandate®)DRUG INFO
See page 20. Chronic administration may have higher incidence of orthostatic hypotension, fever, sexual dysfunction, and hepatic toxicity than other beta blockers.
metoprolol (Lopressor®)DRUG INFO
Beta blocker that is relatively cardioselective at doses < 200 mg. Rx 50-200 mg in 1 or 2 doses.
enalapril (Vasotec®)DRUG INFO
Angiotensin converting enzyme (ACE) inhibitor. Do not use during pregnancy. May be less effective in black patients. See enalaprilat above for IV use.
Rx initial dose 2.5-5 mg in one dose; maintenance 5-40 mg in 1 or 2 doses.
2.2.2. Hypotension (shock)
1. hypovolemic: first sign usually tachycardia. > 20-40% of blood volume loss must occur before perfusion of vital organs is impaired. Includes:
A. hemorrhage (external or internal)
B. bowel obstruction (with third spacing)
2. septic: most often due to gram negative sepsis
3. cardiogenic: includes MI, cardiomyopathy, dysrhythmias (including A-fib)
4. neurogenic: e.g. paralysis due to spinal cord injury. Blood pools in venous capacitance vessels
B. insulin reaction
CARDIOVASCULAR AGENTS FOR SHOCK
Plasma expanders. Includes:
1. crystalloids: normal saline has less tendency to promote cerebral edema than others (see IV fluids, page 878 under control of elevated ICP)
2. colloids: e.g. hetastarch (Hespan®). ✖ CAUTION: repeated administration over a period of days may prolong PT/PTT and clotting times and may increase the risk of rebleeding in aneurysmal SAH40 (see page 1042)
3. blood products: expensive. Risk of transmissible diseases or transfusion reaction
See Table 2-11 for a summary of the effects of dopamine (DA) at various dosages. DA is primarily a vasoconstrictor (ß1 effects usually overridden by α–activity). 25% of dopamine given is rapidly converted to norepinephrine (NE). At doses > 10 mcg/kg/min one is essentially giving NE. May cause significant hyperglycemia at high doses.
Rx Start with 2-5 mcg/kg/min and titrate.
Table 2-11 Dopamine dosage
0.5-2.0 (sometimes up to 5)
renal, mesenteric, coronary, & cerebral vasodilatation, (+) inotrope
α, ß & dopaminergic
releases nor-epi (vasoconstrictor)
dobutamine (Dobutrex®)DRUG INFO
Vasodilates by ß1 (primary) and by increased CO from (+) inotropy (ß2); result: little or no fall in BP, less tachycardia than DA. No alpha release nor vasoconstriction. May be used synergistically with nitroprusside. Tachyphylaxis after ≈ 72 hrs. Pulse increases > 10% may exacerbate myocardial ischemia, more common at doses > 20 mcg/kg/min. Optimal use requires hemodynamic monitoring. Possible platelet function inhibition.
Rx usual range 2.5-10 mcg/kg/min; rarely doses up to 40 used (to prepare: put 50 mg in 250 ml D5W to yield 200 mcg/ml).
amrinone (Inocor®)DRUG INFO
Nonadrenergic cardiotonic. Phosphodiesterase inhibitor, effects similar to dobutamine (including exacerbation of myocardial ischemia). 2% incidence of thrombocytopenia.
Rx 0.75 mg/kg initially over 2-3 min, then drip 5-10 mcg/kg/min.
phenylephrine (Neo-Synephrine®)DRUG INFO
Pure alpha sympathomimetic. Useful in hypotension associated with tachycardia (atrial tachyarrhythmias). Elevates BP by increasing SVR via vasoconstriction, causes reflex increase in parasympathetic tone (with resultant slowing of pulse). Lack of ß action means non-inotropic, no cardiac acceleration, and no relaxation of bronchial smooth muscle. Cardiac output and renal blood flow may decrease. Avoid in spinal cord injuries (see page 935).
Rx pressor range: 100-180 mcg/min; maintenance: 40-60 mcg/min. To prepare: put 40 mg (4 amps) in 500 ml D5W to yield 80 mcg/ml; a rate of 8 ml/hr = 10 mcg/min.
Primarily vasoconstrictor (? counterproductive in cerebral vasospasm, ? decreases CBF). ß-agonist at low doses. Increases pulmonary vascular resistance.
epinephrine (adrenalin globally)DRUG INFO
Rx 0.5-1.0 mg of 1:10,000 solution IVP; may repeat q 5 minutes (may bolus per ET tube). Drip: start at 1.0 mcg/min, titrate up to 8 mcg/min (to prepare: put 1 mg in 100 ml NS or D5W).
isoproterenol (Isuprel®)DRUG INFO
Positive chronotropic and inotropic, → increased cardiac O2 consumption, arrhythmias, vasodilatation (by ß1 action) skeletal muscle > cerebral vessels.
Direct ß stimulation (positive inotropic and chronotropic).
Rx start drip at 8-12 mcg/min; maintenance 2-4 mcg/min (0.5-1.0 ml/min) (to prepare: put 2 mg in 500 ml NS or D5W to yield 4 mcg/cc).
2.3. Sedatives & paralytics
Richmond agitation-sedation scale (RASS)
A validated scale41, 42 that uses positive numbers for agitation and negative numbers for sedation as shown in Table 2-12. Useful for quantitating the desired level of sedation when titrating sedatives for agitated patients.
Procedure for performing RASS assessment:
1. on observation, patient is alert, restless or agitated: score 0 to +4
2. if patient is not alert, state patient’s name and verbally instruct to open eyes and look at speaker: score –1 to –3
3. if no response to verbal stimulus, physically stimulate by shaking shoulder and/or sternal rub: score –4 or –5
2.3.1. Conscious sedation
Use of these agents requires ability to provide immediate emergency ventilatory support (including intubation). Agents include:
• midazolam (Versed®): see page 51
• pentobarbital (Nembutal®): a barbiturate. Rx for 70 kg adult: 100 mg slow IVP
methohexital (Brevital®)DRUG INFO
More potent and shorter acting than thiopental (useful e.g. for percutaneous rhizotomy where patient needs to be sedated and awakened repeatedly). Lasts 5-7 min. Similar cautions with the added problem that methohexital may induce seizures. May no longer be available in the U.S.
Rx Adult: 1 gm% solution (add 50 ml diluent to 500 mg to yield 10 mg/ml), 2 ml test dose, then 5-12 ml IVP at rate of 1 ml/5 secs, then 2 to 4 ml q 4-7 min PRN.
haloperidol (Haldol®)DRUG INFO
SIDE EFFECTS: rare neuroleptic malignant syndrome. ✖ Contraindicated in Parkinson’s disease. Anticholinergic effects may exacerbate urinary retention.
Rx For “rapid sequence tranquilization” (to sedate acutely agitated patient): 5-10 mg haloperidol IM q 15 minutes until patient controlled.
Generally requires intubation and mechanical ventilatory support in the ICU. Doses are generally lower than those used by anesthesiologists for general anesthesia.
thiopental (Pentothal®)DRUG INFO
A short acting barbiturate. 1st dose causes unconsciousness in 20-30 secs (circulation time), depth increases up to 40 secs, duration = 5 mins (terminated by redistribution), consciousness returns over 20-30 mins.
SIDE EFFECTS: dose related respiratory depression, irritation if extravasated, intraarterial injection → necrosis, agitation if injected slowly, an antianalgesic, myocardial depressant, hypotension in hypovolemic patients.
Rx Adult: initial concentration should not exceed 2.5%, give 50 mg test dose moderately rapid IVP, then if tolerated give 100-200 mg IVP over 20-30 secs (500 mg may be required in large patient).
remifentanil (Ultiva®)DRUG INFO
Ultrashort acting micro-opioid receptor agonist. Potency similar to fentanyl. Rapidly crosses BBB. Onset: < 1 min. Offset: 3-10 mins. Lowers ICP. Metabolism: non-hepatic hydrolysis by nonspecific blood and tissue esterases, no accumulation. Synergy with thiopental, propofol, isoflurane, midazolam requires reducing doses of these agents by up to 75%. SIDE EFFECTS: bradycardia, hypotension (these side effects may be blunted by pretreatment with anticholinergics), N/V, muscle rigidity, pruritus (especially facial) dose dependent respiratory depression at doses > 0.05 mcg/kg/min.
Rx Adult: avoid bolus doses. Start with drip of 0.05 mcg/kg/min. Titrate in 0.025 mcg/kg/min increments to a maximum of 0.1-0.2 mcg/kg/min. Add a sedative if adequate sedation not achieved at maximum dose. Wean infusion in 25% decrements over 10 minutes after extubation. SUPPLIED: vials of 1, 2 or 5 mg powder to be reconstituted to 1 mg/ml solution.
fentanyl (Sublimaze®)DRUG INFO
Narcotic, potency ≈ 100 x morphine. High lipid solubility → rapid onset. Offset (small doses): 20-30 mins. Unlike morphine and meperidine, does not cause histamine release. Lowers ICP. SIDE EFFECTS: dose dependent respiratory depression, large doses given rapidly may cause chest wall rigidity. Repeated dosing may cause accumulation. Diminished sensitivity to CO2 stimulation, may persist longer than the depression of respiratory rate (up to 4 hours).
Rx Adult: 25-100 mcg (0.5-2 ml) IVP, repeat PRN. SUPPLIED: 50 mcg/ml; requires refrigeration.
propofol (Diprivan®)DRUG INFO
A sedative hypnotic. Also useful in high doses during aneurysm surgery as a neuroprotectant (see page 1064). Protection seems to be less than with barbiturates. Offset time increases after ≈ 12 hours of use.
Rx for sedation: start at 5-10 mcg/kg/min. Increase by 5-10 mcg/kg/min q 5-10 minutes PRN desired sedation (up to a max of 50 mcg/kg/min).
SIDE EFFECTS: include Propofol Infusion Syndrome: hyperkalemia, hepatomegaly, lipemia, metabolic acidosis, myocardial failure, rhabdomyolysis, renal failure and sometimes death43. First identified in children, but may occur at any age. NB: metabolic acidosis of unknown etiology in a patient on propofol is propofol infusion syndrome until proven otherwise. Use with caution at doses > 50 mcg/kg/min or at any dose for > 48 hrs. Also note that the lipid carrier provides 1.1 kCal/ml and hypertriglyceridemia may occur.
SUPPLIED: 500 mg suspended in a 50 ml bottle of fat emulsion. The bottle and tubing must be changed every 12 hours since it contains no bacteriostatic agent.
Precedex® (dexmedetomidine)DRUG INFO
An alpha-2 adrenoceptor agonist. Acts in locus ceruleus and dorsal root ganglia. Has both sedative and analgesic properties and dramatically reduce the risk of respiratory depression and the amount of narcotic analgesics required. Reduces shivering.
Rx: usual loading dose is 1 mcg/kg IV over 10 minutes (loading dose not needed if patient already sedated with other agents), followed by continuous IV infusion of 0.2-1.0 mcg/kg/hr titrated to desired effect, not to exceed 24 hours (for short sedation or use as a “transition” drug). SIDE EFFECTS: clinically significant bradycardia and sinus arrest have occurred in young, healthy volunteers with increased vagal tone (anticholinergics such as atropine 0.2 mg IV or glycopyrrolate 0.2 mg IV may help). Use with caution in patients with advanced heart block, baseline bradycardia, using other drugs that lower heart-rate, and hypovolemia. SUPPLIED: 2 ml vials of 100 mcg/ml to be diluted in 48 ml NS for a final concentration of 4 mcg/ml for IV use.
2.3.3. Paralytics (neuromuscular blocking agents)
CAUTION: requires ventilation (intubation or Ambu-bag/mask). Reminder: paralyzed patients may still be conscious and therefore able to feel pain, the simultaneous use of sedation is thus required for conscious patients.
Early routine use in head-injured patients lowers ICP (e.g. from suctioning44) and mortality, but does not improve overall outcome45.
Neuromuscular blocking agents (NMBAs) are classified clinically by time to onset and duration of paralysis as shown in Table 3-13. Additional information for some agents follows the table along with some considerations for neurosurgical patients.
ULTRA-SHORT ACTING PARALYTICS
succinylcholine (Anectine®)DRUG INFO
The only depolarizing ganglionic blocker (the rest are competitive blockers). Rapidly inactivated by plasma pseudocholinesterases. A single dose produces fasciculations then paralysis. Onset: 1 min. Duration of action: 5-10 min.
Due to significant side effects (see below), use is now limited primarily to the following indications. Adults: generally recommended only for emergency intubations where the airway is not controlled. In children: only when intubation is needed with a full stomach, or if laryngospasm occurs during attempted intubation using other agents.
✖ CAUTIONS: usually increases serum K+ by 0.5 mEq/L (on rare occasion causes severe hyperkalemia ([K+] up to 12 mEq/L) in patients with neuronal or muscular pathology, causing cardiac complications which cannot be blocked), therefore contraindicated in acute phase of injury following major burns, multiple trauma or extensive denervation of skeletal muscle or upper motor neuron injury. Do not use for routine intubations in adolescents and children (may cause cardiac arrest even in apparently healthy youngsters, many of whom have undiagnosed myopathies). Linked to malignant hyperthermia (see page 5).
May cause dysrhythmias, especially sinus bradycardia (treat with atropine). May get autonomic stimulation from ACh-like action → HTN, and brady- or tachycardia (especially in peds with repeated doses). The fasciculations may increase ICP, intragastric pressure, and intraocular pressure (contraindicated in penetrating eye injury, especially to anterior chamber; OK in glaucoma).
Precurarization with a “priming dose” of a nondepolarizing blocker (usually ≈ 10% of the intubating dose, e.g. pancuronium 0.5-1 mg IV 3-5 minutes prior to succinylcho-line) in patients with elevated ICP or increased intraocular pressure (to ameliorate further pressure increases during fasciculation phase) and in patients who have eaten recently (controversial46). Phase II block (similar to nondepolarizing blocker) may develop with excessive doses or in patients with abnormal pseudocholinesterase.
Rx Adult: 0.6-1.1 mg/kg (2-3 ml/70 kg) IVP (err on high side to allow time for procedure & to avoid multi-dosing complications), may repeat this dose x 1.
Rx Peds (CAUTION: Not recommended for routine use, see above) Children: 1.1 mg/kg. Infants (< 1 mos): 2 mg/kg.
SUPPLIED: 20 mg/ml concentration.
SHORT ACTING PARALYTICS
rocuronium (Zemuron®)DRUG INFO
In large doses, has speed of onset that approaches succinylcholine. However, in these doses, paralysis usually lasts ≈ 1-2 hrs. Expensive.
Rx Adult: initial dose 0.6-1 mg/kg. May be used as infusion of 10-12 mcg/kg/min.
INTERMEDIATE ACTING PARALYTICS
vecuronium (Norcuron®)DRUG INFO
Nondepolarizing (competitive) NMBA. Adequate paralysis for intubation within 2.5-3 minutes of administration. About one third more potent than pancuronium, shorter duration of action (lasts ≈ 30 minutes after initial dose). Unlike pancuronium, very little vagal (i.e. cardiovascular) effects. No CNS active metabolites. Does not affect ICP or CPP. Hepatically metabolized. Due to active metabolites, paralysis has been reported to take 6 hrs to 7 days to recede following discontinuation of the drug after ≥ 2 days use in patients with renal failure47. Must be mixed to use.
SUPPLIED: 10 mg freeze-dried cakes requiring reconstitution. Use within 24 hrs.
Rx Adult and children > 10 years age: 0.1 mg/kg (for most adults use 8-10 mg as initial dose). May repeat q 1 hr PRN. Infusion: 1-2 mcg/kg/min.
Rx Pediatric: children (1-10 yrs) require slightly higher dose and more frequent dosing than adult. Infants (7 weeks - 1 yr): slightly more sensitive on a mg/kg basis than adults, takes ≈ 1.5 x longer to recover. Use in neonates and continuous infusion in children is insufficiently studied.
cisatracurium (Nimbex®)DRUG INFO
Nondepolarizing (competitive) blocker. This isomer of atracurium does not release histamine unlike its parent compound (see below). Provides about 1 hour of paralysis. Also undergoes Hofmann degradation, with laudanosine as one of its metabolites.
Rx Adult and children > 12 years age: 0.15 or 0.2 mg/kg as part of propofol/nitrous oxide/oxygen induction-intubation technique produces muscle paralysis adequate for intubation within 2 or 1.5 minutes, respectively. Infusion: 1-3 mcg/kg/min.
Rx Pediatric: children (2-12 yrs): 0.1 mg/kg given over 5-10 seconds during inhalational or opioid anesthesia.
atracurium (Tracrium®)DRUG INFO
Nondepolarizing (competitive) blocker. After IV bolus: onset 2-2.5 mins, peak 3-5 mins, duration 15-20 mins (initial dose may last up to 30 minutes). Undergoes nonenzymatic Hofmann degradation and ester hydrolysis at normal physiologic pH and temperature, inactivating the drug in ≈ 30 minutes. Therefore useful in patients with liver or renal failure. Reversible with neostigmine (see below). Causes histamine release which can produce hypotension (consider cisatracurium instead, see above). A metabolite, laudanosine, is neuroexcitatory, and accumulation could theoretically cause seizures (no documented cases)46.
SUPPLIED: 5 & 10 ml ampules of 10 mg/ml concentration.
Rx Adult & children > 2 yrs age: 0.4-0.5 mg/kg IVP. Reduce subsequent doses to 0.02 mg/kg.
Rx Neonates (1 month - 2 yrs): 0.3-0.4 mg/kg.
LONG ACTING PARALYTICS
pancuronium (Pavulon®)DRUG INFO
The “prototype” nondepolarizing (competitive) paralytic. Peak: 3-5 mins, duration up to 60 mins. Reversible with anticholinesterases such as neostigmine (see below). Renal elimination.
SIDE EFFECTS: usefulness is limited because the drug is vagolytic and an indirect sympathomimetic which increases cardiac output, pulse rate and ICP. Consider vecuronium as an alternative (see above).
Rx Adult & children: 0.04-0.10 mg/kg IVP (start with 3 mg). Reduce subsequent doses to 0.02 mg/kg.
Rx Neonates: especially sensitive, test dose 0.02 mg/kg.
REVERSAL OF COMPETITIVE MUSCLE BLOCKADE
It takes ≈ 20 minutes for full reversal of pancuronium (Pavulon®) (depending on the amount of time since the last dose). Reversal is usually not attempted until patient has at least 1 twitch to a train of 4 stimulus, otherwise reversal may be incomplete if patient is profoundly blocked and blockade may reoccur as the reversal wears off
1. neostigmine (Prostigmin®): 2.5 mg (minimum) to 5 mg (maximum) IV (start low, no efficacy from > 5 mg and can produce severe weakness especially if the maximum dose is exceeded in the absence of neuromuscular blockade)
PLUS (to prevent bradycardia…), EITHER
• 0.5 mg atropine for each mg of neostigmine
• 0.2 mg glycopyrrolate (Robinul®) for each mg of neostigmine
2.4. Neurogenic pulmonary edema
A rare condition associated with a variety of intracranial pathologies, including: subarachnoid hemorrhage, generalized seizures, and head injury.
Two possibly synergistic mechanisms. Sudden increased ICP or hypothalamic injury may produce a salvo of sympathetic discharge causing redistribution of blood to the pulmonary circulation, resulting in elevation of pulmonary capillary wedge pressures (PCWP) and increased permeability. Secondly, the associated surge of catecholamines directly disrupts the capillary endothelium which increases alveolar permeability.
Supportive, using measures such as positive pressure ventilation with low levels of PEEP (see page 880) and treatment to normalize ICP. A PA-catheter is usually helpful.
There may be some efficacy in using a dobutamine infusion48 supplemented with furosemide as needed. The theoretical advantage of dobutamine over previously attempted alpha- and beta-blockers is that dobutamine does not reduce cerebral perfusion. Nitroprusside may help dilate the pulmonary vasculature.
1. Ellison D H, Berl T: Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 356 (20): 2064-72, 2007.
2. Diringer M, Ladenson P W, Borel C, et al.: Sodium and water regulation in a patient with cerebral salt wasting. Arch Neurol 46: 928-30, 1989.
3. Sherlock M, O’Sullivan E, Agha A, et al.: The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage. Clin Endocrinol (Oxf) 64 (3): Clin Endocrinol (Oxf): 250-4, 2006.
4. Weisberg L S: Pseudohyponatremia: A reappraisal. Am J Med 86: 315-8, 1989.
5. Powers C, Friedman A H: Diagnosis and management of hyponatremia in neurosurgical patients. Contemp Neurosurg 29 (20): 1-5, 2007.
6. Chung H M, Kluge R, Schrier R W, et al.: Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med 83 (5): Am J Med: 905-8, 1987.
7. Lester M C, Nelson P B: Neurological aspects of vasopressin release and the syndrome of inappropriate secretion of antidiuretic hormone. Neurosurgery 8: 725-40, 1981.
8. Kröll M, Juhler M, Lindholm J: Hyponatremia in acute brain disease. J Int Med 232: 291-7, 1992.
9. Harrigan M R: Cerebral salt wasting syndrome: A review. Neurosurgery 38: 152-60, 1996.
10. Ayus J C, Krothapalli R K, Arieff A I: Changing concepts on treatment of severe symptomatic hyponatremia: Rapid correction and possible relation to central pontine myelinolysis. Am J Med 78: 879-902, 1985.
11. Fraser C L, Arieff A I: Symptomatic hyponatremia: Management and relation to central pontine myelinolysis. Sem Neurol 4: 445-52, 1984.
12. Adams R D, Victor M, Mancall E L: Central pontine myelinolysis: A hitherto undescribed disease occurring in alcoholic and malnourished patients. Arch Neurol Psychiatr 81: 154-72, 1959.
13. Ayus J C, Krothapalli R K, Arieff A I: Treatment of symptomatic hyponatremia and its relation to brain damage. N Engl J Med 317: 1190-5, 1987.
14. Berl T: Treating hyponatremia: What is all the controversy about? Ann Intern Med 113: 417-9, 1990.
15. Arieff A I: Hyponatremia associated with permanent brain damage. Adv Intern Med 32: 325-44, 1987.
16. Adrogue H J, Madias N E: Hyponatremia. N Engl J Med 342 (21): 1581-9, 2000.
17. Soupart A, Ngassa M, Decaux G: Therapeutic relowering of the serum sodium in a patient after excessive correction of hyponatremia. Clin Nephrol 51 (6): 383-6, 1999.
18. Oya S, Tsutsumi K, Ueki K, et al.: Reinduction of hyponatremia to treat central pontine myelinolysis. Neurology 57 (10): 1931-2, 2001.
19. De Troyer A, Demanet J C: Correction of antidiuresis by demeclocycline. N Engl J Med 293: 915-8, 1975.
20. Perks W H, Mohr P, Liversedge L A: Demeclocycline in inappropriate ADH syndrome. Lancet 2: 1414, 1976 (letter).
21. Forrest J N, Cox M, Hong C, et al.: Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 298: 173-7, 1978.
22. Wright W L, Asbury W H, Gilmore J L, et al.: Conivaptan for hyponatremia in the neurocritical care unit. Neurocrit Care 11 (1): Neurocrit Care: 6-13, 2009.
23. Maroon J C, Nelson P B: Hypovolemia in patients with subarachnoid hemorrhage: Therapeutic implications. Neurosurgery 4: 223-6, 1979.
24. Wijdicks E F M, Vermeulen M, Hijdra A, et al.: Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysms: Is fluid restriction harmful? Ann Neurol 17: 137-40, 1985.
25. Wijdicks E F M, Vermeulen M, ten Haaf J A, et al.: Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm. Ann Neurol 18: 211-6, 1985.
26. Nelson P B, Seif S M, Maroon J C, et al.: Hyponatremia in intracranial disease. Perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J Neurosurg 55: 938-41, 1981.
27. Hasan D, Lindsay K W, Wijdicks E F M, et al.: Effect of fludrocortisone acetate in patients with subarachnoid hemorrhage. Stroke 20: 1156-61, 1989.
28. Reeder R F, Harbaugh R E: Administration of intravenous urea and normal saline for the treatment of hyponatremia in neurosurgical patients. J Neurosurg 70: 201-6, 1989.
29. Thibonnier M: Antidiuretic hormone: Regulation, disorders, and clinical evaluation. In Neuroendocrinology, Barrow D L and Selman W, (eds.). Concepts in neurosurgery. Williams and Wilkins, Baltimore, 1992, Vol. 5: pp 19-30.
30. Verbalis J G, Robinson A G, Moses A M: Postoperative and post-traumatic diabetes insipidus. Front Horm Res 13: 247-65, 1985.
31. Abe T, Matsumoto K, Sanno N, et al.: Lymphocytic hypophysitis: Case report. Neurosurgery 36: 1016-9, 1995.
32. Imura H, Nakao K, Shimatsu A, et al.: Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus. N Engl J Med 329: 683-9, 1993.
33. Miller M, Dalakos T, Moses A M, et al.: Recognition of partial defects in antidiuretic hormone secretion. Ann Intern Med 73: 721-9, 1970.
34. Drugs for hypertensive emergencies. Med Letter 29: 18-20, 1987.
35. Ferguson R K, Vlasses P H: Hypertensive emergencies and urgencies. JAMA 255: 1607-13, 1986.
36. Cottrell J E, Patel K, Turndorf H, et al.: ICP changes induced by sodium nitroprusside in patients with intracranial mass lesions. J Neurosurg 48: 329-31, 1978.
37. Ram Z, Spiegelman R, Findler G, et al.: Delayed postoperative neurological deterioration from prolonged sodium nitroprusside administration. J Neurosurg 71: 605-7, 1989.
38. Orlowski J P, Shiesley D, Vidt D G, et al.: Labetalol to control blood pressure after cerebrovascular surgery. Crit Care Med 16: 765-8, 1988.
39. Esmolol - a short-acting IV beta blocker. Med Letter 29: 57-8, 1987.
40. Trumble E R, Muizelaar J P, Myseros J S: Coagulopathy with the use of hetastarch in the treatment of vasospasm. J Neurosurg 82: 44-7, 1995.
41. Sessler C N, Gosnell M S, Grap M J, et al.: The Richmond agitation-sedation scale: Validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 166 (10): Am J Respir Crit Care Med: 1338-44, 2002.
42. Ely E W, Truman B, Shintani A, et al.: Monitoring sedation status over time in ICU patients: Reliability and validity of the Richmond agitation-sedation scale (RASS). JAMA 289 (22): JAMA: 2983-91, 2003.
43. Kang T M: Propofol infusion syndrome in critically ill patients. Ann Pharmacother 36 (9): 1453-6, 2002.
44. Werba A, Weinstabi C, Petricek W, et al.: Vecuronium prevents increases in intracranial pressure during routine tracheobronchial suctioning in neurosurgical patients. Anaesthetist 40: 328-31, 1991.
45. Hsiang J K, Chesnut R M, Crisp C D, et al.: Early, routine paralysis for intracranial pressure control in severe head injury: Is it necessary? Crit Care Med 22: 1471-6, 1994.
46. Ohlinger M J, Rhoney D H: Neuromuscular blocking agents in the neurosurgical intensive care unit. Surg Neurol 49: 217-21, 1998.
47. Segredo V, Caldwell J E, Matthay M A, et al.: Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med 327: 524-8, 1992.
48. Knudsen F, Jensen H P, Petersen P L: Neurogenic pulmonary edema: Treatment with dobutamine. Neurosurgery 29: 269-70, 1991.